TUBERCULOSIS

Transcription

TUBERCULOSIS

TUBERCULOSIS
Selected Internet Resources
Compiled and Edited by:
Noel González Gotera
([email protected])
Armando Acosta Domínguez
([email protected])
María Elena Sarmiento García-San Miguel
([email protected])
Vicepresidency of Research
Finlay Institute, La Habana, Cuba
Havana City, December, 2005
La
presente obra es una compilación y selección, abarcadora pero no
exhaustiva, de sitios web sobre tuberculosis, ordenados alfabéticamente y
provistos de sus vínculos (links) a los respectivos sitios en Internet.
Esperamos que la misma resulte útil a los interesados en informaciones
relacionadas con esta temática.

Sobre la presente edición:
Finlay Ediciones, 2005
ISBN: 959-7076-12-8
Finlay Ediciones
Ave. 212 No. 3112 e/ 31 y 37,
La Coronela, La Lisa,
Ciudad de La Habana, Cuba
THE UN SECRETARY-GENERAL KOFI A. ANNAN
Message on World TB Day, 24 March 2005.
Five thousand people die from tuberculosis every day,
although the disease is both preventable and curable.
Clearly, we must work harder if we are to achieve, by
2015, the Millennium Development Goal of halting and
beginning to reverse the spread of TB as one of the
world’s major diseases. Thanks to a massive scale-up of
the DOTS strategy for TB control recommended by the
World Health Organization, with 17 million persons treated in nine years, our prospects for reaching the goal have
improved greatly.
WHO reports that eight in 10 patients are successfully
treated under DOTS programmes, and that 45 per cent of infectious patients were
treated in 2003 -- up from 28 per cent in 2000. But huge obstacles remain, particularly in Africa -- in the form of weak health systems, a depleted health workforce,
and an HIV/AIDS epidemic that is driving TB. As Nelson Mandela said, “We cannot
win the battle against AIDS if we do not also fight TB. TB is too often a death sentence for people with AIDS.” I urge African leaders to make the fight against both
diseases a priority.
The Stop TB Partnership, with its 350 partner governments and organizations,
is making a difference by forging consensus on strategies, coordinated responses,
mechanisms for quality drug supply, and action for new diagnostics, drugs and vaccines. Governments, bilateral agencies, the Global Fund to Fight AIDS, TB and Malaria, and the World Bank are providing more resources. Still, to achieve worldwide
impact, more is needed. And we must provide greater support for the increasingly
wide range of caregivers who help find people ill with TB and assist them with treatment. These providers include not just public health doctors and nurses, but also
community leaders, former patients, women’s groups, and many others.
Such broad mobilization is our strongest weapon in the fight against the disease. On this world TB Day, let us rededicate ourselves to that mission.
Kofi A. Annan
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INTRODUCTION
According to a relatively recent study conducted by TeleGeography, global Internet
traffic was set to increased by 67% during 2003 (Primetrica Inc., August 2003) and
had been identified over 43 millions current registered domains (Cyveillance, May
2, 2003).
Internet activity is alive and thriving outside of the World Wide Web´s 6 billion
pages or more, to include over 65 000 news groups (Cyveillance, May 12, 2003).
The analysis of domain found a total of 19, 4 million live and 4, 3 million parked.
Approximately 2, 5 million of the live domains contain more than 50 pages of content (Cyveillance, Breakdown of Registered Domains, March 2003). According to
statistics valids to July 10, 2000, the number of unique pages on Internet was 2,1
billions and the amount of unique pages added per day reached the amazing figure
of 7,3 million (Cyveillance, Sizing the Internet, July, 2000).
Besides “vast expanses of the Web are completely invisible (deep web and invisible web) to general-purpose search engines such as Altavista, HotBot, Yahoo, and
Google. Even worse, this “Invisible Web” ïs in all likelihood growing significantly
faster than the visible Web that you´re familiar with. It´s not that the search engines
and Web directories are stupid oven badly engineered. Rather, they simply can´t see
millions of high-quality resources that are available exclusively on the Invisible Web”
(The Invisible Web, Chris Sherman and Gary Price, ISBN 091096551X, 2001).
An study reveals that the Internet searchers interested on the health topics find
what they want in a 48% (mostly) and 28% (always), according to Pew Internet
Project, September 2002 Survey.
Health searches and e-mail have become more commonplace, but there is room
for improvement in searches and overall Internet access. Half of American adults
have searched online for health information. Fully 80% of adult Internet users, or
about 93 millions Americans, have searched for at least one of 16 major health topics on line (63% for specific diseases or medical problems). This makes the act of
looking for health or medical information one of the most popular activities online,
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after e-mail (93%) and researching a product or service before buying (83%). (Internet Health and Resources, Pew Internet & American Life Project, Susannah Fox and
Deborah Fallows, 16 July, 2003).
There are so many ways to access health information on the web and such a
broad selection of content that the search process can seem overwhelming. However, searching for health information is easy if you know where to start. The following selected tuberculosis Web sites and links list (comprehensive but not exhaustive)
offer some suggestions. We hope that you may find it useful when looking specifically for tuberculosis information on Internet.
THE AUTHORS
La Habana, Cuba, May 2005.
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TUBERCULOSIS SELECTED WEB SITES AND LINKS
(in alphabetical order)
1. ABC de la Tuberculosis - UITB - Unidad de investigación en ... Informacion sobre tuberculosis, tratamientos, prevencion, vacunas, lineas y proyectos de investigacion, documentos,
casos clinicos, novedades, congresos, ... www.imsb.bcn.es/uitb/
2. About Tuberculosis… Public information on the biology of tuberculosis from the Canadian Lung Association… http://www.lung.ca/tb
3. Action TB…
4. Aeras Global TB Vaccine Foundation… http://www.aeras.org/
5. Airborne Disease Weekly
6. A laymans guide to tuberculosis, atypical tuberculosis and ... Offers A to Z of Tuberculosis and includes general, mental health and medication side effects issues. Includes support
and message board chat room. www.tbandu.co.uk/
7. Amedeo.com, The Medical Literature Guide… http://amedeo.com/index.htm
8. American Lung Association… The American Lung Association® (ALA) was founded
in 1904 to combat tuberculosis. Today this organization fights all forms of lung with special
emphasis on asthma, tobacco control and environmental health. The ALA has worked to
increase federal funding for tuberculosis research and control… http://www.lungusa.org/diseases/lungtb.html
9. American Lung Association Tuberculosis Information (on PBS)…
10. American Thoracic Society… The American Thoracic Society [ATS] is an independently
incorporated, international, educational and scientific society which focuses on respiratory
and critical care medicine. ATS was once called the American Sanatorium Association. It maintains a focus on medical aspects of tuberculosis, whereas the parent organization, American
Lung Association, concentrates on public health issues. Information links on tuberculosis at
this site can identified after using the “search” button… http://www.thoracic.org/
11. Ask NOAH About: Tuberculosis Preguntale a NOAH Sobre la Tuberculosis Information in English and in Spanish presented by the New York Online Access to Health (NOAH)
project.
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12. Atlanta Tuberculosis Prevention Coalition… Our Mission Collaborating Agencies Projects Screening Education Computerized TB registry Personnel Publications Training Funding
Other TB related Sites TB & Medicaid General TB information Georgia TB reference guide...
13. ATS Journals Online... Official Journals of the American Thoracic Society, Stanford
University
Libraries’ HighWire Press® assists in the publication of ATS Journals Online ... www.atsjournals.org/
14. Bill & Melinda Gates Foundation … Grant-making foundation supports initiatives in
education, world health and
population, and community giving in the Pacific Northwest… www.gatesfoundation.org/
15. Books on Tuberculosis at Amazon.co.uk… Find “Genetics and tuberculosis” (Novartis
Foundation Symposium) and more at Amazon.co.uk. Read reviews, buy new and used titles...
http://www.amazon.co.uk...
16. Brown University TB-HIV Research Laboratory… www.brown.edu/Research/TB-HIV_
Lab/
17. BUBL LINK: Tuberculosis… BUBL LINK Catalogue of Internet Resources. Tuberculosis.
Titles. Descriptions. American Lung Association: Diseases A to Z ... cancer, tuberculosis, emphysema ... Internet resources relevant to the respiratory system. Author: OMNI, Nottingham
University. Subjects: asthma, lung cancer, lungs, pneumonia, tuberculosis ... bubl.ac.uk/link/t/
tuberculosis.htm
18. California Tuberculosis Controllers Association…
19. Canada’s Role in Fighthing Tuberculosis - About Tuberculosis… Public information on
the biology of tuberculosis from the Canadian Lung Association. What is tuberculosis and
how is it spread? This resource explains the biology of tuberculosis and the way in which we
deal with it… http://www.lung.ca/tb/abouttb/
20. Case Western Reserve University Tuberculosis Research Unit and HIVNET Projects …
21. CBC News - Tuberculosis: Anatomy of A Killer… Includes facts, videos, reports, and
links on Tuberculosis. Ever heard of White Plague? What about Pott’s disease? Lupus Vulgaris?
King’s evil? No? Okay then, surely you’ve heard of Consumption. All of these diseases are
actually the same disease, better known today as Tuberculosis or TB for short… http://cbc.
ca/news/indepth/background/tb.html... CBC News - Includes facts, videos, reports, and links
on Tuberculosis…
22. CDC Division of Tuberculosis Elimination… News, reports, guidelines, and educational
materials for health professionals… http://www.cdc.gov/nchstp/tb
23. CDC National Prevention Information Network (NPIN) –TB Resources …
24. Center for Pulmonary and Infectious Disease Control – University of Texas Health Center at Tyler
25. Charles P. Felton National Tuberculosis… The goal is to meet the challenge of TB in Harlem by providing innovative prevention, treatment, and training programs to members community and healthcare providers serving the community… http://www.harlemtbcenter.org
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26. Clinician’s Handbook of Preventive Services (TB Section)…
27. Community Awareness Program for Tuberculosis Education from the Wetmore TB
Foundation…
28. Community Health and Anti -Tuberculosis… Charity organisation supporting prevention, treatment and research into respiratory disease both internationally and in Australia…
http://www.chata.org.au
29. Core Curriculum on Tuberculosis: What the Clinician Should Know This is the 4th edition (2000) of this textbook from the U.S. Centers for Disease Control’s Division of Tuberculosis
Elimination. A note on the site states that “The Internet (HTML) version of the Core Curriculum
on Tuberculosis is updated periodically. Therefore, the Internet version may differ from the
print version.”
30. Cure-TB (US-Mexico Referral Program) (Exit DHFS)
31. Danida Assisted Revised National Tuberculosis Control Programme… Provides information about the organization, initiatives, publications, a resource directory as well as the details
about the disease itself. Our goal is o bring down the incidence of TB in India to levels where
it will no longer be a public health problem… http://www.dantb.org/
32. DANTB - Danida Assisted Revised National Tuberculosis Control ... Information about
the organization, initiatives, publications, a resource directory as well as the details about the
disease itself. www.dantb.org/
33. DEVELOPMENT OF VACCINES FOR BOVINE TUBERCULOSIS: REPORT OF THE ISG ... File
Format: PDF/Adobe Acrobat ... a large number of local sites to have a significant impact on TB
in ... opportunities to identify tuberculosis vaccines that are more effective than ... www.defra.
gov.uk/animalh/tb/pdf/vsssc.pdf
34. Division of Tuberculosis Elimination - Institute of Medicine (IOM ... regimens would
have the greatest impact on the TB problem in the near term. ... for Tuberculosis Vaccine Development.39 The strategy should specify ... www.cdc.gov/nchstp/tb/pubs/iom/iomresponse/
goal3.htm
35. DNAvaccine.com... dnavaccine.com/
36. Draft Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in
Health-Care Settings, 2005 available for public comment.
37. Duke Funding Alert: October 10, 2003 ... e-mail address or telephone number); and
3) one common Web site for all Federal ... applications for Tuberculosis Vaccine Testing Research Materials. ... www.ors.duke.edu/find/announce/alert/archive/03/03oct10.html…http://
fedbizopps.cos.com/cgi-bin/getRec?id=20031006a8...
ttp://fedbizopps.cos.com/cgi-bin/
getRec?id=20031006a8
38. EQUI-TB Knowledge Programme… Details the international research program into
pro-poor strategies in tackling Tuberculosis… http://www.equi-tb.org.uk
39. eMedicine Health - Tuberculosis Consumer health resource center providing information on the causes, symptoms, and treatment of TB. http://www.emedicinehealth.com/articles/17621-1.asp
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40. Emerging Infectious Diseases... ftp.cdc.gov/pub/EID/
41. Escuela Centro de Tuberculosis de New Jersey Nacional Médico …
42. Eugene Bell Foundation… Since 1997, Eugene Bell has concentrated on delivering
tuberculosis assistance in the form of medication, equipment, and supplies to all of North
Korea’s thirteen TB hospitals and sixty-three TB care centers… http://www.eugenebell.co.kr/
english/index.htm
43. EuroTB… http://www.eurotb.org/
44. External Tuberculosis Resources… External Tuberculosis Resources. This is a list of other
web sites that have information about tuberculosis. The resources have been categorized by
the ... http://www.cpmc.columbia.edu/resources/tbcpp/extre...
45. FAQ about BCG … Frequently asked questions about the BCG immunisation - a review
article.
www.priory.com/cmol/bcg.htm
46. FindArticles
search?tb=art&qt...
search
for
“”BCG
vaccine””…
http://www.findarticles.com/p/
47. Florida Department of Health (select “Tuberculosis” in the “Subject Choices” box)…
48. Francis J. Curry National Tuberculosis Center…
49. FREE Internet Encyclopedia - MacroReference … MacroReference. Free Internet Encyclopedia. Copyright © 2004 by Clifton Davis. Reproduction in whole or part of this arrangement of links only with permission. ... American Lung Association: TB FAQ. People’s Plague:
Tuberculosis in America (PBS special)(c ... www.cam-info.net/enc/macro.t.html
50. GFATM (PAHO/AMRO) resource page for Latin America and the Caribbean …
51. Glaxo Wellcome and Healthcare - Global http://www.glaxowellcome.co.uk/health/odyssey/tuberc/tuberc3.html
52. Global Alliance for TB Drug Development… Seeks to develop and ensure equitable access to new tuberculosis drugs. Features organization information, disease information, new
drug development, and news… http://www.tballiance.org
53. Global Fund to fight AIDS, tuberculosis and malaria (GFATM)…
54. Hardin MD : Tuberculosis … From the University of Iowa, the *best* lists of Internet
sources in tuberculosis. www.lib.uiowa.edu/hardin\md/tuberculosis.html
55. Health and Development Initiative…
56. healthfinder® - your free guide to reliable health information… AIDS alt med cancer
diabetes food safety Medicare tobacco more . . . the latest government health news health
media online special events calendars prevention and self-care choosing quality care online
health information fraud and...
57. Health Communication Partnership Tuberculosis … Related Internet Sites. CDC Division of Tuberculosis Elimination Education and Training Resources Web Site. Tuberculosis ...
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International Union Against Tuberculosis and Lung Disease ... www.hcpartnership.org/Topics/tuberculosis.php
58. How to obtain Surveillance of Drug Resistance in Tuberculosis Software from the Internet … How to obtain Surveillance of Drug Resistance in. Tuberculosis (SDRTB3) Software from
the Internet. Download and install the software. Before downloading the software, please
read all three steps in the instructions. www.who.int/emc/SDRTB_software/instructions.html
59. Huff & Puff Victoria - Lung Disease Links Australian respiratory support group with
international links to lung disease, medical sites, hospitals and respiratory support groups.
http://www.vicnet.net.au/~huffpuff
60. Imperial College School of Medicine at St.Mary’s Medical Microbiology…
61. Infectious Disease Society of America… IDSA is a medical society representing more
than 5,500 physicians and scientists devoted to patient care, education, research, and community health planning in the area of infectious diseases. IDSA members care for many of the
patients with tuberculosis (TB) in the United States. This site summarizes ISDA activities related
to tuberculosis… http://www.idsociety.org/mo/adv/actions%5Ftuberculosis.htm
62. Initiative for Vaccine Research File Format: PDF/Adobe Acrobat ... Advisory Committee
on new tuberculosis vaccines (TBVAC) ... information and knowledge management for vaccine
R&D: websites, ...
www.who.int/vaccines-documents/DocsPDF05/16317.pdf
63. Institute for Tuberculosis Research - Dedicated to the discovery and development of
new effective, low-cost, therapeutics for the treatment of tuberculosis. Includes description
of research projects, facilities, and methods, and welcomes donations to sponsor drug discovery.
64. International Union Against TB and Lung Disease…
65. IUATLD Secretariat’s Tuberculosis Division …
66. Japan Anti-TB Association … Services include information about the disease itself,
referrals to doctors and hospitals, plus its treatment and medical expenses.
67. Johns Hopkins Center For Tuberculosis Research… Features research, epidemiology,
treatment, drug information, forum, news, articles, and resources… http://www.hopkinstb.org/news/
68. Journal of Occupational and Environmental Medicine - Fulltext ... ... Journal of Occupational & Environmental Medicine... www.joem.org/pt/re/joem
69. Journal of Thoracic Imaging - Fulltext: Volume 18(1) January 2003 ... Www.thoracicimaging.com/pt/re/ jti/
70. KNCV (The Royal Netherlands TB Association)… KNCV Tuberculosefonds … Informatie
over tuberculose. Wat het is, wat de symptomen zijn, hoe tuberculose wordt behandeld en
begeleid, of het te genezen is, of het besmettelijk is.
www.tuberculose.nl/
71. Korean National Tuberculosis Association (KNTA)… Works with the government in
treatment, health worker training and public education on TB, and conducts various technical
and educational projects. www.knta.or.kr/
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72. LARG Health Tuberculosis Patient Resources…
73. Liga Argentina Contra la Tuberculosis y Enfermedades Regionales… Institución privada
de bien público, sin fines de lucro, fundada en 1935. Cuenta con información institucional y
una amplia documentación sobre la problemática ... www.laclatyer.org.ar/
74. Links… Links to Tuberculosis Sites. Line. Click here to link to the Division of Tuberculosis
Elimination Web Site, “TB-Related Links” . ... http://www.phppo.cdc.gov/PHTN/tbmodules/
links.htm
75. Links to other TB Websites… http://www.health.state.hi.us/doh-work/doh/resourc...
76. Links… Mycos Research provides PPDs and links to other Mycobacterium Tuberculosis
sites… http://www.mycosresearch.com/links.htm
77. Links to other TB Websites… Links to Other Tuberculosis Sites... http://www.health.
state.hi.us/doh-work/doh/resourc...
78. Links to material available in languages other than English … TB
79. Links… ... Tuberculosis Sites. Action TB; Ask NOAH About: Tuberculosis from the New
York Online Access to Health (NOAH); Atlanta TB Prevention Coalition ... http://www.umdnj.
edu/~ntbcweb/links.htm
80. Los Angeles County TB Control Program…
81. L.R.S. Institute of Tuberculosis & Respiratory Diseasesases… About the institute, its
objectives, functions, and activities… http://lrsitbrd.nic.in/
82. LSUMC Wetmore Foundation Tuberculosis Education …
82. MedHist: The gateway to Internet resources for the History of Medicine ... The gateway
to Internet resources for the History of Medicine. Top>Diseases>Tuberculosis. Tuberculosis ...
Association for the Study and Prevention of Tuberculosis. It was set up to ... 128.243.217.106/
browse/mesh/detail/D014376.html
82. MedlinePlus: Tuberculosis… Directory of factsheets, news, andarticles…
http://www.nlm.nih.gov/medlineplus/tuberculosis.html
83. Millennium indicators database …
84. Minority Lung Disease Data - Tuberculosis (TB) A fact sheet from the American Lung
Association’s “Lung Disease in Minorities 1999” booklet. The site covers recent U.S. historical
trends. However, the most recent statistics listed are from 1996. A source of U.S. T.B. statistics
from 1999 is the Division of Tuberculosis Elimination’s “1999 Surveillance Report.”
85. Molecular Characterization of Mycobacterium Tuberculosis, NYU…
86. Multidrug-resistant Tuberculosis Annotated Bibliography… Multidrug-resistant Tuberculosis (MDR-TB) - Annotated bibliography J. Woodruff 3/94 (Brief description of what kind of
document this is, and what`s in it, what it`s for) Outline Reviews Epidemiology and High Risk
Groups Diagnosis Treatment...
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87. Multidrug-Resistant Tuberculosis Fact Sheet From the American Lung Association…
88. Mycobacterial Genome Workshop, Division of Microbiology and ... ... tuberculosis
research at or near the present level for about another five years.... The development of an
improved tuberculosis vaccine is of extreme ... www.niaid.nih.gov/dmid/tuberculosis/execsum.
htm
89. MycDB, a Mycobacterium Database
90. Mycobacterium tuberculosis information Diseases Database … Mycobacterium Tub
erculosis,TB,Tuberculosis, Disease Database Information ... 3 synonyms or equivalents were
found. Mycobacterium tuberculosis. aka/or ... Search using Internet medical databases; Search
using Internet search engines (non-specialist); ... www.diseasesdatabase.com/ddb8515.htm
91. Mycobacterium tuberculosis : sites et documents francophones… ... Définition [MeSH
Scope Note ; traduction CISMeF] : Espèce de bactéries, aérobies, responsables de la tuberculose chez l’homme, les primates, ... http://www.chu-rouen.fr/ssf/organ/mycobacteriumtub...
92. MYCOS Research - A Colorado limited liability company providing custom mycobacterial research materials. Features products, services, company information, and research.
93. National Center for Infectious Diseases, Division of AIDS, STD, and TB Laboratory Research…
94. National Institute of Allergy and Infectious Diseases Home Page (NIAID), National Institutes of Health… NIAID Home | About NIAID | News & Information | Activities | Opportunities
NIAID welcomes your comments and suggestions. Please click here to send us an email message, or write to us at: NIAID Office of Communications and Public Liaison Buildin...
95. National Institute for Occupational Safety and Health (NIOSH)
96. National Institutes of Health… The National Institutes of Health [http://www.nih.gov/]
contains a variety of sites related to tuberculosis research. Most programs lie within the National Institute of Allergy and Infectious Diseases [NIAID, http://www.niaid.nih.gov/]. The
National Heart, Lung and Blood Institute [NHLBI, http://www.nhllbi.nih.gov/] also supports
tuberculosis research. Within the NIAID, there are two divisions supporting tuberculosis research. These are the Division of Microbiology and Infectious Diseases…
97. National Jewish Center for Immunology and Respiratory Medicine…
98. National Jewish Medical and Research Center…
99. National Library of Medicines Online Health Services…
100. National Tuberculosis Center in Newark, New Jersey …
101. National Tuberculosis Controllers Association - http://www.ntca-tb.org/
The home page of the National Tuberculosis Controllers Association (NTCA) and its associated organization, the National Tuberculosis Nurse Consultant Coalition (NTNCC). The NTCA
and NTNCC were created in 1995 to bring together the leaders of the tuberculosis control
programs of all 50 states as well as many county and city health departments which organize
their own “TB control” activities…
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102. National Tuberculosis Nurse Consultant Coalition - http://www.ntca-tb.org/ The
home page of the National Tuberculosis Controllers Association (NTCA) and its associated
organization, the National Tuberculosis Nurse Consultant Coalition (NTNCC). See above.
103. Nature Medicine: Tuberculosis WebFocus Includes an historical overview, full-text research articles from Nature Medicine, reviews, news items, commentaries, and links to other
sites…
104. NIAID’s Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF)…
http://www.taacf.org/
105. NIH Tuberculosis Research Materials and Vaccine Testing …
106. NJMS National Tuberculosis Center - An institution performing research on the prevention and treatment of tuberculosis, particularly in inner-city environments in the United
States... NJMS National TB Center - Links Page… Tuberculosis Sites. Action TB. Atlanta TB
Prevention Coalition. Brown University’s TB/HIV Lab. CDC’s Division of TB Elimination... http://
www.umdnj.edu/ntbcweb/links_frm.html and
http://www.umdnj.edu/ntbcweb/tbsplash.
html
107. North West TB Nurses Forum - The Northwest TB Nurses Association consists of nurses
who specialise in the prevention and treatment of Tubercolis in the North West of England.
108. Occupational Exposure to Tuberculosis (NYCOSH)…
109. Occupational Safety and Health Administration (OSHA)… OSHA: Tuberculosis Links
to regulation, compliance, and other issues about occupational exposure to tuberculosis from
the U.S. Occupational Safety & Health Administration…
110. OI: Turberculosis -- ÆGIS … A comprehensive resource on tuberculosis and HIV infection, from AEGIS. www.aegis.com/topics/oi/oi-tb.html
111. Pan American Health Organization (PAHO)… Tuberculosis… http://www.paho.org/
English/HCP/HCT/TUB/tuberculosis.htm
112. Pathology of Tuberculosis a mini-tutorial from Florida State University College of
Medicine
113. Philippine Tuberculosis Society Inc.... Dedicated to the prevention, treatment and
control of TB in the country. Includes information about the disease and the organization…
http://www.ptsi.org.ph
114. PHRI Russian TB Control Program …
115. Preguntale a NOAH Sobre la Tuberculosis Information in English and in Spanish presented by the New York Online Access to Health (NOAH) project.
116. Princeton Project 55… Princeton Project 55 Tuberculosis Initiative a wealth of documentation about TB…
117. Public Health Laboratory Service (PHLS), UK - Tuberculosis …
118. Public Health Research Institute Tuberculosis Center… The Public Health Research
Institute (PHRI) Tuberculosis Center was created to address the re-emergence of tuberculosis
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and the spread of multidrug resistant (MDRTB) strains in New York City. Today it focuses on
understanding and treating tuberculosis with activities in basic research, molecular epidemiology, and treatment of tuberculosis… http://www.phri.org/tb.htm
119. Pulmonology… Comprehensive database of pulmonological disorders… www.fpnotebook.com/LUN.htm
120. PulmonologyChannel… In 1993, WHO (the World Health Organization) declared tuberculosis a global emergency. Tuberculosis (TB) is responsible for the deaths of more youths
and adults than any other infectious disease… http://www.pulmonologychannel.com/tuberculosis...
121. Quantitative Analysis of TB, Los Alamos National Laboratory...
122. Questions and Answers About TB… http://www.cdc.gov/nchstp/tb/faqs/qa.htm
123. Rapid Blood Tests: Infectious Diseases, Tuberculosis, HIV, AIDS, STD… Présentation
d’une ligne de tests rapides RAPID 1-2-3 HEMA, sur le sang total proposés par HDS. VIH,
hépatites, dengue, maladie de Chagas, paludisme, ... www.rapid123.com/
124. Registre de Tuberculosi… Guia per al compliment del full de declaració de cas de
tuberculosi. Programa de prevenció i control de la tuberculosi a Andorra. www.col-legidemetges.ad/docs/fulltb.html
125. Research Institute of Tuberculosis… Conducts research and treatment of TB. Located
in Kiyose City, Tokyo… http://www.jata.or.jp/eindex.htm
126. Research on Tuberculosis, New York State Department of Health…
127. Resources for PPD antigens…
128. Singapore Anti-Tuberculosis Association…
129. Smart Computing® Directory Of Web Sites: Diseases… ... You will also find links to
tuberculosis sites, the latest information on conferences, a preventive therapy database, and
numerous reports. ... http://www.smartcomputing.com/input/websites/viewl...
130. Stanford Center for Tuberculosis Research…
131. Stanford Center for Tuberculosis Research Guestbook ... Websites with good pictures
related with TB will help very much. ... Near infrared spectroscopy for the analysis of tuberculosis antimicrobials. ... www.stanford.edu/group/molepi/guestbook.html
132. Stop TB Canada Initiative …
133. Stop TB Initiative… The Stop TB Initiative is a partnership for global action. The mission of Stop TB is to ensure that every person with TB has all the necessary information and
access to treatment and cure; to protect vulnerable populations from TB and http://www.
stoptb.org
134. Texas Center for Infectious Diseases (TCID)
135. Texas Department of Health - Tuberculosis Elimination Division
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136. Translated Education Materials TB educational material in many languages from the
Minnesota Department of Health…
137. TB Alert… Details about this charity which supports health projects worldwide and
promotes awareness of tuberculosis. Includes publications, a newsletter and links… http://
www.tbalert.org
138. TB Alliance …
139. TbandU… A layman’s guide to Tuberculosis, including all other health and medication issues.
140. TB Control India… An information site providing vital information about the status
of the RNTCP, Revised National Tuberculosis Programme being implemented in India. http://
www.tbcindia.org
141. TB Education Center Resources for Patient Care/Management - Texas Center for Infectious Disease
142. TB Education & Training Resources resources from the U.S. CDC
143. TB/HIV Research Laboratory, Brown University…
144. TB/HIV WHO activity around tuberculosis and AIDS…
145. TB News: Current News Article… http://www.hopkins-id.edu/tb_news/tb_news_
17.html
146. TB Patient Incentive Program (American Lung Association of Wisconsin web site)…
147. TB Policies: Classification of TB http://www.cpmc.columbia.edu/tbcpp/i-classt.html
148. TB Research at Case Western Reserve University
149. TB Resources on the Internet … Text-Only Site. State Directory. Agencies A-Z. About
Oregon.gov. Advanced. Help. Tuberculosis Control. About Us. Contact Us. Tuberculosis Control. Fact Sheets. Guidelines egov.oregon.gov/DHS/ph/tb/links.shtml
150. TB Weekly, a tuberculosis news weekly…
151. TBXrays.com - A graphics only site of x-rays and images of patients with tuberculosis
and other lung disease.
152. The Associate of North West TB Nurses… The Northwest TB Nurses Association consists of nurses who specialize in the prevention and treatment of Tuberculosis in the North
West of England… http://www.tbinfoline.co.uk/
153. The Hong Kong Tuberculosis, Chest and Heart Diseases Association… Provides an
introduction to the association’s services and patient-oriented information on tuberculosis,
heart diseases and hypertension… http://www.ha.org.hk/org/antitb/
154. The Indian Journal of Chest Diseases and Allied Sciences ... www.indegene.com/ijcd/
155. The Indian Journal of Tuberculosis … mohfw.nic.in/lrs/IJTB/
13
156. The International Journal of Tuberculosis and Lung Disease — a ... ... The International
Journal of Tuberculosis and Lung Diseases... www.ingentaconnect.com/content/ iuatld/ijtld/
157. The International Union Against Tuberculosis and Lung Disease… The International
Union Against Tuberculosis and Lung Disease [IUATLD] is a non-profit, non-governmental organization with members throughout the world. It is dedicated to the prevention and control
of tuberculosis and lung disease… http://www.iuatld.org/
158. The Lupin Group – Tuberculosis… Lupin is a national leader in anti-TB drugs. This site
features anti-T.B. drugs produced by the company, frequently asked question, news, directory
of tuberculosis links, and discussion group… http://www.lupinworld.com/antitb.htm
159. The Meaning of a Positive Tuberculosis Test / AAFP Patient Inform... http://home.aafp.
org/patientinfo/tbtest.html
160. The People’s Plague: Tuberculosis in America, PBS Online…
161. The Sequella Foundation… The Sequella foundation promotes basic and clinical research to facilitate the development new tools for TB control by providing support to the
research community and interested companies… http://www.sequellafoundation.org/
162. The TB Investigation Project… A 2002 study investigating tuberculosis in Russia, the
USA, and the UK. Analysis of both the human and the scientific stories behind the fight against
TB. Includes TB links… http://tbproject.tripod.com
163. The Tuberculosis Coalition for Technical Assistance (TBCTA) …
164. The Vaccine Fund - Press Releases ... malaria and tuberculosis vaccines that are so
desperately needed.”... www.vaccinefund.org/
165. Tinplate Hospital (BCG Vaccine)… BCG Vaccine, Prevention of Tuberculosis, Vaccine,
BCG background, General guideline of BCG, Benefits of BCG… http://www.tinplatehospital.
com/bcg.asp
166. Treatment of Tuberculosis - revised recommendations (American Thoracic Society web
site) (PDF, 515 KB)
167. TubercuList… Database on Mycobacterium tuberculosis genetics. Provides a complete
dataset of
DNA and protein sequences linked to the relevant annotations and functional ...
genolist.pasteur.fr/TubercuList/
168. Tuberculosis… Tuberculosis and Public Health for Health Care Professionals. Reviews
on issues in tuberculosis, applied epidemiology, and courses. An affiliation of the International
Union Against Tuberculosis and Lung Disease… http://www.tbrieder.org
169. Turberculosis… A comprehensive resource on tuberculosis and HIV infection, from
AEGIS.
http://www.aegis.com/topics/oi/oi-tb.html
170. Tuberculosis & Airborne Disease Weekly - A weekly publication with searchable ar-
chives…
14
171. Tuberculosis and HIV, HIVemir (HIV: An Electronic Media Information Review)…
172. Tuberculosis and HIV, Project Inform Hotline…
173. Tuberculosis and Related Infections Unit…
174. Tuberculosis and Related Infectious Disease - Watson W. Wise ... ... Tuberculosis Sites
(Univ. of Medicine and Dentistry, New Jersey); Tuberculosis & HIV (The Body: An AIDS and HIV
Information Resource) ... http://library.uthct.edu/tb.htm
175. Tuberculosis Antimicrobial Acquisition & Coordinating Facility (TAACF) …
176. Tuberculosis Association of Ohio County… Provides programs and services to Ohio
County, WV… http://www.tboc.org/
177. Tuberculosis Clinical Resources… Health: Diseases and Conditions: Tuberculosis. Additional Tuberculosis Sites (These sites have not been reviewed.) ... http://capstoneclinic-dl.slis.
ua.edu/clinical/pulm...
178. Tuberculosis Clinical Resources… Additional Tuberculosis Sites (These sites have not
been reviewed.) YAHOO - Health:Medicine:Respiratory Diseases ... http://ruralnurseorganization-dl.slis.ua.edu/clini...
179. Tuberculosis Control in Chicago A comprehensive information site for tuberculosis, a
mycobacterial infectious
disease, that is developed and maintained by local volunteers. www.tbchicago.org/
180. Tuberculosis Control – India… This site provides information about tuberculosis and
its control in India… http://www.tbcindia.org/
181. Tuberculosis Control Program (New York City Department of Health)…
182. Tuberculosis Control Program Website… internet URL http://www.med.upenn.edu/
TBPA/tbcp.html ... This web site has been created at the University of Pennsylvania Health System as part of a project entitled Tuberculosis Education in an Academic Health System, funded
through the National Heart, Lung and Blood Institute at NIH.
183. Tuberculosis Facts… Factsheet with cause, symptoms, risk factors, diagnosis, complications, treatment, and prevention. http://www.astdhpphe.org/infect/tb.html...
184. Tuberculosis Fact Sheet, Maryland Department of Health…
185. Tuberculosis Facts Factsheet with cause, symptoms, risk factors, diagnosis, complications, treatment,
and prevention. www.astdhpphe.org/infect/tb.html
186. Tuberculosis http://www.afscme.org/afscme/wrkplace/tbfs1.htm
187. Tuberculosis http://www.seanet.com/~tzhre/tuber.htm
188. Tuberculosis in Children - Keep Kids Healthy… Tuberculosis information and answers
to common questions about TB in children, including the difference between tuberculosis
infection and disease, ...
www.keepkidshealthy.com/welcome/ infectionsguide/tuberculosis.html
15
189. Tuberculosis - Index- Pulmonology … In 1993, WHO (the World Health Organization)
declared tuberculosis a global emergency. Tuberculosis (TB) is responsible for the deaths of
more youths and adults ... www.pulmonologychannel.com/tuberculosis/
190. Tuberculosis Information ... and Site Hosting - Web Hosting - Internet Store and
Ecommerce Solution Provider - High Speed Internet. Popular Searches: Tuberculosis Information ... ccfdca.www1.50megs.com/TB.htm
htm
191. Tuberculosis-Información Básica … www.netsalud.sa.cr/ms/estadist/enferme/tuberc.
192. Tuberculosis Information Management System (TIMS) …
193. Tuberculosis - Information / Diagnosis / Treatment / Prevention … The Complete
Guide to Health Care Resources on the Internet ... Search millions of published articles for
news on Tuberculosis. The HighBeam_ Research newspaper and magazine archive ... healthcyclopedia.com/.../mycobacterial/tuberculosis.html
194. Tuberculosis.net - THE Source for Tuberculosis Teaching Materials… Tuberculosis.net
strives to provide information about tuberculosis to the public and health-care community…
http://tuberculosis.net/
195. Tuberculosis.Net Forum… Resources for tuberculosis education, including a TB forum,
images, FAQs… http://tuberculosis.net
196. Tuberculosis, New York Online Access to Health (NOAH)…
197. Tuberculosis News - Topix.net - Latest news stories on the disease.
198. Tuberculosis, North Eastern Health Care Network, Melbourne Australia…
199. Tuberculosis - Patient Oriented Resource http://johns.largnet.uwo.ca/largh/patients/
tb.html
200. Tuberculosis Primary Care Teaching Module, UCSF & Stanford…
201. Tuberculosis pulmonar… Información general, datos, manifestaciones, síntomatología, tratamiento y enlaces… http://www.geocities.com/hmiguelito/indicede.htm
202. Tuberculosis Research Centre studying effective treatment in India…
203. Tuberculosis Research Unit, Case Western Reserve University…
204. Tuberculosis Resources… Columbia University`s website with information about tuberculosis, TB testing and treatment. Spanish and English… http://www.cpmc.columbia.edu/
resources/tbcpp
205. Tuberculosis Resources - Information about tuberculosis… Up-to-date information
about tuberculosis written by the Bureau of Tuberculosis Control of the New York City Department of Health is now available via New York Online Access to Health (NOAH). Information
includes what you need to know about tuberculosis, the tuberculin skin test, treatment to prevent tuberculosis and TB: getting cured… http://www.cpmc.columbia.edu/resources/tbcpp/
16
206. Tuberculosis Resources on the Internet… Source:HealthNet. Title. URL. Publisher(s)
Comments. PubMed. http://www.ncbi.nlm.nih.gov/ entrez/ query.fcgi. National Center for
Biotechnology Information at the National Library of Medicine ,NIH ... and presented by Johns
Hopkins Cener for Tuberculosis Research ... part 2 of Table II. Global Tuberculosis Control Report ... www.psgaidsinfo.org/tuberculosis_resurces_on_the_internet.htm
207. Tuberculosis Screening Services (TSS)… Information on services including TB skin
testing, pre-employment screenings, and Hepatitis B vaccinations with evening appointments
and group rates. All services satisfy Louisiana State Health Department requirements… http://
www.tbtest.com/
208. Tuberculosis (TB)…
209. Tuberculosis… Tuberculosis and Public Health for Health Care Professionals. Reviews
Union Against Tuberculosis and Lung Disease… http://www.tbrieder.org
210. Tuberculosis, The Luxembourg Health Server SANTEL…
211. Tuberculosis - Topix.net - News on tuberculosis. [RSS]
212. Tuberculosis - Tuberculosis and Public Health for Health Care Professionals. Reviews
Union Against Tuberculosis and Lung Disease.
213. Tuberculosis, Yahoo Web Database…
214. Tuberculosis Vaccines: State of the Science, Tuberculosis Research...
http://www.niaid.nih.gov/dmid/tuberculosis/tbvacci...
215. Tuberculosis Vaccine Action Plan, Blueprint for Tuberculosis Vaccine Development,
National Institute of Allergy ... http://www.niaid.nih.gov/publications/blueprint/pa...
216. Tuberculosis Web Sites http://www.lib.siu.edu/websites/health/tb.html
217. Tuberculosis Web Sites ... Consumer Health Sites. Enfermedades - Tuberculosis. This
Spanish language page from the Centers for Disease Control contains links to pamphlets including “Tuberculosis - !Enterese!” ... Core Curriculum on Tuberculosis is updated periodically.
Therefore, the Internet version may differ ... www.lib.siu.edu/hp/divisions/sci/health/tb.html
218. Tuberculosis - Wikipedia, the free encyclopedia… http://en.wikipedia.org/wiki/Tuber-
culosis
219. Tuberculosis workplace standards related to TB from the U.S. Occupational Safety
and Health…
220. www.tuberculosis.ru/
221. Understand and Fight Tuberculosis - Information for health care professionals… From
the Tuberculosis Division of the International Union Against Tuberculosis and Lung Disease
(IUATLD)… http://www.tbrieder.org/
17
222. Unidad de investigación en Tuberculosis de Barcelona... Informacion sobre tuberculosis, tratamientos, prevencion, vacunas, lineas y proyectos de investigacion, documentos, casos
clinicos, novedades, congresos, eventos y cursos… http://www.imsb.bcn.es/uitb/
223. Unité de Génétique Moléculaire Bactérienne ... projects is also available via the web
sites at Integrated Genomics,… live tuberculosis vaccines Mycobacterium bovisBCG and Mycobacterium microti. ... www.pasteur.fr/recherche/unites/Lgmb/mycogenomics.html
224. USDA Funded Projects ... Develop candidate tuberculosis vaccines for cattle and deer;
3. ... www.nal.usda.gov/awic/pubs/TB/USDAFunded.htm
225. Vaccines, Division of Microbiology and Infectious Diseases… http://worldaidsday.nih.
gov/dmid/vaccines...
226. Veiled Face of Tuberculosis - Find the author’s attitude towards diagnostics of renal
tuberculosis, the way the investigations were performed, studied samples, and a note on the
author. Site is in English and Croatian…
227. Wadsworth Center (New York State Department of Health) …
228. Welcome on the TB Vaccine Cluster Site… Click on to enter. Updated : Tue, Jun 13,
2000. Site realised by Marie Guibert. http://www.pasteur.fr/recherche/EC_TBvaccine/
229. WHO Tuberculosis - Prevention and Control Web Site This World Health Organization
site includes several publications and fact sheets with an international focus, including the
2002 Global Tuberculosis Control Report, Treatment of Tuberculosis: Guidelines for National
Programmes (available in English, French, and Spanish), TB/HIV: A Clinical Manual, Tuberculosis
in Prisons (available in English and Russian), and information about drug-resistant TB.
230. World Bank - tuberculosis
231. World Health Organization… Tuberculosis… http://www.who.int/tb/en/
232. World Health Organization Global Tuberculosis Programme…
233. World TB Day, March 24, 2005 information from the U.S. CDC
18
List of Noted Tuberculosis Victims
From Wikipedia, the free encyclopedia. (Redirected from List of famous tuberculosis victims). This is a list of famous people and celebrities who had, or are believed to have had,
tuberculosis.
Writers and poets:
Jane Austen, Honoré de Balzac, Anne Brontë, Charlotte Brontë, Emily Brontë,
Charles Farrar Browne, Elizabeth Barrett Browning, Robert Burns, Lord Byron,
Albert Camus?, Anton Chekov, Tristan Corbière, Stephen Crane. René Daumal,
Jean de Brunhoff, Guy de Maupassant, Fyodor Dostoevski, Paul Laurence Dunbar,
Ralph Waldo Emerson, Dashiell Hammett, Saima Harmaja, Robert Heinlein?, Miguel
Hernández, Washington Irving, Helen Hunt Jackson, Alfred Jarry, Samuel Johnson,
Franz Kafka, John Keats, Charles Kingsley, Sidney Lanier, D. H. Lawrence, Betty
MacDonald?, Katherine Mansfield, Somerset Maugham, Molière, Eugene O’Neill,
George Orwell, Walker Percy, Edgar Allan Poe, Alexander Pope, Llewelyn Powys,
Winthrop Mackworth Praed, John Reed, Edmond Rostand Jean-Jacques Rousseau
John Ruskin, Albert Samain, Friedrich Schiller, Sir Walter Scott, Percy Bysshe Shelley
?, Tobias Smollett, Laurence Sterne, Robert Louis Stevenson, Alan Sillitoe, Dylan
Thomas, Francis Thompson, Henry David Thoreau, Leo Tolstoy?, Voltaire, Thomas
Wolfe, Ji�í Wolker.
Artists:
Frédéric Bartholdi, Marie Bashkirtseff, Aubrey Beardsley, Harry Clarke, Paul
Gauguin, Amedeo Modigliani, Elizabeth Siddal ?, Pamela Anderson.
Composers:
Frédéric Chopin, Stephen Foster, Wolfgang Amadeus Mozart, Niccolo Paganini,
Giovanni Battista Pergolesi, Henry Purcell, Johann Schein, Cat Stevens?.
Religious figures:
John Calvin, Cardinal Richelieu, St Thérèse de Lisieux, St Bernadette Soubirous.
Leaders:
Simón Bolívar, Edward VI of England, Ulysses S. Grant, Andrew Jackson, Muhammed Ali Jinnah, Sir Wilfrid Laurier, Louis XIII of France, Louis XVII of France, Nelson Mandela, Napoleon II of France, Manuel L. Quezon, Eleanor Roosevelt, Dmitri
Pavlovitch Romanov, Alexander Stephens, Tutankhamun, John Young.
19
Others:
Niels Abel, mathematician Renée Adorée, Beulah Annan, Frédéric Bastiat, Alexander Graham Bell, Sarah Bernhardt, Louis Braille, James Burke, Anders Celsius,
Cheng Man-ch’ing, Tai Chi Chuan master, Charlie Christian, Arline Feynman, W. C.
Fields, Augustin-Jean Fresnel, Brenda Fricker, Abel Gance, Jay Gould, Emmett Hardy,
Richard Harris (actor)?, Doc Holliday, Immanuel Kant, Freddie Keppard, René Laënnec French physician; inventor of the stethoscope, Vivien Leigh, Christy Mathewson,
Dmitri Mendeleev?, James “Bubber” Miley jazz trumpeter, Barry Morse?, Anne Neville (queen consort of Richard III) (probably), Florence Nightingale, Mabel Normand,
Etti Plesch?, Joseph Mary Plunkett, Virginia Eliza Clemm Poe (wife of Edgar Allan
Poe), Herman Poto�nik, Gavrilo Princip, Jimmie Rodgers, Bernhard, Riemann, mathematician Erwin Schrödinger, Takasugi Shinsaku (1839-1867), samurai Okita Soji
(1844-1869), Japanese swordsman and troop captain in the Shinsengumi, Baruch
Spinoza, Adrianus Turnebus, Georges Vezina, Lev Vygotsky, Rube Waddell, William
Winchester (son of Oliver Winchester, husband of Sarah Winchester), Link Wray,
Eugene Wigner?.
Note: ? died of something unrelated to tuberculosis.
Fictional characters:
Ukyo Tachibana from the Samurai Shodown video game series Sayo from the
Rurouni Kenshin anime, Hyatt from the Excel Saga anime, Helen Burns from Jane
Eyre by Charlotte Brontë, Little Nell from The Old Curiosity Shop (Charles Dickens),
Mimi from La Bohème (Giacomo Puccini et. al.), Violette from Verdi’s La Traviata,
Buddy Willard from The Bell Jar by Sylvia Plath, Lin Dai-yu from The Story of Stone
by Cao, Satine from Moulin Rouge.
Reference:
Rothman, Sheila M. (1994). Living in the Shadow of Death: Tuberculosis and the Social Experience of Illness
in American History. ISBN 0801851866 .
20
SOME CUBAN MASTER PAINTERS VICTIMS OF TB...
... AND HIS WORKS
Fidelio Ponce de León:
Was born in 1895, at Camagüey city, Cuba, and dies on February
19th, 1949, Havana city. Initiated studies in San Alejandro Academy from
1913 through 1918, year in which disappeared until 1923. He moved to a
suburb neighborhood where he teaches drawings to poor kids and works
on commercial arts. Return to Havana in 1930, alcoholic and with tuberculosis symptoms. The Ponce´s style, thematics and formal treatment,
combines to create very pasty and “milkies” oil canvass, with lengthly
and poorly definited human figures, and characterized also by his monochromatism, abstractions, and melancholic feelings related with diseases,
death and religion. Ponce, which had a great personality, was a student
of Master Leopoldo Romañach and his work was influenced by his academic procedures. He was obsessed with the white color, which he used
to call “pintura nacarada” in order to project light color from it. He enjoyed
Kandinsky’s famous words: “...white is a great silence full of possibilities”.
In 1934, participated in the “XVII Salón de Bellas Artes” with his work
“Paisaje”. His first exhibitions at the Lyceum, becomes a great success for
him. His work “Las Beatas” is awarded with a prize from El Salon Nacional,
as well as prizes from El Salon de Arte Moderno in Havana, in 1937, during
this period belongs also his superb work “Tuberculosis”. At this time his
career is in a roll; traveled to New York and open exhibitions in the Delphis
Studio. Again, received first prize for his work “Los Niños” from the Salon
Nacional, and then disappeared until 1940. The Museum of Modern Art
in New York obtain his work: “Mujeres” as part of its permanent collection. In 1944, Ponce participated in the “Cuban Painters Exposition” at the
Museum of Modern Art in New
York (“San Ignacio de Loyola”);
in 1946 in the “Cuban Modern Paint”, Bellas Artes Palace
at Mexico City; in 1947 in the
“Cuban Painters”, Bellas Artes
Museum, Buenos Aires; and in
1947 in “Cuban Modern Painters”, Washington Collections,
Washington, D.C. The Havana
Lyceum organized an exposition about all his work in April,
1949; and in 1995, the National
Museum, Bellas Artes Palace, at
Havana city, organized a comprehensive exhibition about
his work, commemorating his
centenary.
21
Tuberculosis
Carlos Enríquez (1900 - 1957)
“El Rapto de las Mulatas
/ Brown girls abduction”
Arístides Fernández (1904-1934)
“Autorretrato / Self-Portrait”
“Lavanderas / Washing Women”
22
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The internationally-recommended
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There is growing interest in the
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More information
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The global TB network agreed to
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The expanded strategy reinforces
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More information
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MDR-TB is a specific form of drugresistant TB due to a bacillus
resistant to at least isoniazid and
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More information
Practical Approach to Lung
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The Practical Approach to Lung
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More information
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In many countries, private health
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More information
Tuberculosis in prisons
TB is not an unavoidable
consequence of incarceration and
can be controlled through the
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More information
Tuberculosis and gender
In most of the world, more men
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Treatment of
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Canada's Role in Fighting Tuberculosis, Yesterday, Today, and Tomorrow.
CANADA's ROLE in
FIGHTING TUBERCULOSIS
About Tuberculosis What is tuberculosis and how is it
spread? This resource explains the biology of tuberculosis and
the way in which we deal with it.
Tuberculosis History in Canada Tuberculosis
is one of the oldest diseases of humans. Find out how it
use to be fought, through sanatoria and mass community
surveys.
Tuberculosis in Canada Today A "cure" was found
Teaching Resources
for tuberculosis in the 1940s, but it is not gone from Canada.
Why does TB remain and what are Canadians doing about it?
Site Credits
Glossary
This digital collection was produced under contract to Canada's Digital Collections
program, Industry Canada. The website was produced by a CDC team at the
Saskatchewan Lung Association.
http://www.lung.ca/tb/ [23/08/05 17:08:30]
Aeras Global TB Vaccine Foundation
●
●
●
Two billion people - one third of the world's population - have been infected
with TB.
Someone is newly infected with TB every second.
Nearly 2 million people die of TB every year.
Distinguished scientist
M.M. Sharma of Mumbai,
India, has been named to
the Aeras Board of
Directors. Read more...
The G8 Summit's final
communique commits the
world's wealthiest nations
to boost action to combat
TB and other killer
diseases in Africa. Read
the G8 communique on
Africa. Aeras applauds G8
commitments to PublicPrivate Partnerships and
new tools to fight TB and Danida, the Danish development agency,
other diseases. Read
announced an agreement to support development
of a vaccine trial site in South Africa. Aeras will
more...
partner with Medicon AS, a leading Danish
Aeras and partners urge research company, and the South Africa TB
leaders of the G8 nations Vaccine Initiative (SATVI) to develop the site.
to support Public-Private Read more…
Denmark Becomes First
European Country to Support
Aeras
Partnerships working on
new drugs, diagnostics
and vaccines for global
diseases of poverty. Read
more…
http://www.aeras.org/ (1 of 2) [23/08/05 17:10:36]
Aeras Global TB Vaccine Foundation
Aeras and UCLA have
executed a non-exclusive
license agreement for a
new TB vaccine technology
that will allow Aeras to
develop and market the
vaccine in the developing
world. The new vaccine,
known as rBCG30, was
developed by Dr. Marcus
Horwitz at UCLA’s David
Geffen School of Medicine.
Read more…
Aeras and Statens Serum
Institut of Copenhagen,
Denmark, have announced
a new collaboration on the
pre-clinical and clinical
development of SSI's
tuberculosis vaccine
candidate, HyVac4, which
will be developed as a
booster vaccine to extend
the protection of the
currently available TB
vaccine, BCG.
Read more…
© 2004 Aeras Global TB Vaccine Foundation, 7500 Old Georgetown Road, Suite 800, Bethesda, MD
20814, USA
Phone: +1-301-547-2900 • [email protected] • privacy policy
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WHO | <em>Tuberculosis</em>
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Tuberculosis
Advocacy report
WHO/CDS/TB/2003.321
ISBN 92 4 259070 3 (NLM classification: WF 310)
The publication, prepared for the World
Health Organization by editors and
photographers from Colors magazine,
puts a human face on the TB epidemic
and the deadly interaction between TB
and HIV. Outlining the efficacy of the
DOTS programme, the report makes clear
that continued commitment and
expanded resources are vital to combat
TB.
Links
Despite eight million new cases of TB being reported annually – and
two million deaths a year – the report reveals the many
misconceptions people have about the disease and how this
ignorance is reflected in the misery of those infected with TB across
the world.
THE FILM
Tuberculosis
An informational film based on the
report Tuberculosis.
:: View the film
THE REPORT
Tuberculosis
:: Photo gallery
:: Press release
:: Report - text only [html]
:: English/French [pdf 1.1mb]
:: English/Spanish [pdf 1.1mb]
"The images are disturbing," said Colors editor-in-chief Renzo di Renzo, "but in fact they give just a mere
glimpse of the enormous challenges faced every day by TB health care workers."
http://www.who.int/tb/publications/advocacy_report_2003/en/index.html [05/12/05 22:16:01]
WHO | TB cases and deaths linked to HIV now at alarming levels in Africa
All WHO
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Countries
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TB cases and deaths linked to HIV now at alarming levels in
Africa
Rising rates contrast sharply with accelerated progress in other regions
London/Geneva - 24 March, 2005 - In most areas
of the world, the battle against tuberculosis is
being successfully fought, but in Africa the disease
has reached alarming proportions with a growing
number of TB cases and deaths linked to HIV, the
World Health Organization said in a new report
released today.
:: News release
:: Access the full report online
:: Report summary (English) [pdf
81kb]
:: Report summary (French) [pdf
95kb]
:: Report summary (Spanish) [pdf
89kb]
The Global Tuberculosis Control report for 2005
finds that global TB prevalence has declined by
more than 20% since 1990 and that incidence
rates are now falling or stable in five of the six regions of the world. The glaring exception is Africa,
where TB incidence rates have tripled since 1990 in countries with high HIV prevalence and are still
rising across the continent at a rate of 3-4% annually.
Even Uganda, an African HIV reduction success story, is today curing fewer TB patients than it did four
years ago. More than half of all people with TB in Uganda remain without access to life-saving DOTS*
services due to strained general health facilities.
"Evidence in this report provides real optimism that TB is beatable, but it is also a clear warning," said
WHO Director-General Dr LEE Jong-wook. "As Nelson Mandela has said, we can't fight AIDS unless we do
much more to fight TB, and it is time to match his words with urgent action in Africa on the two
epidemics together."
There has been major progress in China and India, which account for one third of the global TB burden.
Both are leading the accelerated response to TB control by rapidly scaling up DOTS. As a result, the
number of cases treated under DOTS worldwide rose 8% in 2003 compared to the previous year. Other
countries such as Indonesia and the Philippines are showing similar progress.
Assuming strong commitment and resources are sustained, four regions - the Americas, Eastern
Mediterranean, South East Asia and Western Pacific - are on track to reach the United Nations Millennium
Development Goal of reducing TB incidence by 2015. The two exceptions are Africa due to the TB/HIV coepidemic, and Europe where there are high levels of multidrug-resistant TB and slow advances in DOTS
in countries of the former Soviet Union.
http://www.who.int/tb/features_archive/wtbd2005/en/index.html (1 of 2) [05/12/05 22:21:30]
WHO | TB cases and deaths linked to HIV now at alarming levels in Africa
"Dedicated frontline health workers are making a difference, reaching out to the most vulnerable," said
Dr Mario Raviglione, Director of WHO's Stop TB Department. "But we need to push even further, to work
with new partners in both public and private health sectors, and in all regions, to reach more than half of
all patients that are still without access to DOTS treatments."
Since 1995, over 17 million people with TB have benefited from effective treatment under DOTS. But
more could be achieved within countries, and in research into new diagnostics, drugs and vaccines, if the
annual US$ 1 billion funding gap for TB control was filled.
The urgency of addressing TB has been highlighted in the UK-led Commission for Africa, which linked
improved TB control to strengthened health systems, as well as calling for full funding of WHO's 'Two
Diseases, One Patient' strategy for improved TB and HIV intervention.
"It is a remarkable achievement that we are on target to reach the goal of halving TB cases by 2015 in
most places," said the UK's International Development Secretary, Hilary Benn. "The Department for
International Development is a strong supporter of TB programmes in some of the countries which have
been making the fastest progress. However, as both the Global TB Control report and the Commission for
Africa report stress, the destructive link between TB and AIDS in Africa is causing an increase in cases. I
call on the international community to step up efforts to tackle both of these diseases together."
*DOTS is the internationally recommended strategy for controlling TB, consisting of five elements:
●
●
●
●
●
Government commitment to TB control
Diagnosis through bacteriology and an effective lab network
Standardized short-course chemotherapy with full patient support throughout treatment
Uninterrupted supply of quality-assured drugs
Recording and reporting to measure patient and programme outcomes
World TB Day on 24 March is a Stop TB Partnership initiative aimed at raising TB awareness
internationally. WHO is one of 325 members of the Stop TB Partnership committed to controlling and
ultimately eliminating TB as a public health problem. Since the Partnership's formation in 2001 the
number of patients detected for TB has increased by two thirds.
:: Access the full report online
For more information, please contact:
●
●
●
Geneva: Michael Luhan Stop TB Partnership, + 41 22 791 1379 [email protected]
London: Glenn Thomas WHO Stop TB, +41 79 509 0677 [email protected];
Paris: Michael Aublanc for Stop TB Partnership, +33 1 69 286 286, [email protected]:
http://www.who.int/tb/features_archive/wtbd2005/en/index.html (2 of 2) [05/12/05 22:21:30]
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Articles published in Eur J Epidemiol
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January 2005
1. KUBO N , Furusyo N, Nakashima H, Kashiwagi K, et al
Strenuous physical labor is important as a cause of elevated alanine aminotransferase levels in Japanese
patients with chronic hepatitis C viremia.
Eur J Epidemiol 2005;20:251-61.
PubMed
Related articles Abstract available
January 2004
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Prevalence of HCV infection among health care workers in a hospital in central Italy.
PubMed
3. MEHR AJ , Ardakani MJ, Hedayati M, Shahraz S, et al
Age-specific seroprevalence of hepatitis A infection among children visited in pediatric hospitals of
Tehran, Iran.
PubMed
4. ERDOGAN MS , Otkun M, Tatman-Otkun M, Akata F, et al
The epidemiology of hepatitis a virus infection in children, in Edirne, Turkey.
PubMed
5. ARVANITIDOU M , Mamassi P, Vayona A
Epidemiological evidence for vaccinating wastewater treatment plant workers against hepatitis A and
hepatitis B virus.
PubMed
6. FISKER N , Mygind LH, Krarup HB, Licht D, et al
Blood borne viral infections among Danish health care workers--frequent blood exposure but low
http://amedeo.com/medicine/hep/eurjepid.htm (1 of 3) [05/12/05 22:22:37]
prevalence of infection.
PubMed
7. SCHINAIA N , Kodra Y, Sarmati L, Andreoni M, et al
Prevalence of HHV-8 infection in Albanian adults and association with HBV and HCV.
PubMed
8. DJEBBI A , Mejri S, Thiers V, Triki H, et al
Phylogenetic analysis of hepatitis C virus isolates from Tunisian patients.
PubMed
9. ZALLER N , Nelson KE, Aladashvili M, Badridze N, et al
Risk factors for hepatitis C virus infection among blood donors in Georgia.
PubMed
10. SENCAN I , Sahin I, Kaya D, Oksuz S, et al
Assessment of HAV and HEV seroprevalence in children living in post-earthquake camps from Duzce,
Turkey.
PubMed
11. GHABOULI MJ , Sabouri AH, Shoeibi N, Bajestan SN, et al
High seroprotection rate induced by intradermal administration of a recombinant hepatitis B vaccine in
young healthy adults: comparison with standard intramuscular vaccination.
PubMed
12. DENIS F , Ranger-Rogez S, Alain S, Mounier M, et al
Sreening of pregnant women for hepatitis B markers in a French Provincial University Hospital (Limoges)
during 15 years.
PubMed
13. BUTLER T , Kariminia A, Levy M, Kaldor J, et al
Prisoners are at risk for hepatitis C transmission.
PubMed
January 2003
14. BACKMUND M, Meyer K, Wachtler M, Eichenlaub D
Hepatitis C virus infection in injection drug users in Bavaria: risk factors for seropositivity.
Eur J Epidemiol 2003; 18: 563-8.
PubMed
15. CHLABICZ S, Grzeszczuk A, Lapinski TW, Prokopowicz D, Panasiuk A
Search for hepatitis delta virus (HDV) infection in hepatitis C patients in north-eastern Poland.
Comparison with anti-HDV prevalence in chronic hepatitis B.
Eur J Epidemiol 2003; 18: 559-61.
PubMed
16. GOGOS CA, Fouka KP, Nikiforidis G, Avgeridis K, Sakellaropoulos G, Bassaris H et al
Prevalence of hepatitis B and C virus infection in the general population and selected groups in SouthWestern Greece.
PubMed
17. JAIN A, Rana SS, Chakravarty P, Gupta RK, Murthy NS, Nath MC et al
The prevalence of hepatitis C virus antibodies among the voluntary blood donors of New Delhi, India.
PubMed
18. LA TORRE G, De Vito E, Langiano E, Petta P, Colarossi G, Cipriani L et al
Epidemiology of hepatitis C virus antibodies in blood donors from the province of Latina, Italy.
PubMed
19. REDA AA, Arafa MA, Youssry AA, Wandan EH, Ab de Ati M, Daebees H
Epidemiologic evaluation of the immunity against hepatitis B in Alexandria, Egypt.
Eur J Epidemiol 2003; 18: 1007-11.
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Canada's Role in the Fight Against Tuberculosis Today.
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:: ABC de la Tuberculosis - UITB - Unidad de investigación en tuberculosis de Barcelona ::
english version
ESTE SITE HA CAMBIADO DE SITIO. POR
FAVOR ACTUALICE SUS ENLACES:
http://www.aspb.es/uitb/
Su navegador le redigirá en unos segundos a la nueva
dirección, para hacerlo de forma manual pinche aquí.
Unidad Temática Concedida por el Fondo de Investigaciones Sanitarias (FIS) en 1995
12257 visitantes.
Visitas por días y por países
(Última actualización: 13 de Diciembre 2005 )
http://www.imsb.bcn.es/uitb/ [03/01/06 23:37:35]
english version
Unidad Temática Concedida por el Fondo de Investigaciones Sanitarias (FIS) en 1995
12258 visitantes.
Visitas por días y por países
(Última actualización: 13 de Diciembre 2005 )
Objetivos de la UITB
Producción de conocimiento científico de relevancia sobre el control, diagnóstico, tratamiento
y prevención de la TBC.
Requisitos generales
En 1994, el fondo de Investigaciones Sanitarias de la Seguridad social abría la posibilidad de
solicitar una unidad Temática de Investigación en Tuberculosis, de acuerdo con estos
requisitos:
1. Existencia de un Proyecto Integrado (Epidemiología, Clínica y Microbiología) enfocado sobre
las siguientes áreas de conocimiento: TBC en general, TBC y SIDA.
2. Exigencia de contar con todos los recursos y los enfermos de tuberculosis del area de
referencia.
Red de Unidades de Investigación (REUNI)
Unidad de Investigación en Tuberculosis
Tuberculosis en general/sida
Epidemiología
Clínica
http://www.aspb.es/uitb/ (1 of 2) [03/01/06 23:38:42]
Microbiología
Evolución cronológica
Ya en 1987, en una reunión científica sobre Programas de Vigilancia y Control celebrado en
Bilbao, se evidenció la necesidad de impulsar la investigación sobre Tuberculosis. La
Conferencia Nacional de Consenso de 1991 también puso de manifiesto esta necesidad. En
1994 se presentó al FIS el primer proyecto integrado de la Unidad deInvestigación en
Tuberculosis de Barcelona, la cual empezó a ser operativa a partir de finales de 1995.
Taller
sobre
Programas
de
vigilancia
de la TBC
en España
Conferencia
de
consenso
Reuniones,
grupos de
trabajo
1er
proyecto
integrado*
Aprobación
memoria
científica
Aprobación
ayuda
infraestructura
Disponibilidad
recursos
infraestructura
1987
1991
1990-92
V-94
VI-95
IX-95
I-96
*Finalmente no hubo recursos para unidades temáticas
Para ver las estadísticas de uso de esta web
Honduras Sites!
El directorio de México
Búsqueda Google
http://www.aspb.es/uitb/ (2 of 2) [03/01/06 23:38:42]
A laymans guide to tuberculosis, atypical tuberculosis and mycobacterial disease.
The site now includes tuberculosis GUIDELINES covering diagnosis,
treatment, medication, health & safety and many other issues
The Facts
of Tuberculosis can now be automatically translated in 16 languages by clicking
A to Z of Drugs
on any floating flag.
AtoZ of General Health Welcome to TB and U I feel I should state immediately the fact that this site is NOT run by
medical professionals or sponsored by medical companies but is solely run by an individual. The
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other mycobacterial diseases. The links have been carefully chosen; the majority of which are
Chelonae
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Welcome on the TB Vaccine Cluster Site
Updated : Tue, Jun 13, 2000
Site realised by Marie Guibert
http://www.pasteur.fr/recherche/EC_TBvaccine/ [04/01/06 1:55:08]
USDA Funded Projects
USDA FUNDED PROJECTS
ACCESSION NO: 0194743 SUBFILE: CRIS
PROJ NO: CALV-MORRIS01-01Z029 AGENCY: CSVM CALV
PROJ TYPE: STATE PROJ STATUS: TERMINATED
START: 01 SEP 2001 TERM: 31 AUG 2002 FY: 2002
Investigator: Tell, L. A.
Performing Institution:
Medicine & Epidemology
University of California (Vet-Med)
Davis, California 95616
THE SUITABILITY OF POLYMERASE CHAIN REACTION FOR THE SCREENING OF
MYCOBACTERIA IN AVIAN FECES
NON-TECHNICAL SUMMARY: Mycobacteriosis is an insidious disease which causes mortalities in
birds and is also a zoonotic concern. Affected birds shed organisms in their feces that remain viable in
the environment for months to years and poses a threat to domestic animals, other birds and humans.
This project will help to develop a more rapid and reliable screening method for the detection of
Mycobacteria avium complex bacteria than conventional culture methods.
OBJECTIVES: This project tests the hypothesis that polymerase chain reation (PCR) testing using
extracted mycobacterial deoxyribonucleic acid (DNA) from avian feces can provide a more rapid and
realiable screening method for the detection of Mycobacteria avium complex bacteria than conventional
culture methods.
APPROACH: Potential diagnostic procedures using extracted DNA for PCR from clinical samples have
been plagued by the presence of various inhibitors of the PCR reaction. This study is specifically
designed to assess three different DNA extraction protocols of avian feces for the presence or absence of
these potential PCR inhibitors and the overall efficiency and the suitability of the resulting DNA for PCR
reactions. Once an optimal method is identified, it will be used to evaluate the extraction and detection of
DNA from feces spiked with living Mycobacterium avium complex cells.
PROGRESS: 2001/09 TO 2002/08
This study was designed to assess four DNA extraction protocols of avian feces for the presence or
http://nal.usda.gov/awic/pubs/TB/USDAFunded.htm (1 of 38) [04/01/06 2:04:35]
absence of potential PCR inhibitors, thus defining an optimal method for DNA extraction from bird fecal
samples. The first experiment compared three DNA extraction methods and heat treatment of the
extracted fecal DNA samples for their ability to overcome fecal PCR inhibition. Methods for extracting
DNA from feces of healthy Japanese quail (Coturnix coturnix japonica) included (a) bead beating + EL
(BB+EL), (b) bead beating + silicone dioxide (BB+SiO2), and (c) bead beating + phenol/chloroform. To
evaluate each extraction methods' ability to overcome PCR inhibition, extracted fecal DNA samples were
spiked with control M. avium subsp. avium DNA and quantitative real-time TaqMan PCR analysis was
performed. The BB+EL and BB+SiO2 methods returned positive PCR results. BB+EL resulted in the
highest purity and number of mycobacteria. Heating samples before PCR analysis decreased the mean
number of mycobacteria for all fecal DNA extraction methods. In the second experiment, living M.
avium subsp. avium cells were mixed with feces from healthy Japanese quail at concentrations of 1 x 106
CFU/g, 10 x 106 CFU/g, or 60x 106 CFU/g. Samples underwent DNA extraction using BB+EL,
followed by quantitative TaqMan PCR. Heated and unheated samples were analyzed. The mean number
of mycobacteria detected in feces with a spiking concentration of M. avium subsp. avium of 1 x 106
CFU/g was only 1 (range, 0 to 2.3) for both heated and unheated samples. Thus, the lower limit of
detection for quantitative PCR using the methods described is approximately 1x106 CFU/g or less. In
summary, this study demonstrated that DNA extraction methods used in sample preparation can have a
substantial impact on the DNA yield, purity, and amplification during subsequent PCR analysis on avian
fecal samples. The best preparation method tested incorporated bead beating and enzymatic lysis using a
commercial kit designed for use on stool samples. The lower limit of detection on avian fecal samples
spiked with M. avium subsp. avium was 1 million CFU/gram, so this test may be of most use in
identifying highly infective birds.
IMPACT: 2001/09 TO 2002/08
Mycobacteriosis is a bacterial disease that causes morality in birds and can cause human disease as well.
Affected birds shed organisms in their feces that may remain viable in the environment for months to
years. Currently, infected birds are identified by culturing mycobacteria from fecal samples, a process
taking weeks for results. This study assessed a DNA based assay system that could detect high numbers
of the bacteria within one day of sample processing, and thus could help in the rapid screening of
contagious animals.
PUBLICATIONS: 2001/09 TO 2002/08
Lisa A. Tell, Wayne L. Smith, Christian M. Leutenegger, Janet E. Foley, Richard L. Walker, Martha L.
Needham, Katheryn J. Jones, and James C. Cullor 2003. The suitability of polymerase chain reaction
testing for the identification of Mycobacterium avium subsp. avium in avian feces. Submitted to Journal
of Veterinary Diagnostic Investigation
PROJECT CONTACT:
Name: Tell, L. A.
Phone: 530-752-1363
Fax: 530-752-0414
Email: [email protected]
PROJ NO: COL00627 AGENCY: CSREES COL
PROJ TYPE: HATCH PROJ STATUS: EXTENDED
START: 01 JUL 1997 TERM: 30 JUN 2003 FY: 2002
Investigators: Nett, T. M.; Blair, C. D.; Bowen, R. A.; Orme, I. M.; Pearson, L. D.; Salman, M. D.
Microbiology, Immunology and Pathology
Colorado State University
Fort Collins, Colorado 80523
CONTROL OF INFECTIOUS DISEASES OF LIVESTOCK
OBJECTIVES: 1. Determine the molecular epidemiology of bluetongue virus, vesicular stomatitis
virus, Mycobacterium bovis, and other important livestock pathogens in Colorado and exploit this
information for development of new control strategies for these diseases. 2. Develop a new generation of
DNA based vaccines, antipathogen therapies, and diagnostic techniques for viral and bacterial livestock
pathogens. 3. Apply modern molecular and quantitative techniques to identify, characterize, and control
arthropod vectors and vector-borne and parasitic diseases of livestock. 4. Characterize the immunologic
and molecular bases and identify specific genes and gene products that condition disease, disease
resistance and protection in livestock and develop new virus and molecular expression systems to
characterize relevant pathogen and host genes.
APPROACH: Molecular, immunological, and biochemical approaches will be used to elucidate the
pathogenetic mechanisms of infectious diseases of livestock and to develop new vaccines, therapies, and
diagnostics for important veterinary pathogens. This information will be exploited to develop new
control strategies for these important diseases. New technologies, such as polymerase chain reaction
amplification, randomly amplified polymorphic and mitochondrial DNA, phylogenetic analyses,
molecular epidemiologic approaches will be used to identify risks and propose management approaches
to maximize animal productivity.
PROGRESS: 2002/01 TO 2002/12
Multidrug resistant S. enterica serotype Newport isolates from the CSU Veterinary Diagnostic
Laboratory encode antibiotic resistance markers on a large, resident plasmid and some of these markers
are located within a class 1 integron. This is the first report of the occurrence of this particular class 1
integron in S. Newport isolates. Previously, this particular class 1 integron had only been reported in
other drug resistant Enterobacteriaceae, such as Klebsiella pneumoniae, Citrobacter freundii, Serratia
marcescens, and Escherichia coli. The S. Newport class 1 integron was found to encode resistance to
trimethoprim, spectinomycin/streptomycin, and sulfonamides; and contained a defective version of the
quaternary ammonium compound resistance gene. The resident plasmid in these isolates also contained
genes for tetracycline and b-lactam and cephalosporin resistance, although these genes were not
contained within the class 1 integron. The results of these studies indicate that, unlike multidrug resistant
S. typhimurium DT104 (whose antibiotic resistance is encoded within an integron located on the
chromosome), multidrug resistance of S. Newport isolates is due to genes encoded on a resident plasmid.
The significance of this finding is that these resistance markers could presumably be transferred to other
Salmonella serotypes by conjugation and emphasizes the need to understand transfer of drug resistance in
Salmonella. Range and feedlot cattle with a high intake of sulfur can develop polio-encephalomalacia
(PEM), a neurological condition of ruminants characterized by necrosis of the cerebral cortex. An
important factor in the development of PEM is the sulfur reducing capacity of the ruminal microflora.
Little is known about the microbial population(s) involved in the production of neurotoxic concentrations
of H2S. In this study, the natural ruminal ecosystem was studied by comparative 16S ribosomal RNA
analysis followed by specific analysis of sulfate-reducing bacteria using DNA extracted from rumen fluid
collected from test cattle before, during, and after transition to high sulfur water. 16S rDNA was cloned
and 50 clones were analyzed from each rumen sample with restriction enzymes. Extreme diversity was
observed both within a time point among different animals and between time points. Sulfate-reducing
bacteria (SRB) belonging to the genera Desulfovibrio and Desulfomicrobium were detected in all of the
animals. In addition, Desulfobulbus species were detected in animals during the second time point when
ruminal H2S became maximal. Reverse Southern Analysis to determine the abundance of bacterial
species in the rumen failed to reveal any particular dominant species in cattle consuming high sulfur
concentrations.
IMPACT: 2002/01 TO 2002/12
Drug resistant bacteria are becoming more of a health concern in animal products. The finding that
multidrug resistance occurs in S. enterica serotyp Newport indicates that such resistance is spreading to
several genera of bacteria. The occurrence of drug resistance in this species indicates that the resistance
may be transferred to other species of Salmonella and indicates the importance of developing a better
understanding of the transfer of drug resistance across species. It was demonstrated that the many
microbes in the rumen of cattle are associated with production of toxic levels of hydrogen sulfide.
Therefore, strategies to control complex populations of ruminal microbes, rather than a single species
will be necessary to control polioencephalomalacia in cattle.
1. Kurowski, P., Locke, A., and C. Gentry-Weeks. May 19, 2002. Characterization of integrons in
Salmonella enterica serovar Newport, Abstract A-106. In Abstracts of the 102nd General Meeting of the
American Society for Microbiology, 102nd General Meeting of the American Society for Microbiology,
Salt Lake City, UT.
2. Allen, T.E., Sherrill, K.J., Crispell, S.M., Perrott, M., Carlson, J.O., DeMartini, J.D. The Jaagsiekte
Sheep Retrovirus Envelope Gene Induces Transformation of the Avian Fibroblast Cell Line DF-1 but
Does Not Require a Conserved SH2 Binding Domain. Journal of General Virology., 83: 2733-2742
(2002)
3. M.J. Magill1, D.H. Gould1, J.J. Wagner2, N.M DuTeau1; Characterization of Ruminal Microflora
Associated With Pathologic Hydrogen Sulfide Production in Cattle Exposed to High Levels of Dietary
Sulfur. American Society for Microbiology 102nd General Meeting, May 19-23, 2002, Salt Lake City,
UT 1Colorado State University, Fort Collins, CO, 2Continental Beef Research, Lamar, CO
4. Thesis; Colorado State University: Magill, Molly Jean. Characterization of ruminal microflora
associated with pathologic hydrogen sulfide production in cattle exposed to high levels of dietary sulfur /
submitted by Molly Jean Magill. 2002.
PROJECT CONTACT:
Name: Nett, T. M.
Phone: 970-491-7051
Fax: 970-491-2250
PROJ NO: IDA01179 AGENCY: CSREES IDA
PROJ TYPE: HATCH PROJ STATUS: TERMINATED
Investigators: Zaugg, J. L.; Bulgin, M. S.; Anderson, B. C.; England, J. J.
Animal & Veterinary Science
University of Idaho
Moscow, Idaho 83843
BIOLOGY AND CONTROL OF EMERGING DISEASES SHARED BY LIVESTOCK AND
WILDLIFE
NON-TECHNICAL SUMMARY: Diseases (brucellosis, tuberculosis and scrapie) of profound
importance to the livestock industry have emerged as having actual, or potential interaction with wildlife.
The purpose of this study is to investigate key aspects of the biology and control of bovine brucellosis,
tuberculosis and scrapie emerging diseases shared by livestock and wildlife.
OBJECTIVES: 1. Determine if mule deer are experimentally susceptible to scrapie infection. 2.
Evaluate the utility of the palpebral site to test for tuberculosis in cervids. 3. Determine if Brucella
abortus RB51 vaccine, delivered orally, will stimulate an immune response in bison and elk.
APPROACH: 1. Intracerebrally inoculate mule deer fawns and domestic lambs with scrapie-infected
brain tissue. Montior for illness. Screen palpebral lymph nodes for prions at 18 and 24 months, and full
necropsy at 36 months post inoculation. 2. Inoculate elk and mule deer with Mycobacterium avium
organisms. Compare hypersensitive reactions to tuberculin intradermal inoculation made in the upper
eyelids, to those standard test sites in the cervical region. 3. Elk will be fed Brucella RB51 vaccine as a
top dressing in four, five-day series. Blood samples will be taken and evaluations conducted to determine
if, and when an immune response is achieved.
PROGRESS: 1999/07 TO 2002/06
Nothing was accomplished in this time period because we were awaiting the availability of mule deer
fawns from Fish and Game in the late spring.
IMPACT: 1999/07 TO 2002/06
The results of the investigation will have significant impact on disease management of range sheep and
wildlife management.
No publications reported this period
PROJECT CONTACT:
Name: Zaugg, J. L.
Phone: 208-454-8657
Fax: 208-454-8659
PROJ NO: 3625-32000-034-00D AGENCY: ARS 3625
PROJ TYPE: USDA INHOUSE PROJ STATUS: TERMINATED
START: 01 OCT 1997 TERM: 26 OCT 2001 FY: 2001
Investigators: Whipple D L; Waters W R; Palmer M V; Miller J M;
National Animal Disease Ctr
Ames, Iowa 50010
PATHOGENESIS, DIAGNOSIS, AND EPIDEMIOLOGY OF BOVINE TUBERCULOSIS
OBJECTIVES: Characterize interactions between various host species, such as cattle and white-tailed
deer, and Mycobacterium bovis; develop and evaluate improved tests for diagnosis of M. bovis infection
in animals; and develop improved methods for differentiation of M. bovis isolates. NEW FUND OBJ:
Identify candidate antigens that would be efficacious in a mucosal vaccine for prevention of tuberculosis
in cattle, cervids (deer), and other wildlife.
APPROACH: Animals will be experimentally challenged w/M. bovis and blood and tissue samples will
be collected at different times to determine response of host to the organisms. Bacteriologic,
histopathologic, and immunologic methods will be used to characterize host responses. Tissue samples
w/b collected from naturally infected animals to determine distribution/characteristics of lesions. A
gamma interferon assay for diagnosis of TB in deer and elk is being developed; w/b evaluated to
determine test sensitivity/specificity. Blood samples from infected and noninfected animals w/b used for
test evaluation. A method using the polumerase chain reaction w/b developed for rapid detection of M.
bovis in tissue samples. Methods for DNA fingerprinting M. bovis isolates will be improved by using
different DNA probes and enzymes. A method using PCR for direct detection and typing of M. bovis in
fresh tissue samples w/b modified for use w/formalin-fixed tissues. NADC,AmesIA:Bldg2A12,BL1-3
IBC-0193 Apprvd to 6/29/00;-0224 Apprvd to 6/3/00; -0239 Apprvd to 12/26/00
PROGRESS: 2000/10 TO 2001/09
1. What major problem or issue is being resolved and how are you resolving it? Bovine tuberculosis,
which is caused by Mycobacterium bovis, is an infectious disease that affects many species of animals as
well as human beings. Animals infected with M. bovis can shed organisms as they exhale or cough and in
various secretions including saliva, milk and urine. Elimination of animals infected with M. bovis is
important to prevent the spread of disease among animals and to human beings. The United States
initiated a program to eradicate tuberculosis from cattle in 1917 when the prevalence of disease was
approximately 5%. In general, the eradication program has been successful and today, less than 0.002%
of cattle are infected with M. bovis. However, a low prevalence of disease has persisted over the last 1015 years and it has not been possible to eradicate bovine tuberculosis from the United States using
available technology. Improved diagnostic tests and control measures are needed to detect and eliminate
the few remaining cattle and herds that have bovine tuberculosis. In addition, tuberculosis has been
detected in captive deer and elk and in wild white-tailed deer, coyotes, raccoons, bear, bobcat, opossum,
and fox. In some cases, there is epidemiological evidence to suggest that tuberculosis has been
transmitted from deer to cattle. The presence of tuberculosis in wildlife poses a serious threat to the
national eradication program. Other countries with tuberculosis in wildlife species have been unable to
eradicate the disease from the domestic livestock population. The Bovine Tuberculosis research project
at the National Animal Disease Center (NADC)is conducting research to develop a better understanding
of the interactions between various host species and M. bovis. This information will be used to develop
improved diagnostic tests and vaccines. Methods to identify and differentiate strains of M.bovis are being
developed and used to aid in epidemiological investigations of outbreaks of tuberculosis in animals. 2.
How serious is the problem? Why does it matter? Bovine tuberculosis is considered a public health
threat because human beings can become infected with M. bovis through contact with infected animals or
by ingestion of contaminated food and milk. Elimination of tuberculosis from cattle is important to
provide food and milk to the public that is free of M. bovis. Eradication of tuberculosis from wildlife is
important to prevent transmission of disease from wildlife to domestic livestock. Elimination of bovine
tuberculosis from domestic livestock also is important to maintain free trade with the many trading
partners of the United States. Trade restrictions between the United States and Canada and between
Mexico and the United States have occurred because of bovine tuberculosis in animals. 3. How does it
relate to the National Program(s) and National Component(s)? The Bovine Tuberculosis research
project is assigned to the Animal Health National Program (103) and relates to the vision of this program
to ensure animal health through improved disease detection and control. The objectives of the project are
to 1) develop and evaluate improved tests for diagnosis of tuberculosis in cattle, deer and other
species,which relates to the National Program Component on Pathogen Detection; 2) develop improved
methods for differentiation of M. bovis isolates, which relates to the National Program Component on
Epidemiology of Disease; 3) define the interactions between various host species and M. bovis, which
relates to the National Program Component on Host/Pathogen Interactions and 4) develop and evaluate
vaccines for control and prevention of tuberculosis in animals, which relates to the National Program
Component on Disease Control Strategies. 4. What were the most significant accomplishments this
past year? A. Single Most Significant Accomplishment during FY 2000 year: Improved tests for
diagnosis of tuberculosis are needed so that animals infected with M. bovis can be identified and
eliminated as a source of infection to other animals and human beings. ARS scientists at NADC
conducted experiments to examine the immune responses of animals infected with M. bovis to identify
characteristics that could be used for diagnosis of infection. We developed a rapid diagnostic test that can
be used for detection of M. bovis infection in multiple species of animals. After further validation and
approval, the test may be used for the national program to eradicate tuberculosis from animals in the
United States. B. Other Significant Accomplishment(s), if any: In order to conduct controlled studies on
tuberculosis in animals, a system to experimentally infect animals with M. bovis is needed so that they
develop signs of disease that are similar to those observed in naturally infected animals. ARS scientists at
NADC developed a method to experimentally infect white-tailed deer, cattle, and other animals with
aerosolized M. bovis. We determined that animals experimentally infected with aerosolized develop
lesions and other signs of disease that mimic those seen in naturally infected animals. M. bovis The new
method for experimentally infecting animals with M. bovis is being used for controlled studies on
tuberculosis in animals. C. Significant Accomplishments/Activities that Support Special Target
Populations: None to report. 5. Describe the major accomplishments over the life of the project
including their predicted or actual impact. Since 1998, bovine tuberculosis has been detected in 16
herds of cattle in northeast Michigan where tuberculosis is endemic in the wild white-tailed deer
population. ARS scientists at the NADC experimentally infected white-tailed deer and allowed cattle to
have access to feed that had been offered to the deer and to pens that had been soiled by the deer. We
determined that cattle can become infected with M. bovis through indirect contact with experimentally
infected white-tailed deer. These results provide evidence that cattle do not need to have direct contact
with infected white-tailed deer in order for them to develop bovine tuberculosis and helps explain how
cattle in Michigan became infected with M. bovis. ARS scientists at the NADC experimentally infected a
group of deer and monitored routes of shedding and transmission to other deer. We determined that deer
infected with M. bovis shed organisms in saliva, nasal secretions, urine and feces and that infection is
readily transmitted from experimentally challenged deer to other deer sharing the same pen. These results
explain how tuberculosis is transmitted within a population of deer and will be used to develop strategies
for control of the disease. Current surveys to determine the prevalence of tuberculosis in wild whitetailed deer are based on examination of tissues in the head to detect lesions. In a study that involved
detailed examination of the entire deer carcass, we determined that about 50% of the infected deer did
not have lesions in the head. These results indicate current methods to detect tuberculosis in wild whitetailed deer underestimate the prevalence of disease by 50% and that improved methods for detection are
needed. Supplemental feeding and baiting of white-tailed deer in the winter in Michigan has been
practiced for many years and is thought to contribute to the spread of M. bovis among deer. ARS
scientists at the NADC experimentally inoculated samples of six feeds typically used for baiting deer and
stored them for various lengths of time at different temperatures. We determined that M. bovis survives
on all feeds when frozen for at least 4 months. These results have been used by regulatory officials to
make recommendations regarding feeding and baiting of deer in Michigan. A new test for detection and
identification of M. bovis in tissue samples that are collected for microscopic examination was
developed. When animals are slaughtered, meat inspectors collect tissue samples from animals that are
suspected of having tuberculosis. Tissue samples are examined for microscopic evidence of tuberculosis
and for the presence of organisms. Stains used to detect M. bovis in a tissue sample also stain other
organisms so that it is not possible to identify the organism in the sample. The new test detects a specific
piece of DNA that is present only in organisms that cause tuberculosis. The new test permits more
accurate and rapid identification of animals with tuberculosis than was previously possible. The test is
used extensively at the request of state and federal regulatory officials to confirm suspected cases of
tuberculosis in animals. We adapted and standardized methods for differentiation of strains of M. bovis.
Differences among various strains of M. bovis can be identified by using specific genetic markers. Using
these markers, it is possible to determine if different animals are infected with a common strain or
different strains of M. bovis. This information is used by epidemiologists to determine possible sources
of infection in outbreaks of tuberculosis in animals. 6. What do you expect to accomplish, year by
year, over the next 3 years? FY 2002: 1) Further characterize the disease produced when cattle and deer
are experimentally challenged with aerosolized M. bovis. 2) Determine if M. bovis can be transmitted
from experimentally infected raccoons to uninfected penmates. 3) Determine routes of transmission of
M. bovis from does to fawns. 4) Begin to characterize immune response of white-tailed deer to M. bovis.
5) Determine the sensitivity and specificity of a new diagnostic test 6) Continue research to develop
improved methods for differentiation of M. bovis isolates. FY 2003: 1) Further characterize the
progression of disease and immune responses of white-tailed deer infected with M. bovis. 2) Continue
research to determine the sensitivity and specificity of a new diagnostic test. 3) Identify potential
vaccines that can be used for prevention and control of tuberculosis in wildlife and domestic animals. 4)
Continue research to develop improved methods for differentiation of M. bovis isolates FY 2004: 1)
Determine the safety and effectiveness of candidate vaccines. 2) Continue research to develop and
evaluate improved diagnostic tests. 7. What science and/or technologies have been transferred and to
whom? When is the science and/or technology likely to become available to the end user (industry,
farmer, other scientists)? What are the constraints if known, to the adoption & durability of the
technology product? ARS scientists assigned to the Bovine Tuberculosis Research Project routinely
presented research findings to scientists, state and federal action agencies, and industry groups. In some
cases, results of research conducted by ARS scientists are used as the basis for regulatory action. ARS
scientists received invitations to present results of research to specfic groups, such as the Michigan
Department of Natural Resources, because of the direct impact that the research findings have on
recommendations of the group. ARS scientists are members of several organizations, committees, and
working groups and provide scientific expertise on a broad range of issues relating to bovine
tuberculosis. A patent has been approved for a new test that was developed by ARS scientists for
diagnosis of tuberculosis. (Invention Report No. 0152.01 "Diagnosis of Tuberculosis Infection Through
Analysis of Nitrite Production of Leukocytes Stimulated with Mycobacterial Antigens") 8. List your
most important publications in the popular press (no abstracts) and presentations to non-scientific
organizations and articles written about your work Presented results of research on CMU Public
Television program "Bovine Tuberculosis in Michigan: The Controversy," Spring, 2001. Presented talks
entitled "Use of the gamma-interferon assay for diagnosis of tuberculosis in cattle," "Naturally occurring
tuberculosis in white-tailed deer" and "Raccoons and Mycobacterium bovis: Maintenance or Spill-Over
Host" to participants of Bovine Tuberculosis in Michigan, conference 2001, March 5- 6, 2001, Lansing,
Michigan. Registered participants of the conference included state and federal animal health officials,
departments of natural resource and community health, livestock industry groups, private land owners,
hunt clubs, state legislators, congressional representatives, and members of the press. Presented talk
entitled "Emergence of tuberculosis in wildlife: Impact on animal agriculture and public health" at
Beltsville Symposium "Healthy Animals 2000", September, 2000.
1. Palmer, M.V., Whipple, D.L., Waters, WR. Experimental deer to deer transmission of Mycobacterium
bovis. American Journal of Veterinary Research. 2001. v. 62. p. 692-696.
2. Palmer, M.V., Whipple, D.L. Deer to deer transmission of Mycobacterium bovis. 43rd annual meeting
of the American Association of Veterinary Laboratory Diagnosticians. 2000. p. 22.
3. Waters, W.R., Palmer, M.V., Pesch, B.A., Olsen, S.C., Wannemuehler, M.J., Whipple, D.L. MHC
class II-restricted, CD4+ T cell proliferative responses of peripheral blood mononuclear cells from
Mycobacterium bovis-infected white-tailed deer. Veterinary Immunology and Immunopathology. 2000.
v. 76 p. 215-229.
4. Waters, W.R., Palmer, M.V., Pesch, B.A., Olsen, S.C., Wannemuehler, M.J., Whipple, D.L.
Lymphocyte subset proliferative responses of Mycobacterium bovis-infected cattle to purified protein
derivative. Veterinary Immunology and Immunopathology. 2000. v. 77. p. 257-273.
5. Waters, W.R., Palmer, M.V., Pesch, B.A., Olsen, S.C., Wannemuehler, M.J., Whipple, D.L.
Lymphocyte subset proliferative responses of Mycobacterium bovis-infected cattle: gd TCR+ and CD4+
cells are the predominant cells responding. The Great Lakes International Imaging and Flow Cytometry
Association Meeting, Detroit, MI 2000. Abstract No. 14.
6. Waters, W.R., Palmer, M.V., Whipple, D.L. Lymphocyte subset proliferative responses of tuberculous
cattle and white-tailed deer to Mycobacterium bovis purified protein derivative. In: Proceedings of the
Keystone Symposia entitled Molecular and Cellular Aspects of Tuberuclosis Research in the Post
Genome Era, Taos, NM. 2001. Abstract p. 98.
7. Whipple, D.L., Palmer, M.V., Slaughter, R.E., Jones, S.L. Comparison of purified protein derivatives
and effect of skin testing on results of a commercial gamma interferon assay for diagnosis of tuberculosis
in cattle. Journal of Veterinary Diagnostic Investigation. 2001. v. 13. p. 117-122.
PROJ NO: 3625-32000-034-03R AGENCY: ARS 3625
PROJ TYPE: USDA INHOUSE PROJ STATUS: TERMINATED
START: 01 DEC 2000 TERM: 31 OCT 2001 FY: 2001
Investigators: Whipple D L; Waters W R; Palmer M V
Ames, Iowa 50010
TRANSMISSION AND DIAGNOSIS OF MYCOBACTERIUM BOVIS INFECTION IN ANIMALS
OBJECTIVES: Transmission of Mycobacterium bovis deer to cattle by exposure to feed contaminated
by tuberculous white-tailed deer; in utero transmission of M. bovis in white-tailed deer; milk containing
M. bovis as a source of infection for white-tailed deer fawns; and evaluation of the gamma interferon
assay for diagnosis of bovine tuberculosis.
APPROACH: Deer will be experimentally challenged with M. bovis and offered excess feed in a
portable bunk. After deer have eaten, the bunk with feed will be moved to a pen with cattle. This will be
repeated daily for up to 4 weeks. Cattle will be monitored for infection using standard diagnostic tests.
Pregnant white-tailed deer will be challenged with M. bovis. About 1 week before due date, fawns will be
delivered by cesarean and samples will be collected for isolation of M. bovis. Bottle-raised fawns will be
fed goat milk replacer that contains different doses of M. bovis on 5 consecutive days. Fawns will be
monitored for immune responses and shedding of organisms for 6 months. Animals will be necropsied
and samples will be collected to evaluate distribution of lesions and organisms. The gamma interferon
assay will be evaluated by comparing of the assay with those of skin testing, culture and histopathology.
PROGRESS: 2000/10 TO 2001/09
1. What major problem or issue is being resolved and how are you resolving it? 2. How serious is
the problem? Why does it matter? 3. How does it relate to the National Program(s) and National
Component(s)? 4. What were the most significant accomplishments this past year? D. Progress
Report This report serves to document research conducted under a reimbursable agreement between ARS
and the USDA, Animal and Plant Health Inspection Service. Additional details can be found in the report
for the parent project, 3625-32000-034-00 D, Pathogenesis, diagnosis, and epidemiology of bovine
tuberculosis. Tuberculosis caused by Mycobacterium bovis has been detected in free-ranging white-tailed
deer in northeast Michigan. This is the first wildlife reservoir of tuberculosis identified in the United
States. Since 1998, tuberculosis has been diagnosed in 16 herds of cattle in the affected region of
Michigan and white-tailed deer have been identified as the likely source of infection. Because little is
known about the transmision of infection from white-tailed deer to other animals, we initiated the
following research projects during FY 2001: 1) Transmission of M. bovis from white-tailed deer to cattle
by exposure to feed contaminated by tuberculous deer; 2) maternal transmission of M. bovis in whitetailed deer; and 3) milk containing M. bovis as a source of infection for white-tailed deer. We are also
conducting research to examine the use of the gamma interferon assay for diagnosis of tuberculosis in
cattle. All of these projects are currently underway and results will be reported during FY 2002. 5.
No publications reported this period.
PROJ NO: 3625-32000-063-00D AGENCY: ARS 3625
PROJ TYPE: USDA INHOUSE PROJ STATUS: NEW
Investigators: Whipple D L; Palmer M V; Waters W R
Ames, Iowa 50010
DIAGNOSIS AND CONTROL OF TUBERCULOSIS IN LIVESTOCK AND WILDLIFE
OBJECTIVES: Develop and evaluate improved tests for diagnosis of Mycobacterium bovis infection in
different animal species; Develop improved methods for differentiation of M. bovis isolates; Characterize
M. bovis infection in domestic livestock and wildlife.
APPROACH: Sensitivity and specificity of tests for detection of M. bovis infection in live animals will
be determined. We will determine if new antigens can be used to improve skin tests and in-vitro
diagnostic tests. Improved PCR assays for direct detection of M. bovis in various specimens will be
developed by modification of existing tests. Improved methods for isolation of M. bovis from various
samples will be developed by changing processing methods and decontaminants. Improved methods for
DNA fingerprinting of M. bovis isolates will be developed by adapting published methods. Animals will
be exposed to M. bovis by different routes and clinical signs, immune system parameters, and lesion
distribution will be monitored. Routes of transmission of M. bovis from infected animals to uninfected
animals will be assessed by periodic sampling of oral and nasal secretions, urine, and feces. BSL-1-3-N;
Certified through April 10, 2002.
PROJ NO: 3625-32000-063-01R AGENCY: ARS 3625
PROJ TYPE: USDA INHOUSE PROJ STATUS: NEW
START: 01 FEB 2002 TERM: 30 SEP 2003 FY: 2002
Investigators: Whipple D L; Waters W R; Palmer M V
Agricultural Research Service
Ames, Iowa 50010
DIAGNOSIS AND PATHOGENESIS OF TUBERCULOSIS IN ANIMALS
OBJECTIVES: Evaluate immune responses of reindeer sensitized to Mycobacterium bovis BCG;
Evaluate immune responses and diagnostic tests in reindeer experimentally infected with pathogenic M.
bovis; Evaluate lesions in reindeer experimentally infected with M. bovis; Evaluate immune respones and
lesion development in white-tailed deer experimentally infected with M. bovis.
APPROACH: A group of reindeer will be sensitized with M. bovis BCG and matched with a group of
non-sensitized control animals. Blood samples will be collected and skin tests will be conducted
periodically throughout the study period. Various immune function assays will be conducted to monitor
immune responses. In the second study, reindeer will be challenged with virulent M. bovis. Blood
samples will be collected and skin tests will be conducted similar to the first study. In addition, tissue
samples will be collected at various times to characterize the progression of disease in reindeer. Whitetailed deer will be experimentally challenged with M. bovis using two routes of inoculation and three
dosages. Immune responses will be monitored by evaluating blood collected at various times and
conducting skin tests. Lesions will be characterized at the conclusion of the study. BSL-1-3-N; Certified
through April 10, 2002.
PROJ NO: LAV-1856-SVM AGENCY: CSVM LA.V
PROJ TYPE: STATE PROJ STATUS: EXTENDED
START: 01 JUN 1995 TERM: 30 JUN 2003 FY: 2002
Investigator: Groves, M. G.
Pathobiological Sciences
Louisiana State University
Baton Rouge, Louisiana 70893
SCREENING OF COMPOUNDS FOR ANTI-TUBERCULOSIS ACTIVITY
OBJECTIVES: Numerous novel synthetic compounds and natural products made available from the
repositories of the NCI will be evaluated for anti-tuberculosis activity.
APPROACH: Compounds are screened against M. tuberculosis H37Rv and single drug-resistant strains
of M. tuberculosis by evaluation of minimum inhibtory concentration, minimum bactericidal
concentration and post-antibiotic effect, using the BACTEC 460 radiorespirometric system. Promising
compounds are subsequently tested in tissue culture for cytotoxicity and ultimately in infected mice.
Highly efficacious compounds may ultimately be developed as animal drugs, targeting tuberculosis in
production animal medicine.
PROGRESS: 2002/01 TO 2002/12
At least one-third of the world population is infected with Mycobacterium tuberculosis (Mtb) with an
esitmated 3 million deaths per year. Our project is an urgent response to the need to replace our best antiTB drugs which have been rendered ineffective by the widespread prevalence of multiple drug resistance
(MDR) seen in the widespread increase of TB in association with the AIDS pandemic. In the largest TB
drug discovery program in the world this past year we have screened approximately 10,000 compounds
of synthetic or natural origin for anti-tuberculosis (TB) activity, bringing the total tested in 5 years to
more than 68,000.This program represents a unique cooperation between government agencies
(NIAID,NCI, FDA), the pharmaceutical industry and international sources to coordinate and funnel test
compounds for testing in the special facilities of the LSU VETMED Biocontainment Level-3 laboratory.
Compounds are run through a multi-level screening program. In the primary test all compounds are
tested for anti-TB efficacy in an in vitro culture screening phase to establish minimum inhibitory
concentrations (MIC). Effective compounds are tested for potential toxicity in a tissue culture
cytotoxicity system. Finally, effective (Low MIC) and non-cytotoxic compounds are tested for efficacy
against intracellular Mtb in infected cell cultures of mononuclear phagocytes the preferred host cell of
the TB bacillus.Candidate compounds that pass through all 3 test phases are referred to another lab for
testing in animal models of TB. Another 10,000 compounds are being tested in a 1 year extension of this
project.
IMPACT: 2002/01 TO 2002/12
Failure to control the spread of MDR tuberculosis will result in a public health disaster for developed as
well as developing countries. The development of new drugs is essential to control TB.
PROJ NO: LAV-1967-SVM AGENCY: CSVM LA.V
PROJ TYPE: STATE PROJ STATUS: EXTENDED
START: 01 JUN 1996 TERM: 30 JUN 2003 FY: 2002
Investigator: Klei, T. R.
Pathobiological Sciences
Louisiana State University
Baton Rouge, Louisiana 70893
MAINTENANCE OF AN ARMADILLO COLONY FOR LEPROSY RESEARCH
OBJECTIVES: The nine-banded armadillo is a permissive host for leprosy and is essential for
providing enormous numbers of Mycobacterium leprae as a research resource. The production of M.
leprae allows for the purification and production of skin test antigens for detecting new cases of clinical
disease. The objective of this project is to identify, condition and screen armadillos to determine their
suitability for in vivo propogation of M. leprae.
APPROACH: Armadillos will be captured in the wild from areas non-enzootic for armadillo leprosy.
Animals' suitability for inclusion in the colony will be determined by normal hematology, serology and
fecal exams, freedom from Mycobacterium sp infections, and negative for M. leprae based on antibody
titer and PCR. An assisted breeding program will be developed for captive armadillos.
PROGRESS: 2002/01 TO 2002/12
Leprosy is a chronic debilitating infectious disease caused by Mycobacterium leprae. Though significant
progress has been made in its treatment using multiple drug regimes, more than 850,000 new cases
occurred globally in 1999. Thus technologies are needed to interrupt the transmission of leprosy and
eliminate it as a public health problem. In addition, with recognition of persistence of leprosy in human
populations.there has been new appreciation for the importance of detection of sub-clinical infection and
occult reservoirs. A major obstacle to these lines of investigation is the fact that the leprosy bacillus
cannot be cultrured in vitro. However, M. leprae can be propagated in the tissues of the infected nine
banded armadillo, the only animal host known to be highly susceptible to leprosy. Through contact with
NIAID we maintain a colony of more than 100 M. leprae-infected armadillos to provide the scientific
community with its principal source of Mycobacterium leprae and associated research reagents. Several
different strains of M. leprae are maintained and we continue a quality assurance testing program on
these tissues and are refining our protocols with new research on aspects of inoculum control, animal
selection, susceptibility to leprosy and testing and management of experimental infections. The highly
bacilliferous tissues produced are shared principally with another contractor at Colorado State University
and secondarily with other investigators around the world.
IMPACT: 2002/01 TO 2002/12
The leprosy bacillus cannot be cultured in vitro. We are the world's sole source of sufficient batches of
armadillo-derived M. leprae for development of skin test antigens, a potential leprosy vaccine and
immunologically specific antigens required to study the basic pathogenesis of this disease.
PROJECT CONTACT:
Name: Klei, T. R.
Phone: 225-578-9903
Fax: 225-578-9916
PROJ NO: MICL01999 AGENCY: CSREES MICL
PROJ TYPE: HATCH PROJ STATUS: NEW
START: 01 SEP 2001 TERM: 31 AUG 2006 FY: 2002
Investigators: Bolin, S. R.; Maes, R.; Grooms, D.; Mullaney, T.; Bolin, C.; Kiupel, M.; Kaneene, J.
Pathobiology & Diagnostic Investigation
Michigan State University
East Lansing, Michigan 48824
DIAGNOSIS AND EPIZOOTIOLOGY OF EMERGING INFECTIOUS DISEASES OF
LIVESTOCK AND POULTRY
NON-TECHNICAL SUMMARY: Critical information is needed to detect, diagnose, and predict
transmission of newly emerged infectious disease. This project will obtain information on pathogenesis
and transmission of newly emerged infectious diseases of livestock and poultry.
OBJECTIVES: Objective 1: Develop methods for diagnosis of emerging and reemerging diseases of
livestock and poultry. The infectious agents targeted for research include bovine enteric calicivirus
(BECV), Michigan rabbit calicivirus (MRCV), and porcine circovirus (PCV). Objective 2.: Determine
pathogenesis, modes of transmission, and distribution of emerging diseases of livestock and poultry. The
diseases targeted for research are postweaning multisystemic wasting syndrome of swine, neonatal
diarrhea of cattle, and Michigan rabbit hepatitis/hemorrhagic disease. Objective 3: Determine effects of
sample handling on laboratory test s for diagnosis of bovine tuberculosis.
APPROACH: A) Derivation of cell lines. Primary cell lines will be derived from embryonic tissues of
several species and tested for use in virus isolation. The embryos will be obtained from pregnant animals
that are brought to the Animal Health Diagnostic Laboratory for necropsy examination. Either filtered
fecal samples known to contain BECV, or liver homogenates know to contain MRCV, will be used to
inoculate the cells. Convalescent antiserum and polymerase chain reaction (PCR) tests will be used to
detect viral replication in cells. B) Expression of viral proteins. Viral proteins produced in eukaryotic
and/or prokaryotic expression systems will be used for detection of antibody against viruses that do not
grow in cell culture. The baculovirus expression system has proven very useful for expression of foreign
proteins and will be used extensively for production of recombinant protein. C) Nucleic acid based
diagnostic tests including PCR tests and in situ hybridization will be developed for newly emerged
diseases. D) Standard procedures for determining pathogenetic mechanisms, modes of disease
transmission, and disease distribution will be applied to newly emeerged diseases such as postweaning
multisystemic wasting syndrome and Michigan rabbit viral heaptitis. E) Determine the effects of sample
handling on laboratory tests for bovine tuberculosis. The gamma interferon whole blood test for bovine
TB requires viable and functional white blood cells. Blood will be subjected to conditions that affect
viability white blood cells or function of white blood cells. Pokeweed mitogen will be used as a positive
control to assess effects of harsh conditions on white blood cell function.
PROGRESS: 2002/01 TO 2002/12
In January of 2001, an outbreak of fatal disease occured in a rabbitry in Michigan. A calicivirus was
detected in tissue emulsions using negative staining and transmission electron microscopy. The nucleic
acid sequence for the virus has been derived and it indicates a new group of rabbit caliciviruses has been
identified. The virus did not replicate in cell culture; therefore, the gene encoding the capsid protein for
that virus was cloned into a baculovirus expression system for production of intracellular antigen in
cultured insect cells. This has allowed development of a diagnostic test for detection of antibody against
the calicivirus in rabbit serum. The whole blood gamma interferon test for bovine tuberculosis, a reemerging disease in Michigan, was recently approved in the U.S. for use as an ancillary diagnostic
procedure. During 2002, 30 cattle were sensitized with antigen from Mycobacterium bovis to evaluate
effects of sample handling on performance of the gamma interferon test. Optimal holding and transport
temperature for blood used in the gamma interferon test was determined to be between 4 and 15 degrees
celsius. West Nile Virus (WNV) emerged in Michigan in 2001 with minimal impact on human or animal
health, other than death of several crows. However, in 2002, there were numerous fatal cases of WNV
infection in humans and in horses. Fatality rates also were high in several avian species in zoological
collections in Michigan. Equipment has been obtained and facilities modified to allow serological
surveys for WNV acitivity in 2003.
IMPACT: 2002/01 TO 2002/12
The development of a diagnostic test for rabbit calicivirus has allowed screening of rabbits for viral
infection before purchase for research purposes. Determining the effects of sample handling, especially
holding and transport temperature for blood, has been reported to the Tuberculosis Committee of the U.S.
Animal Health Association. Blood obtained as part of the tuberculosis control program in Michigan is
now held between 4 and 15 degrees celsius. This has had a beneficial impact on testing cattle for
tuberculosis.
PROJECT CONTACT:
Name: Bolin, S. R.
Phone: 517-432-9926
Fax: 517-353-4426
PROJ NO: MICL07645 AGENCY: CSREES MICL
PROJ TYPE: SPECIAL GRANT PROJ STATUS: TERMINATED
CONTRACT/GRANT/AGREEMENT NO: 00-34427-8853 PROPOSAL NO: 2000-03132
START: 01 JUN 2000 TERM: 31 MAY 2002 FY: 2002 GRANT YR: 2000
GRANT AMT: $159,035
Investigator: Kaneene, J. B.; Fitzgerald, S.; Wolf, C.
Population Medicine Center
Michigan State University
East Lansing, Michigan 48824
EPIDEMIOLOGY AND RISK ANALYSIS OF MYCOBACERIUM BOVIS IN WILD AND
DOMESTIC ANIMALS IN MICHIGAN
NON-TECHNICAL SUMMARY: Wild white-tailed deer in northeastern Michigan have developed a
sustained bovine tuberculosis infection, which poses health threats for other wildlife, livestock, and
human beings. Research on how the disease became established in deer, and how the disease is being
passed from deer to other animals, is needed by state and federal agencies for the development of
programs to eradicate this disease. The research is divided into three projects - epidemiological studies,
an experimental study, and a risk analysis for bovine TB in northeastern Michigan using information
from the first two projects. The first project, epidemiological studies, seeks to find the relationship
between supplemental feeding and TB in deer; the second study looks to see if TB contamination by
infected deer can be found in the environment; the third looks at other wildlife to see if they can carry TB
infections; and the fourth is an epidemiological study to look at conditions that promote the spread of TB.
The second project experimentally tests whether common pigeons can become infected with TB and
whether they can spread the infection over large areas. The third project, the risk analysis, will develop
mathematical models to describe and predict the spread of TB from deer to cattle and humans.
OBJECTIVES: The research will consist of three integrated projects. Project 1: Epidemiological study
of Mycobacterium bovis in wild and domestic animals - Hypothesis: The spatial distribution of TB
occurrence in wild white-tailed deer is associated with the spatial distribution of supplemental feeding,
physical landscape factors, and location-specific human activity. Specific Aims: A. Determine the spatial
relationships in the transmission of bovine TB in white-tailed deer, relating to supplemental feeding
habits, factors in the physical landscape such as land use and land cover, and location-specific human
activity. B. Determine the survivability of M. bovis in the environment (in feces, feeds, water, soils, and
other substrates) C. Determine if there are other wild or domestic hosts for M. bovis transmission through
epidemiologic studies of naturally infected hosts D. Determine the factors that influence the transmission
of M. bovis within and across species, both captive/domesticated (deer, cattle, sheep, goats, dogs, cats)
and wild (deer, elk, coyote, raccoons, opossums, mustelids, bear, bobcats) Project 2: Experimental
inoculation of M. bovis into Pigeons - Hypothesis: Pigeons (Columba livia) are not highly susceptible to
M. bovis infection by oral inoculation, and will not shed the organism and contribute to the spread of
tuberculosis between wild and domestic mammals. Specific Aims: A. Study the relative susceptibility of
pigeons inoculated with M. bovis of deer-origin by oral and intraperitoneal routes B. Attempt to isolate
M. bovis from inoculated pigeons through fecal culture at multiple times post-inoculation, and from
various organ tissues at multiple times post-inoculation. C. Evaluate organ tissues microscopically at
multiple times post-inoculation, to understand the pathogenesis of M. bovis infection in pigeons. D.
Compare experimental results on pigeons with previous studies conducted on crows and starlings. Project
3: Risk analysis of bovine TB for surveillance and control programs - Hypothesis: Risk analysis models
for M. bovis infection from wildlife sources to livestock and humans will be generated. Specific Aims:
A. Develop a risk analysis model of M. bovis infection in cattle and other domestic livestock, captive
cervids, and humans in Michigan. B. Capture spatial and dynamic aspects of disease through wildlife and
livestock populations. C. Use epidemiological parameters from Project 1 to parameterize the risk model.
APPROACH: Project 1: Specific Aim A: A retrospective epidemiological study will be conducted,
examining the association between M. bovis and various factors, including data on supplemental feeding,
physical landscape factors, and deer. Specific Aim B: Environmental samples, including soils, feeds,
water sources, and fecal material, will be taken from deer feeding sites identified in Specific Aim A.
Sample materials will be collected and shipped to NVSL for bacterial isolation, identification, and
typing. Specific Aim C: A cross-sectional study using information from wildlife surveillance will be used
to identify different species with bovine TB. Necropsies will be conducted when possible, tissues will be
examined grossly, and selected tissues will be harvested for bacterial isolation and routine histopathology
and acid-fast staining. The presence of M. bovis will be confirmed through culture and PCR analysis of
tissues collected at necropsy by the NVSL. Routes of infection and shedding will be assessed based on
necropsy results. Specific Aim D: A retrospective epidemiological analysis will be conducted by
examining the association between the transmission of M. bovis and various risk factors, including M.
bovis prevalence in deer, supplemental feeding, and physical landscape factors. Project 2: M. bovis from
Michigan will be propagated for use as an inoculum. Pigeons will be inoculated with by oral gavage or
intraperitoneal inoculation. A second room will contain non-inoculated control birds. All birds will have
fecal cultures performed pre-inoculation and on days 1, 30, 60 and 90 days. Oral-inoculated birds and
control birds will have additional fecal cultures performed on days 2 and 3. Body weights will be
recorded at days 0, 15, 30, 45, 60, 75, and 90. Groups of two oral-inoculated birds, two IP-inoculated
birds, and two control birds will be humanely euthanized by intravenous pentobarbital on days 30, 60 and
90 pi. At necropsy, total body weights, liver, lung and spleen weights will be recorded; all tissues
examined grossly; and selected tissues will be harvested for mycobacterial isolation and formalin-fixed
for routine histopathology and acid-fast staining. Attempts will be made to isolate M. bovis at 30, 60, and
90 days post-inoculation, from fecal culture and various organ tissues. Organ tissues will be evaluated
microscopically at 30, 60, and 90 days post-inoculation. Project 3: Risk analysis of bovine TB for
surveillance and control programs Risk assessment: A prospective stochastic simulation model will be
developed to estimate the risk of a dairy or beef cattle herd developing TB infection, utilizing cattle herdrelated factors, deer-related factors, and other geographic factors. Results from the risk assessment model
will be forwarded to federal and state agencies, which can use this information to improve TB
eradication programs, and extension which can disseminate this information to the public. The results
will also be used in a proposed farm-level risk management model which will interface with the risk
simulation model.
PROGRESS: 2000/06 TO 2002/05
Project 1: Epidemiological study of M. bovis in wild and domestic animals Specific aims: determine 1)
spatial relationships of bovine TB to deer feeding, environmental conditions, and location-specific
human activity; 2) environmental survivability of M. bovis; 3) conduct studies of naturally infected hosts;
4) determine factors that influence the transmission of M. bovis in domestic and wild animals. A study
was conducted to examine the association between TB in deer and location, environment, and
supplemental feeding. Spatial clusters of TB were seen, and associations between risk factors and TB
prevalence were found. Preliminary results have been presented at conferences, and final results are
being prepared for submission to a refereed journal. Environmental samples (soil, feed, water, feces)
collected at feeding sites and TB-positive farms were tested for the M. bovis by the National Veterinary
Services Laboratories: 200+ samples were tested for and none yielded M. bovis. The lag time from
sample collection to processing may have affected our ability to recover M. bovis. Data on other wildlife
species from TB surveillance were reported (Bruning-Fann et al., 2001). Results of an epidemiological
study of a cat with M. bovis will be published (Kaneene et al., 2002b). Cats and other wildlife species
may contract TB through consumption of infected deer carcasses. Project 2: Experimental inoculation of
M. bovis into pigeons Specific aims: 1) study the susceptibility of pigeons inoculated with M. bovis by
oral and intraperitoneal routes; 2) isolate M. bovis from inoculated pigeons from feces and various organ
tissues; 3) evaluate organ tissues microscopically to understand the pathogenesis of M. bovis infection in
pigeons; 4) compare results on pigeons with previous studies on crows and starlings. 12 pigeons
inoculated with M. bovis (6 by oral gavage and 6 by intratracheal injection) and 6 control birds were in
the study. Two birds shed M. bovis 1 day post-inoculation and 0 were shedding at 30 days. One
intratracheally-inoculated bird developed granulomatous pneumonia with acid-fast bacilli, and tissues
were culture-positive for M. bovis. Pigeons can passively shed M. bovis in feces following inoculation.
Pigeons appear refractory to oral infection, but intratracheal inoculation may lead to active disseminated
infection. Results have been prepared for publication (Zwick et al., 2002). Project 3: Risk analysis of
bovine TB for surveillance and control programs Specific aims: 1) develop a risk analysis model of M.
bovis in Michigan livestock; 2) capture dynamic spatial aspects of disease in wildlife and livestock; 3)
use results from Project 1 to parameterize the risk model. An epidemiological study of M. bovis in cervid
ranches was conducted and has been published (Kaneene et al., 2002a). A case-control study of cattle
herds with M. bovis was done to identify risk factors for inclusion in the risk model, and results of the
study have been accepted for publication (Kaneene et al., 2002c). The risk analysis model has been
developed, and a stochastic simulation model to predict herd risk for TB based on management practices
is being developed.
IMPACT: 2000/06 TO 2002/05
Results of this project show that, in wildlife, supplemental feeding and the presence of specific deer
habitats were associated with levels of bovine tuberculosis in the deer population, TB-infected deer were
the source of infection for other wild animals, including domestic cats, and pigeons are capable of
shedding M. bovis after being experimentally infected. Livestock farmers can reduce the chances of their
herds becoming TB-infected by using practices that keep wildlife away from cattle and feed, such as
maintaining good fencing and keeping feed and water away from wildlife.
1. Bruning-Fann, C.S., Schmitt, S.M., Fitzgerald, S.D., Fierke, J.S., Friedrich, P.D., Kaneene, J.B.,
Clarke, K.A., Butler, K.L., Payeur, J.B., Whipple, D.L., Cooley, T.M., Miller, J.M., and D.P. Muzo.
2001. Bovine Tuberculosis in Free-ranging Carnivores from Michigan. J. Wildlife Dis. 37(1): 58-64.
2. Butler, K.L., Fitzgerald, S.D., Berry, D., Church, S., Reed, W.M., and J.B. Kaneene. 2001.
Experimental Inoculation of European Starlings (Sturnus vulgaris) and American Crows (Corvus
brachyrhynchos) with Mycobacterium bovis. Avian Dis. 45:709-718.
3. Kaneene, J.B., VanderKlok, M., Bruning-Fann, C.S., Palmer, M.V., Whipple, D.L., Schmitt, S.M., and
R. Miller. 2002a. Prevalence of Mycobacterium bovis infection in cervids on privately-owned ranches. J
Am Vet Med Assoc. 220(5):656-659.
4. Kaneene, J.B., Bruning-Fann, C.S., Granger, L.M., Miller, R., and B.A. Porter-Spalding. 2002c.
Environmental and management factors associated with bovine tuberculosis on Michigan cattle farms. J
Am Vet Med Assoc. (in press).
5. Kaneene, J.B., Bruning-Fann, C., Dunn, J., Mullaney, T.P., Berry, D., Massey, J., Thoen, C.O.,
Halstead, S., and K. Schwartz. 2002b. An Epidemiological Investigation of Bovine Tuberculosis in a
Cattery. Am J Vet Res. (in press).
6. Miller, R., Kaneene, J.B., Fitzgerald, S.D., Schmitt, S.M. Evaluation of the Influence of Supplemental
Feeding of White-Tailed Deer (Odocoileus virginianus) on the Prevalence of Bovine Tuberculosis in the
Michigan Wild Deer Population. J Wildlife Dis. (in press, 2001).
7. Butler, K.L., Fitzgerald, S.D., Berry, D.E., Church, S.V., Reed, W.M., Sikarskie, J.G., and J.B.
Kaneene. 2002. Experimental Inoculation of North American Opossums (Didelphis virginiana) with
Mycobacterium bovis. J. Wildl. Dis. (in press).
8. O'Brien, D.J., Schmitt, S.M., Fierke, J.S., Hogle, S.A., Winterstein, S.R., Cooley, T.M., Moritz, W.E.,
Butler, K.L., Fitzgerald, S.D., Berry, D.E., and J.B. Kaneene. 2001. Some epidemiologic aspects of
Mycobacterium bovis in free-ranging white-tailed deer, Michigan, USA, 1995-2000. Prev Vet Med. (in
press).
9. Zwick, L.S., Fitzgerald, S.D., Berry, D., Church, S., Kaneene, J.B., Reed, W.M. Experimental
inoculation of pigeons (Columba livia) with Mycobacterium bovis. 2002. Avian Dis. (in preparation).
PROJECT CONTACT:
Name: Kaneene, J. B.
Phone: 517-353-5941
Fax: 517-432-0976
PROJ NO: MO-VMRB0514 AGENCY: CSREES MO.
PROJ TYPE: HATCH PROJ STATUS: TERMINATED MULTISTATE PROJ NO: NC-107
START: 01 OCT 1996 TERM: 30 SEP 2001 FY: 2001
Investigator: Estes, D. M.
Veterinary Medicine
University of Missouri
Columbia, Missouri 65211
BOVINE RESPIRATORY DISEASE: RISK FACTORS, PATHOGENS, DIAGNOSIS AND
MANAGEMENT
OBJECTIVES: Define molecular mechanisms of pathogenesis of bovine respiratory tract disease.
APPROACH: Our studies are designed to delineate in vivo in the SCID-bo mouse, the contribution of
helper and cytotoxic T cells and the cytokines they produce to elimination or control of replication of the
model organism, Mycobacterium bovis. Our working hypothesis to be tested in this proposal is that
resistance to or control of infection will correlate with the development of a TH1-like response (IFN- and
IL-12 produced and not IL-4 or IL-10) in vivo which will augment both macrophage
activation/microbicidal activities and intracellular killing of M. bovis by cytotoxic (either CD4 or CD8+)
cells. We propose that in the later stages of disease, IFN- is key to maintenance and enhancement of
cytotoxic T cell activity (CTL) which is required to eliminate the organism from persistently infected
cells. Second, we will focus on the transcriptional control and kinetics of expression of cytokines known
to function in this capacity in vivo in the manipulated (cell subset-depleted) or unmanipulated SCID-bo
mouse during the innate (acute disease; first 20-30 days) and acquired response (chronic disease, >30
days). We will examine organ and local cytokine mRNA expression in vivo over time for those
modulators known to serve as "early" differentiation factors for TH0 lymphocytes to potentially either
TH1 or TH2-type, specifically IL-4, IL-10, IL12-p40 and IFN- .--All studies involving cytokine
expression will be correlated with bacterial.
PROGRESS: 1996/10 TO 2001/09
Our laboratory is evaluating DNA vaccine approaches to induction of naive and memory cytolytic T cell
(CTL) to subunit antigens. This project is currently evaluating responses to an antigenic target from
Mycobacterium bovis, the causative agent of bovine type tuberculosis. One potential readout following
vaccination with costimulatory molecule(s) and antigen is to evaluate antigen specific CTL lines for
effector capabilities following DNA immunization under the various protocols. Thus, the first sets of
experiments we performed in the chimeric mouse model were proof of concept experiments related to the
practical limitations of obtaining sufficient numbers of cells of the appropriate specificity to generate T
cell lines or clones. We have successfully generated antigen-specific T cell lines from immunized
animals.
IMPACT: 1996/10 TO 2001/09
DNA vaccines are an ideal platform for delivering antigens into the class I pathway and thus eliciting
potent CTL responses. Species differences in responsiveness to CpG motifs and the resulting
inflammatory response suggest the potential need for added costimulation. This series of studies have
examined this requirement in part and set the stage for continuing studies in large animals.
1. Zhang, Y., L.K.M. Shoda, D.M. Estes, G.H. Palmer and W.C. Brown. 2001. Activation of B
lymphocytes, monocytes and macrophages of cattle by a CpG oligoedeoxynucleotide (ODN 2059)
containing the GTCGTT motif. J. Inter.& Cytokine Research 21:871-881
2. 5th Annual Conference on Vaccine Research, Baltimore, MD., May 2002. Mycobacterium bovis BCG
vaccination of cattle: activation and proliferation of lymphocyte subsets upon stimulation with
mycobacterial antigens. W.R. Waters, B.J. Nonnecke, T.E. Rahner, M.V. Palmer, D.L. Whipple, M.R.
Foote, A.C. Maue, and D.M. Estes.
PROJ NO: MONB00032 AGENCY: CSREES MONB
PROJ TYPE: ANIMAL HEALTH PROJ STATUS: NEW
START: 01 OCT 2002 TERM: 30 SEP 2005
Investigator: Quinn, M. T.
Veterinary Molecular Biology
Montana State University
Bozeman, Montana 59717
ANALYSIS OF BISON INNATE DEFENSE AGAINST MICROBIAL PATHOGENS
NON-TECHNICAL SUMMARY: The American Bison (Bison bison) is a wild/semi-domesticated
ruminant that encounters serious infectious diseases, such as tuberculosis and brucellosis. This project
studies the types of antimicrobial proteins present in bison neutrophils and how active they are against
several relevant pathogens. A better understanding of these proteins could potentially lead to practical
applications to controlling infectious disease in bison and other wildlife.
OBJECTIVES: We hypothesize that bison neutrophils contain mobilizable proteins, which have direct
antimicrobial properties with therapeutic potential against persistent bison diseases such as tuberculosis.
To address this hypothesis, we propose the following aims: 1) Characterize biochemically and
functionally the types of antibacterial proteins present in bison neutrophils and 2) Probe for and clone
selected bison neutrophil antimicrobial proteins.
APPROACH: Objective 1 will require the collection of blood from captive bison and further isolation
and purification of neutrophils. We will then use one or more procedures to extract a subset of proteins,
which is likely to contain neutrophil antimicrobial proteins (AMPs), as determined by bacterial killing
assays. Finally, we will systematically screen the proteins we have extracted, for killing activity against
E. coli, S. aureus, and M. bovis BCG. Following completion of objective 1, we hope to have identified
one or more proteins that have interesting antimicrobial activity; we then propose to find and clone the
gene(s) for these proteins, so that they can be produced as recombinant proteins for further detailed
mechanistic and microbiological testing. One possibility is that the protein of interest is one of the bison
bactenecins, which we have already begun to characterize, and we will continue cloning these genes as
described below. If the protein does not appear to be one of the bactenecins, we will use N-terminal
sequencing to obtain sufficient code to design primers for further sequencing/cloning.
PROJECT CONTACT:
Name: Quinn, M. T.
Phone: 406-994-5721
Fax: 406-994-4303
PROJ NO: NYC-433333 AGENCY: CSREES NY.C
START: 01 JUN 2000 TERM: 30 SEP 2004 FY: 2002
Investigator: Russell, D. G.
Veterinarian Microbiology & Immunology
Cornell University
Ithaca, New York 14853
PATHOGEN MYCOBACTERIA: M.TUBERCULOSIS, M. BOVIS, AND M. AVIUM
NON-TECHNICAL SUMMARY: Mycobacterial species are important pathogens in both animals and
humans. Study into the lifestyles of mycobacteria species pathogenic to animals and humans such as M.
tuberculosis, M. leprae, M. bovis and M. avium reveals extensive parallels in their mechanisms of
intracellular survival and persistence. The laboratory is devoted to the study of microbial pathogens that
exploit the macrophage as their host cell.
OBJECTIVES: The laboratory is dedicated to the study of pathogen mycobacteria. The primary area of
interests are as follows: 1. Analysis of the biology of the interaction between the macrophage and the
bacillus with respect to the intracellular environment and the regulation of host cell function. 2. The
elucidation of the metabolism of the intracellular bacillus and its exploitation as possible targets of drug
action. 3. The appreciation of the modulation of the infection foci and the role of the granuloma in the
persistence of infection.
APPROACH: Cell Biology of Intracellular Infections by Mycobacterium avium: This delicate interplay
between the bacterium, and its potentially microbicidal host cell is little understood. Previous work in the
laboratory has fostered the belief that, with respect to the interaction with macrophages and the immune
responses at site of infection, there are many parallels between pathogenic mycobacteria species,
including Mycobacterium bovis. For this reason emphasis is also placed on exploitation of genetic
approaches available for other mycobacterial species, notably M. tuberculosis and M. bovis, for the
resolution of mechanisms common to all pathogenic mycobacteria. 2. Elucidation of Intermediate
Metabolism and Carbon Source Acquisition by M. bovis and M. tuberculosis: We have extensive
experience in modelling intracellular infections by both prokaryote and eukaryote pathogens and propose
to apply this expertise to determining the contribution of the glyoxylate shunt pathway to infection. 3.
Formation and Maintenance of the Granuloma and it role in Infection by Mycobacterium spp: We have
carried out a systematic analysis of bacterial lipidoglycans released and trafficked through infected
macrophages. These comprise 7 major species of lipids some, or all, capable of inducting granulomas in
mice. The ability of these lipids to expand the influence of the bacteria beyond the infected macrophages
and induce granuloma formation suggest that they play roles key to the evolution of this response. Our
recent development of an in vivo model exploiting these lipids will enable the functional determination
of the roles of these molecules in granuloma induction.
PROGRESS: 2002/01 TO 2002/12
Mycobacterium tuberculosis is a phenomenally successful pathogen that infects approximately 1/3 of its
host species, mankind. Its success lies in its capacity to establish and maintain its infection within the
hosts' phagocytes. In the short term this is achieved through arresting the normal maturation of its
phagosome and blocking its fusion with acidic, hydrolytic lysosomes. We have been studying this aspect
of the pathogen's biology through the isolation of transposon-mutagenized bacteria defective in arresting
the maturation of the phagosome. Mutants isolated in this screen demonstrate an altered intracellular
distribution and are attenuated for survival inside macrophages. In the longer term the continuation of
infection relies on the bacterium's capacity to respond to and to modulate the changing environment
within the immune host. The bacterium's metabolism appears geared to respond to environmental shifts
experienced in activated versus resting macrophages. In resting macrophages the bacterium replicates
freely and appears to rely extensively on the TCA cycle, however upon activation of the macrophage the
bacterium mobilizes the glyoxylate cycle, usually associated with a dependence on fatty acids as primary
carbon source. The promoter for the gene encoding the glyoxylate cycle enzyme isocitrate lyase appears
regulated tightly by factors such as oxygen tension and carbon source. We have adopted a genetic
approach that exploits this regulation to identify environmental factors and the bacterial sensors and
effectors responsible for this shift. Finally, the tissue surrounding the infected macrophages develops into
a granuloma. This structure, the tubercle, fulfills functions for both pathogen and host. For the host the
granuloma walls off the infection and restricts spread, but for the bacterium the granuloma actually
ensures persistence of the infection. The bacterium is able to persist because the granuloma structure
ensures that the lymphocytes capable of activating the macrophages are maintained as a mantle or cuff
around the periphery of the granuloma, away from the infected macrophages in the center. Bacterial cell
wall lipids are released by intracellular bacteria and appear to play an active role in the formation and
maintenance of this structure. The biological activities of these lipids are being explored in an in vivo
granuloma model.
IMPACT: 2002/01 TO 2002/12
Infections by Mycobacterium spp. continue to be a serious problem for the health of both humans and
livestock. Results of these studies will provide a better understanding of the pathogen's biology through
the isolation of transposon-mutagenized bacteria defective in arresting the maturation of the phagosome.
1. Beatty, W., Rhoades, E.R., and Russell, D.G. 2002. Association of a macrophage galactose-binding
protein with Mycobacterium-containing phagosomes. Cell. Microbiol. 4. 167-176.
2. Smith, C.V., Huang, C-C., Miczak, A.M., Russell, D.G., Sacchettini, J.C., and Honer zu Bentrup, K.
2003. Biochemical and Structural studies of Malate synthase from Mycobacterium tuberculosis. J. Biol.
Chem. 278. 1735-1743.
3. Russell, D.G., Mwandumba, H.C., and Rhoades, E.R. 2002. Mycobacterium and the coat of many
lipids. J. Cell. Biology. 158. 421-426
4. Liu, K., Yu, J. and Russell, D.G. 2003. pckA-deficient mutants of Mycobacterium bovis BCG show
attenuated virulence in mice and in macrophages. Microbiology. 149. 1829-1835
5. Rhoades, E.R., Hsu, F-F., Torrelles, J.B., Chatterjee, D. and Russell, D.G. 2003. Identification and
macrophage-activating activity of glycolipids released from intracellular Mycobacterium spp. Mol.
Microbiol. 48. 875-888
PROJECT CONTACT:
Name: Wood, J. R.
Phone: 607-253-3759
Fax: 607-253-3756
PROJ NO: NYCV-433338 AGENCY: CSREES NYCV
START: 01 JUN 2000 TERM: 30 SEP 2004 FY: 2002
Investigator: Russell, D. G.
Microbiology and Immunology
Cornell University
Ithaca, New York 14853
PATHOGEN MYCOBACTERIA: M. TUBERCULOSIS, M. BOVIS, AND M. AVIUM
NON-TECHNICAL SUMMARY: Study into the lifestyles of mycobacteria species pathogenic to
animals and humans such as M. tuberculosis, M. leprae, M. bovis and M. avium reveals extensive
parallels in their mechanisms of intracellular survival and persistence. The laboratory is devoted to the
study of microbial pathogens that explit the macrophage as their host cell.
OBJECTIVES: The laboratory is dedicated to the study of pathogen mycobacteria. The primary area of
interests are as follows: 1. Analysis of the biology of the interaction between the macrophage and the
bacillus with respect to the intracellular environment and the regulation of host cell function. 2. The
elucidation of the metabolism of the intracellular bacillus and its exploitation as possible targets of drug
action. 3. The appreciation of the modulation of the infection foci and the role of the granuloma in the
persistence of infection.
APPROACH: Cell Biology of Intracellular Infections by Mycobacterium avium: This delicate interplay
between the bacterium, and its potentially microbicidal host cell is little understood. Previous work in the
laboratory has fostered the belief that, with respect to the interaction with macrophages and the immune
responses at site of infection, there are many parallels between pathogenic mycobacteria species,
including Mycobacterium bovis. For this reason emphasis is also placed on exploitation of genetic
approaches available for other mycobacterial species, notably M. tuberculosis and M. bovis, for the
resolution of mechanisms common to all pathogenic mycobacteria. 2. Elucidation of Intermediate
Metabolism and Carbon Source Acquisition by M. bovis and M. tuberculosis: We have extensive
experience in modelling intracellular infections by both prokaryote and eukaryote pathogens and propose
to apply this expertise to determining the contribution of the glyoxylate shunt pathway to infection. 3.
Formation and Maintenance of the Granuloma and it role in Infection by Mycobacterium spp: we carried
out a systematic analysis of bacterial lipidoglycans released and trafficked through infected
macrophages. These comprise 7 major species of lipids some, or all, capable of inducting granulomas in
mice. The ability of these lipids to expand the influence of the bacteria beyond the infected macrophages
and induce granuloma formation suggest that they play roles key to the evolution of this response. Our
recent development of an in vivo model exploiting these lipids will enable the functional determination
of the roles of these molecules in granuloma induction.
PROJECT CONTACT:
Name: Wood, J. R.
Phone: 607-253-3759
Fax: 607-253-3756
PROJ NO: ORE00031 AGENCY: CSREES ORE
PROJ TYPE: ANIMAL HEALTH PROJ STATUS: REVISED
START: 01 JUL 2003 TERM: 30 SEP 2004 FY: 2002
Investigator: Kent, M. L.
Microbiology
Oregon State University
Corvallis, Oregon 97331
CHARACTERIZATION OF MYCOBACTERIUM SPP. FROM FISHES OF OREGON
NON-TECHNICAL SUMMARY: Diseases impact both wild and captive fishes. One of these is a
bacterial disease called 'fish mycobacteriosis' or 'fish tuberculosis.' Many strains or species of
Mycobacterium occur in fish, and we will use both traditional methods and molecular biology to resolve
their identity. The project examines the taxonomy of Mycobacterium pathogenic bacteria in fishes in
Oregon This study has demonstrated that several more Mycobacterium spp. infect fishes than previously
thought. Some of these strains may be related to pathogens of humans.
OBJECTIVES: Our overall objectives are 1) to continue to resolve the taxonomy of Mycobacterium
species infecting various commercially important fishes in Oregon, focusing on a more variable region of
the rDNA gene (ITS), 2) to evaluate the virulence of selected strains using macrophage assays, and 3) to
develop PCR-based diagnostic tests using these isolates. Such tests would ultimately be employed by fish
health researchers and diagnostic laboratories in the Department of Microbiology, the College of
Veterinary Medicine, and Oregon Department of Fisheries & Wildlife. Moreover, with we will evaluate
the potential virulence of the strains in culture to mammals and fish using in vitro macrophage models.
Using human, mouse and fish cell lines we will evaluate whether strains from fish are pathogens to both
mammals and humans, fish pathogens only, or merely opportunists
APPROACH: rDNA sequences.. We will obtain rDNA sequences using both direct PCR from tissues
and PCR from isolated colonies In addition, we will continue to use our new primers for amplification of
problematic samples, especially fish tissue samples, as they amplify smaller products and thus appear to
be more sensitive for certain samples These primer sets provide SSU sequence, and to more precisely
characterize and differentiate our isolates (e.g., the closely related salmonid isolates), we will examine a
more variable region of the gene (the ITS) using published primers After the various isolates are
sequenced, we will compare sequences using BLAST Search to compare with existing strains in
GenBank. Furthermore, we will conduct phylogenetic comparisons using standard molecular systematics
programs available through PAUP, etc. Virulence. We will characterize the virulence of representative
strains obtained from our epidemiological and taxonomy studies using in vitro macrophage assays. To
evaluate the ability of the bacterium to infect and survive in macrophages, we propose to employ the
systems currently in use in Dr. Bermudez's laboratory. We plan to determine: (1) efficiency of invasion
and (2) the ability of survive and replicate inside macrophages. For those experiments we propose to use
carp macrophage cell line, the zebrafish macrophage cell line we have recently established from
zebrafish spleens, and mouse macrophage cell line RAW 246.7. We also plan to use as controls for the
experiments a human isolate of Mycobacterium avium, a fish derived Mycobacterium marinum (also a
human isolate) and a non-virulent Mycobacterium smegmatis. The strain to be tested and the controls will
be cultured and then used to infect macrophages in a ratio of 0.1 to 1, 1 to 1 and 10 to 1
(bacteria:macrophage). Invasion will be determined after 1 hour. The inoculum will be plated onto 7H11
agar plates to determine the number of bacteria. Infected macrophage monolayers will be washed several
times with buffer in order to remove extracellular bacteria and then the monolayers will be lysed by
incubating them with water for 10 min as described (Bermudez and Young 1988; Bermudez et al. 1994).
Then 0.025% SDS will be added to the suspension for 10 additional minutes to prevent clumping. The
suspension will be plate onto 7H11 plates to determine the number of viable intracellular bacteria. The
efficiency of invasion will be calculated as a percentage of the initial inoculum used to infect the
monolayers. To determine the ability of the bacteria to grow intracellularly, monolayers will be
established and infected in a similar manner as described above. The intracellular bacteria will be
allowed to grow and 4 and 7 days after infection the monolayers will be lysed and the number of
intracellular bacteria quantified as reported (Wagner et al. 2002). The bacterial growth or decrease of the
number of intracellular bacteria will be calculated as the variation of the number of bacteria inside
macrophages 1 h after infection.
PROGRESS: 2002/01 TO 2002/12
NEW PRIMERS: We have had moderate success amplifying 16s rDNA using the Talaat primers which
worked well for cultures, but we obtained mixed results with tissue samples. We designed new primer
sets, dividing this region into two sections. These sets proved to be more sensitive and we were able to
obtain product from difficult tissues. ZEBRAFISH ISOLATES: (Facility 1) Using the 16S primers and
restrictive enzyme approach for identification of fish mycobacteria we identified the first zebrafish
isolates that we investigated as M. marinum. In contrast, when we sequenced this specimen, it clustered
as a sister taxon to M. haemophilum, a human pathogen not recognized as a pathogen of fishes. We
considered that this may be a terrestrial contaminant, but refuted this hypothesis as we obtained identical
sequence from a PCR product amplified from the heart of additional fish from the same colony. Infected
fish exhibited massive invasion and associated tissue reaction in the visceral organs. In addition, some of
the fish with the M. haemophilum-like infection showed an unusual pathological condition with
numerous mycobacteria colonies within the central nervous system not associated with inflammatory
changes. (Facility 2.) A second research facility suffered a massive outbreak of mycobacteriosis in which
the entire colony was ultimately destroyed. Using our new 16s rDNA primers and those of Talaat et al.
(1997), we also obtained 16s rDNA sequence from two zebrafish from this epizootic. This isolate cluster
within a clade was comprised of M. septicum and M. peregrinum. These species are related to M.
fortuitum, forming a clade of fast growing bacteria known to be pathogens of humans. (Facilty 3.) We
maintain a sentinel fish monitoring program at the two zebrafish facilites at the University of Oregon
Zfish Facility - i.e., exposing zebrafish to effluent water from the entire system. Although no outbreaks
have been observed, we recently detected mycobacteiosis in a few sentinel fish based on histology. We
have obtained an isolate from these fish in culture, and it will be added to our phylogenetic analyses.
(Salmon Isolates.) We obtained five isolates from salmonids from the OSU fish pathogen culture culture
at the Hatfield Marine Science Ctr . All salmonid isolates, including one from Australia were very
closely related, showing only a maximum sequence difference of 4 bp over about 850 bp of the 16S
rDNA. These isolates cluster together as a group, near M. chelonae, a recognized pathogen of fishes.
(Marine Fish Isolates.) We obtained a culture from a moribund sable fish maintained at the Hatfield
Marine Science Ctr. which was clustered with the salmonid isolates near M. chelonae. We have several
kidneys (frozen) from rockfishes with Mycobacterium infections. To date we have not been able to
culture Mycobacterium spp. from these tissues. However, direct PCR using new primers that we
designed allowed us to obtain about 850 of reliable sequence. This specimen was identical to M.
monteflorense, a recently described Mycobacterium species from moray eels from Florida. This is the
first report of the infection in another fish species and from the Pacific Ocean.
IMPACT: 2002/01 TO 2002/12
The genus Mycobacterium causes several diseases in animals, including tuberculosis in humans (i.e. M.
tuberculosis). Particularly with emergence of AIDS, in recent years many new Mycobacterium species
have been recognized as virulent or opportunistic human pathogens. Our study has revealed that several
other species of Mycobacterium can cause disease in fishes than what was previously recognized,
including human pathogens such as M. haemophilum. These results provide further evidence that fishes
may be reservoirs for Mycobacterium infections that are potential pathogens for humans.
Kent, M.L., V. Watral, J.L. Matthews, C.M. Whipps. Proceedings of the 43rd Western Fish Disease
Workshop. 25- 26 June 2002. Corvallis, Oregon, p. 11.
PROJECT CONTACT:
Name: Kent, M. L.
Phone: 541-737-5088
Fax: 541-737-2166
PROJ NO: ORE00275 AGENCY: CSREES ORE
START: 01 OCT 2002 TERM: 30 SEP 2007
Investigator: Kent, M. L.
Microbiology
Oregon State University
Corvallis, Oregon 97331
INFECTIOUS DISEASES OF IMPORTANCE TO WILD AND CULTURED FISHES
NON-TECHNICAL SUMMARY: Fishes represent various important economic commodities in the
Pacific Northwest. As with terrestrial animals, diseases may severely impact the well-being and
economic viability of fish industries. This study investigates the host and geographic range, pathogenesis,
taxonomy, modes of transmission, and treatment of infectious diseases of importance to wild and
cultured fishes, particularly those afflicting fishes in the Pacific Northwest region. The ultimate goal of
this research is to provide information to assist fish health managers and veterinarians to minimize the
impact of these diseases
OBJECTIVES: 1. Characterize diseases of importance to salmonids, zebrafish and rockfish. 2.
Elucidate the taxonomy and phylogenetics of these diseases. 3. Develop sensitive and specific diagnostic
tests for these diseases.
APPROACH: 1.Diseases of importance in these fishes will be determined by complete necropsy and
subsequent laboratory analyses, including pathology, bacteriology, and virology. Conducting in vivo
transmission studies will elucidate the pathogenesis of various pathogens. 2.Molecular systematic
approaches will lead studies on identifications and phylogenetic relationships of the pathogens in study.
In addition, traditional morphology and culture characteristics will be included. 3.For bacteria and
parasites, will focus on using ribosomal DNA sequences for the development of sensitive and specific
PCR based tests.
PROJECT CONTACT:
Name: Kent, M. L.
Phone: 541-737-8652
Fax: 541-737-2166
PROJ NO: TEX08409 AGENCY: CSREES TEX
PROJ TYPE: HATCH PROJ STATUS: EXTENDED
Investigator: Adams, L. G.; Davis, D. S.; Ficht, A. R.
Veterinary Pathobiology
Texas A&M University
College Station, Texas 77843
BOVINE & CERVID TUBERCULOSIS: DIAGNOSIS, VACCINATION, PATHOGENESIS,
AND GENETIC DISEASE RESISTANCE
NON-TECHNICAL SUMMARY: Tuberculosis in cattle and wildlife causes economic and public
health concerns. The purpose of this project is to: 1.) Develop new diagnostic tests; 2.) Develop
candidate tuberculosis vaccines for cattle and deer; 3.) Develop fundamental understanding of cattle and
deer tuberculosis disease processes; and 4.) Produce cattle and deer genetically resistant to tuberculosis.
OBJECTIVES: 1. Develop new diagnostic tests. 2. Develop candidate tuberculosis vaccines for cattle
and deer. 3. Develop fundamental understanding of cattle and deer tuberculosis disease processes. 4.
Produce cattle and deer genetically resistant to tuberculosis. 5. Assess impacts of optimally implement
new technologies for control of tuberculosis.
APPROACH: 1. Develop rapid and sensitive tests that permit multiple testing of the same animal and
do not require repeated handling, including: PCR based tests for M. bovis specific DNA; cytokine
profiles; and restriction fragment length polymorphism (RFLP) analysis of M. bovis DNA. 2. Develop a
marker deletion vaccine with companion diagnostic for a specific antigen which is normally produced by
the wild-type disease agent but is deleted from the vaccine strain, thus the diagnostic test recognizes only
animals infected with wild-type field strains of M. bovis but not marker-deletion TB vaccinated animals.
3. Define the host-pathogen relationships that are critical to infection and development of disease
following exposure of livestock to M. bovis. 4. Define major new host genes encoding factors important
in the disease pathogenesis of tuberculosis infection vs. disease in these farmed species. 5. Predict the
epidemiologic and economic impact and application of existing and potential strategies for eradication of
TB from animals.
PROGRESS: 2002/01 TO 2002/12
A search for bovine macrophage genes differentially expressed after Mycobacterium bovis infection was
done by Differential Display Reverse Transcription Polymerase Chain Reaction (DDRT-PCR). The
differential expression of eight clones was confirmed by reverse Northen blot and ribonuclease
protection assays. Most of the genes identified were associated with an overexpression pattern after
infection. Differential gene expression was observed at all the time points studied (0, 12, 24h), however
the majority of the changes in gene expression occurred at the early stages post-infection. A GenBank
sequence database search identified the differentially expressed genes as the putative bovine homologues
of serum amyloid A protein (SAAP), legumain, signaling lymphocytic activation molecule (SLAM),
alveolar macrophage-derived chemotactic factor II, ferritin heavy-chain and osteopontin. Results from
this study reveal that M. bovis modulates the gene expression of bovine macrophages shortly after
infection.
IMPACT: 2002/01 TO 2002/12
Better understanding of the regulation of gene expression in the bovine host target cell, the macrophage,
particularly genetically controlled factors controlling survival of Mycobacterium bovis, provide the
rationale for improved control of tuberculosis.
1. Adams, L. G. 2001. In vivo and in vitro diagnosis of Mycobacterium bovis infection. Rev. sci. tech.
Off. Int. Epiz. 20:302-324.
2. Gutierrez-Pabello, Jose A., David N. McMurray, and L. Garry Adams. 2002. Upregulation of
Thymosin of B-10 by Mycobacterium bovis Infection in Bovine Macrophages is Associated with
Apoptosis. Infection & Immunity, 70:2121-2127.
3. Chacon, O., Z. Feng, N.B. Harris, N.E. Caceres, L.G. Adams, and R.G. Barletta. 2002. Mycobacterium
smegmatis D-alanine racemase mutants are not dependent of D-alanine for growth. Antimicrobial Agents
and Chemotherapy. 46:47-54.
PROJECT CONTACT:
Name: Adams, L. G.
Phone: 979-845-9816
Fax: 979-862-1088
PROJ NO: VA-135642 AGENCY: CSREES VA.
Investigators: Smith, S. A.; Hrubec, T. C.; Densmore, C. L.
College of Veterinary Medicine
Virginia Polytechnic Institute
Blacksburg, Virginia 24061
DEVELOPMENT OF A TOOL TO ASSESS BACTERIAL INFECTIONS IN HYBRID STRIPED
BASS
NON-TECHNICAL SUMMARY: Aquaculture is one of the top 30 agricultural commodities; however,
monetary losses from diseases and disease control efforts are significant. Aquaculture is hampered by a
lack of tools to accurately diagnose disease. This research proposes to develop hematology and blood
biochemistry as a diagnostic tool to assess bacterial diseases in hybrid striped bass and will allow
producers to assess and monitor the health of their stock.
OBJECTIVES: This study has 5 specific objectives: 1) Determine progressive hematologic changes
associated with MAS infection by analyzing blood collected at set intervals post infection. 2) Determine
any change (either activation or suppression) in macrophage function because of bacterial infection
(macrophages play a crucial role in defense from bacterial pathogens). 3) Determine the pathophysiology
(uptake, dissemination and tissue damage) of Aeromonas hydrophila in the tissues by histopathological
evaluation. 4) Correlate the pathophysiology with changes in blood analytes, 5) Establish which blood
changes, if any, are characteristic of MAS infection allowing diagnosis of diseased individuals and
populations. Developing a tool for the early detection of bacterial diseases would decrease the incidence
and economic loss from disease in production hybrid striped bass and would result in greater numbers of
fish reaching marketable size. Additionally the results of this study will assist in the diagnosis of
infectious disorders in other species of fish.
APPROACH: Hybrid striped bass will be housed in 1000 gal recirculating system in a separate building
from the bacteria exposed fish to prevent accidental infection of stock fish. Isolates of A. hydrophila will
be obtained from the National Fish Health Research Laboratory and cultured with non-selective media.
Three experimental groups of fish will be used based on route of exposure: water borne, intramuscular
(IM) and saline injected controls. For the water borne challenge, bacterial suspensions will be added to
the water, fish will be exposed for 30 min to the bacteria and then bacteria flushed out of the system. For
the IM injections, fish will be sedated with MS-222 (150 mg/L) and injected IM with bacteria. The saline
injected group will be handled similar to IM infected fish. A total of 72 fish will be used in each
treatment group with18 fish placed in four replicate tanks. Fish will be acclimated to the experimental
tanks for 3 weeks prior to initiating the experiment. Blood and tissue samples will be collected at 7
equally spaced time intervals following bacterial exposure and analyzed for hematological and blood
biochemical parameters, macrophage activity and tissue histopathology. Fish will be rapidly netted and
placed in aerated, buffered MS-222 anesthetic. When anesthetized, fish will be bled from the caudal
vessels. Sampled fish will not be returned to the tanks to prevent repeat sampling of fish. For
hematologic analysis, blood will be placed into individual EDTA blood tubes held on ice and analyzed
for: packed cell volume, plasma protein, total red and white cell counts, differential white cell counts,
hemoglobin and red cell indices (mean cell volume, mean cell hemoglobin, and mean cell hemoglobin
concentration). For biochemical analysis, blood will be placed into individual heparinized tubes held on
ice. The tubes will be centrifuged immediately and the plasma removed to analyze the following with an
automated chemistry analyzer: total protein, albumin, globulin, creatinine, total bilirubin, alkaline
phosphatase, aspartate aminotransferase, glucose, cholesterol, sodium, chloride, potassium, calcium,
magnesium, and phosphorus. Hematologic reference intervals will be determined for the stock group of
fish and will be used as the standard of comparison for any changes in blood values due to the bacterial
infections. Macrophages will be isolated from the spleen and pronephros of control and exposed fish at
the 7 sampling times. Flow cytometry will be used to determine macrophage function and activation by
monitoring chemiluminescence and phagocytic activity. Additionally, tissue samples will be collected
and fixed in 10% neutral buffered formalin, paraffin embedded, sectioned, and stained with hematoxylin
and eosin and Gram stain. Tissue sections will be analyzed for the presence of bacteria and pathological
changes associated with the bacterial infection. The general linear model function of SAS System will be
used to perform analysis of variance to test for treatment effects, time effects and treatment time
interactions. Correlation will be used to associate tissue pathology with hematologic changes.
PROGRESS: 2001/10 TO 2002/09
Cultured juvenile hybrid striped bass and cultured juvenile summer flounder were exposed to
Mycobacterium marinum by inoculation and water borne routes, respectively. At various times postexposure, a sample of fish was collected, humanely euthanized and necropsied. Tissues were submitted
for standard histopathology and a pathological description developed for the time course of the pathology
associated with the infection. Both species of fish had tissue pathology as a result of the infection, but
had differing courses and amounts of pathology. The hybrid striped bass typically had the classical
granulomas, while the summer flounder typically had a severe granulomatous inflammatory response
without discrete granuloma formation. The time course for pathology in both species was described.
IMPACT: 2001/10 TO 2002/09
This study documents the progressive pathological changes in fish associated with a specific bacterial
disease, mycobacteriosis, and provides a diagnostic description for assessing the health of fish in the face
of this infection. As a result, veterinarians and other fish health professionals will have a method for
evaluating chronic disease changes in hybrid striped bass and summer flounder.
1. Hughes, K.P, R.B. Duncan. and S.A. Smith. 2002. Renomegaly associated with a mycobacterial
infection in summer flounder, Paralichthys dentatus. Fish Pathology 37:83-86.
2. Hughes, K.P., R.B. Duncan, S.A. Smith. 2002. Mass in oral cavity of cultured summer flounder,
Paralichthys dentatus. Lab Animal 31:25-27.
3. Wolf, J.C. and S.A. Smith. 1999. Comparative severity of experimentally-induced mycobacteriosis in
striped bass Morone saxatilis and hybrid tilapia Oreochromis spp. Diseases of Aquatic Organisms.
38:191-200.
PROJECT CONTACT:
Name: Schurig, G. G.
Phone: 540-231-4992
Fax: 540-231-5815
PROJ NO: VA-137185 AGENCY: CSREES VA.
Investigators: Smith, S. A.; Pasnik, D. J.; Schurig, G. G.
College of Veterinary Medicine
Virginia Polytechnic Institute
Blacksburg, Virginia 24061
IMMUNOMODULATORY EFFECTS OF RECOMBINANT MYCOBACTERIAL VACCINE IN
FISH
NON-TECHNICAL SUMMARY: Mycobacteriosis is a devastating bacterial disease of wild, and more
importantly, cultured food fish species such as striped bass and flounder. The production of a safe,
effective mycobacterial vaccine will reduce the incidence and severity of this infectious disease in
commercial food fish populations allowing healthier fish to reach the market.
OBJECTIVES: The goal of this project is to create a safe, effective vaccine for piscine mycobacteriosis,
an important chronic, progressive bacterial disease of fish causing systemic granulomas in virtually any
tissue and often leading to death of the fish. Using an established vaccine vector and protocol proven
successful for a commercial brucellosis vaccine (RB51), a mycobacterial vaccine will be constructed for
an aquatic strain of Mycobacterium marinum. Striped bass, an economically-important cultured food fish
species shown to be highly susceptible to mycobacteriosis, will be immunized with the vaccine and both
humoral and cell-mediated immunity will be monitored post-exposure. After determining the optimum
concentration and route of administration necessary to generate an immune response in the fish, the
effectiveness of the mycobacterial vaccine will be tested with a live bacterial challenge of immunized
and non-immunized fish. Ultimately, a safe, effective mycobacterial vaccine would decrease the
aquaculture industry's dependence on antibiotics, improve the overall immunocompetence and health of
the fish, and decrease financial losses due to this fish disease.
APPROACH: A vaccine for fish mycobacteriosis will be constructed using the M. marinum 85A
protective antigen and strain RB51 of B. abortus overexpressing the Cu/Zn superoxide dismutase (SOD)
antigen. The recombinant strain will be obtained by transforming strain RB51 with a pBBR1MCS-based
plasmid containing the genes for SOD (sodC) and the 85A antigen (fbpA). The basis for the selection of
the 85A antigen is threefold: 1) the 85A antigen is one of the major secreted fibronectin binding proteins
of all mycobacterial species including M. bovis and M. marinum, 2) the 85A antigen induces an effective
protection against infection in other mycobacterial species, and 3) the 85A antigen shows high homology
with various mycobacterial species suggesting that the antigen may be cross-protective against other
mycobacterial species. Expression of sodC will be driven by its own promoter while that of fbpA will be
driven by the groE heat shock promoter of Brucella. The fbpA from M. marinum will be obtained by
amplification via PCR from the genomic DNA. Overexpression of SOD and expression of the 85A
antigen in the recombinant RB51 strain will be confirmed by Western blot analysis. The recombinant
strain will be subjected to heat-shock by incubating the cultures for 30 minutes at 42 degrees C to upregulate the production of the mycobacterial protein. After treatment, the bacteria will be washed in PBS,
resuspended to obtain approximately 1011 colony forming units (CFU) per ml, and frozen at -80 degrees
C. When the fish are ready for immunization, the bacteria will be subjected to 300 krad of radiation
which renders the bacteria completely inactivated without any effect on its adjuvant and antigenic
properties. Thus, the mycobacterial recombinant vaccine will be rendered completely non-infectious
without changing its immunomodulatory effects. Two routes of immunization, intraperitoneal injection
(IP) and water immersion (WI) will be tested. Juvenile striped bass will be divided into 5 groups/route of
140 fish each and individually identified. One group for each route will be sham-immunized with sterile
saline, while the other four groups will receive concentrations of x10E8, x10E9, x10E10, and x10E11.
On Days 0, 14, 28, and 42, fish will be bled and the serum analyzed by indirect ELISA for humoral
antibodies to the RB51 strain of B. abortus and the M. marinum 85A antigen. The cell-mediated response
will be evaluated by a lymphoproliferative assay where splenocytes will be harvested on Days 28, 42, 90,
and 120 and cultured in 96-well plates in the presence of M. marinum 85A antigen, B. abortus RB51
crude extract, concanavalin A (positive control), or no additives (negative control). The cells will be
cultured for 3-5 days and then pulsed with 1 micron Ci of [3H] thymidine/well for 18 hours, harvested,
and placed in a liquid scintillation counter to evaluate [3H] thymidine incorporation. On Days 42, 90, and
120, fish from each group will also be challenged with M. marinum. Tissue samples of fish from this
study will be routinely processed, stained with hematoxylin and eosin (H & E) and Zeihl-Neelson stain,
and examined by microscopy for granulomas or other pathology.
PROGRESS: 2001/10 TO 2002/09
A DNA vaccine for fish mycobacteriosis was constructed against the M. marinum 85A protective antigen
using standard protocols. The basis for the selection of the 85A antigen is threefold: 1) the 85A antigen is
one of the major secreted fibronectin binding proteins of all mycobacterial species including M. bovis
and M. marinum, 2) the 85A antigen induces an effective protection against infection in other
mycobacterial species, and 3) the 85A antigen shows high homology with various mycobacterial species
suggesting that the antigen may be cross-protective against other mycobacterial species. Two routes of
immunization, intraperitoneal injection (IP) and intrmuscular injection (IM) were tested. Juvenile striped
bass were divided into 5 groups/route of 140 fish each and individually identified. One group for each
route was sham-immunized with sterile saline, while the other four groups received concentrations of
108, 109, 1010, and 1011. On Days 0, 14, 28, and 42, fish were bled and the serum analyzed by indirect
ELISA for humoral antibodies to the M. marinum 85A antigen. The cell-mediated response were
evaluated by a lymphoproliferative assay where splenocytes were harvested on Days 28, 42, 90, and 120
and cultured in 96-well plates in the presence of M. marinum 85A antigen, concanavalin A (positive
control), or no additives (negative control). The cells were cultured for 3-5 days and then pulsed with
1uCi of [3H] thymidine/well for 18 hours, harvested, and placed in a liquid scintillation counter to
evaluate [3H] thymidine incorporation. On Days 42, 90, and 120, fish from each group were challenged
with M. marinum. Tissue samples of fish from this study will be routinely processed, stained with
hematoxylin and eosin (H & E) and Zeihl-Neelson stain, and examined by microscopy for the presence
of granulomas or other pathology. To date, hybrid striped bass have been immunized with the DNA
vaccine and their humoral and cell-mediated immune responses have been documented. These responses
appear to be dose-dependant, with higher vaccine doses eliciting stronger immune responses. Preliminary
histopathology results suggest that the vaccine may have some protective effects against live bacterial
challenge.
IMPACT: 2001/10 TO 2002/09
As mycobacteriosis is a serious bacterial disease of cultured fish, the construction of an effective vaccine
against this pathogen will protect the fish ensuring that healthier and greater numbers of fish reach
marketable size. In addition, since these bacteria are potential zoonotic pathogens, a vaccine should
decrease the exposure of humans to this infectious agent.
PROJECT CONTACT:
Name: Schurig, G. G.
Phone: 540-231-4992
Fax: 540-231-5815
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Mycobacterium tuberculosis Transmission in a
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DEVELOPMENT OF VACCINES FOR BOVINE
TUBERCULOSIS: REPORT OF THE ISG VACCINE
SCOPING SUB-COMMITTEE
JULY 2003
CONTENTS.
Contents
Chairman’s
Introduction
Recommendations
Badger Vaccines
Cattle Vaccines
References
Appendix 1
Appendix 2
Appendix 3
Appendix 4
Appendix 5
Appendix 6
Appendix 7
Appendix 8
Appendix 9
Appendix 10
Appendix 11
Appendix 12
Appendix 13
Appendix 14
Appendix 15
PAGE
2
3
Epidemiological investigations into bovine TB – the
potential for the use of vaccines in cattle and wildlife.
Badger vaccination: ecological and epidemiological
considerations
BCG vaccination of wildlife
BCG in wild-life and domestic livestock; virulence and
efficacy
Protocols for the development and evaluation of BCG
vaccination against M.bovis infection in badgers
Vaccines for the control of bovine tuberculosis:
commercial product development and regulatory
approval
Issues relating to the procurement of badgers for
vaccine research
Feasibility & costs for providing accommodation for
badgers
Immunological assays to support the development and
evaluation of a vaccine against badger tuberculosis
Requirements of a field trial to test BCG in badgers
Vaccination of badgers against bovine TB – ecological
considerations
Vaccination of cattle with BCG to protect against
M.bovis
Chairman’s discussion paper on format of final report
Vaccination of cattle against TB
Terms of Reference & Committee Members
2
6
8
13
16
17
23
29
39
45
48
53
58
62
69
72
82
101
106
108
1. CHAIRMAN’S INTRODUCTION.
1.1 Bovine TB is a serious disease of cattle in Great Britain. The incidence of
the disease is increasing and extending beyond the traditionally TB infected
areas in the West Country. It is a disease of complex epidemiology involving
a wildlife reservoir of infection, the size and contribution of which to the
disease in cattle, is not known. Control of the disease is ultimately likely to
require a multi-faceted approach which will require a better scientific
understanding of the disease in both cattle and wildlife. To achieve this, Defra
has put in place a broad based programme of research on which it can be
expected that future control policy options will be based.
1.2 Vaccination of either cattle or wildlife is considered to be a potential, long
term, policy option. The Independent Scientific Group on Cattle TB (ISG) has
previously commented on the importance of vaccine research and advised
that this option should be kept under active consideration. Vaccines are often
talked about in simplistic terms that ignore the paucity of scientific information
available, and the financial and time dimensions required for developing a
successful vaccine. This reflects a presumption that a vaccine strategy, for
cattle or badgers, is scientifically, technically and operationally easy to put in
place. In response to a request from ministers to better inform them on the
development needs and potential value of vaccines the ISG established a
Sub-Committee comprising some ISG members plus external experts
(Appendix 15) to carry out an objective review of the feasibility for pursuing a
TB vaccination strategy for either cattle or wildlife. Consideration was given to
ongoing research and to identify further research which would be needed to
develop and test vaccines and successfully extend their use into the field.
1.3 The Sub-Committee approached the task by identifying questions and
issues that needed to be considered and inviting members of the SubCommittee and other external experts to prepare position papers to aid its
discussions and deliberations. To fully record the approach adopted by the
Sub-Committee and to illustrate the breadth of its discussions these
documents form Appendices to this report.
The Sub-Committee also
recognised that as technology develops and new scientific data become
available, further reviews are likely to be needed; the prepared position
papers will form a useful reference point for future deliberations.
1.4 From an operational perspective the field use of a cattle vaccine should
present few problems since there is direct access to the target species and
the vaccine could be given directly to each individual animal by injection.
However there are difficult scientific questions that need to be considered as
well as policy issues before use of a vaccine in the field could be
contemplated; it is worthy of note that all other countries with an intransigent
cattle TB problem have rejected the option of using currently available cattle
vaccines (in effect, only BCG is available) on the grounds of its relatively poor
efficacy and that its use would limit the ability to export breeding cattle.
1.5 We recognise that the demands of an ideal cattle vaccine are particularly
severe since the vaccine would need to prevent the establishment of
3
persistent infection and eliminate transmission. Such ideal demands will be
difficult to meet and it may be that the best that can realistically be achieved is
a reduction in pathology and transmission. Under current testing regimes, a
vaccine should also not give a positive reading in the tuberculin skin test since
this would confuse the regular herd testing procedures and create serious
regulatory problems. Although it may be possible to develop a diagnostic test
that distinguishes between vaccinated and infected animals, the more
important issue is whether vaccinated animals, even if fully protected, may
respond positively in a diagnostic test following challenge with M. bovis. This
is particularly relevant, given the likelihood that a wildlife reservoir of TB
infection will persist in the environment. The development of a diagnostic test
that meets these requirements may prove difficult.
1.6 Currently we do not feel that a suitable candidate vaccine is available for
use in cattle. Nevertheless, we believe that the option to use a cattle vaccine
in the future should be retained, and ongoing research to develop candidate
vaccines should continue to be supported. We recognise that adoption of
vaccination would require not only more effective vaccines but also the
development of improved diagnostic tests.
1.7 We have considered the potential future use of new improved vaccines in
cattle either in conjunction with a new diagnostic test or on their own in the
absence of herd testing. We accept that such vaccine strategies, applied
either nationally or zonally, would require a significant change to TB disease
control policy. Dispensing with herd testing would place greater demands on
other measures for protection of public health and could require tightening of
regulations concerning the sale of non-pasteurised milk products and carcass
inspection in slaughterhouses. The anticipated increasingly stringent EU rules
on visible lesioned carcasses would place even greater demands on a
vaccine in order to avoid wasteful carcass condemnation.
1.8 The primary goal of a badger vaccine would be to reduce the rate of
transmission of TB to cattle rather than to protect each individual badger.
Because of this, vaccination of wildlife would require a less demanding
vaccine than vaccination of cattle. Nevertheless, there are significant
scientific hurdles that have to be considered and overcome, even to get to the
point of conducting a field trial. Such a vaccine of course would only be
effective if most cattle TB infection derived from badgers, a point that is
currently being investigated in the Randomised Badger Culling Trial (RBCT).
1.9 Before serious consideration could be given to using a badger vaccine in
the field, it would be necessary to establish that the vaccine will influence the
course of the disease in badgers. Only then could a field trial be considered.
Then the logistics of successfully vaccinating a badger population in the wild
would need to be considered; this would present a major challenge and could
not be undertaken lightly. It would also need to avoid non-target species.
Large-scale vaccination of badgers would be necessary to have a significant
impact on the disease in cattle. This would be logistically difficult to achieve
without an oral vaccine, although this in turn creates its own challenges, both
4
in terms of developing an oral vaccine which stimulates an effective immune
response and its effective delivery.
1.10 One of the problems in developing a vaccine strategy for badgers is the
limited knowledge of the epidemiology and dynamics of TB in badgers. Some
new epidemiological data will be forthcoming from the ongoing RBCT and
other related research, which will indicate how vaccines in the field may best
be utilised. There are still important issues to resolve and at the moment any
attempt to model the disease, so as to provide better information on the
design of potential vaccine strategies and to predict their likely outcome, has
serious limitations.
1.11 The report and its appendices consider these issues, highlight the
questions that the Sub-Committee has needed to address and illustrate the
complexity of adopting vaccination-based TB control policies for either cattle
or wildlife. The option of the use of vaccines should in our view be retained.
Most of the necessary research has been commissioned, is in place and very
effectively linked to an International TB vaccine development programme
involving both veterinary and medical research workers. However, we have
identified areas of research that we believe are necessary to ensure that
progress towards taking a vaccine into the field is optimised. It is,
nonetheless, clear that there is no quick fix or short cut that can be taken to
speedily put in place a vaccine control policy option. In the short, or even
longer term, alternative control options will need to be adopted in order to
achieve better control of the disease in cattle.
1.12 I wish to thank members of the Sub-Committee and its Secretariat, for
their hard work and diligence in carrying out their task. I am particularly
grateful to the authors of papers that appear in the report. I hope that the
report is clear and comprehensive and that it has realistically considered and
presented the “vaccine option”.
1.13 Finally it is with great sadness that we learned of the premature and
sudden death of Dr Jo Colston. Jo was a close friend to many of us. Not only
was he a valued and extremely active member of the Sub-Committee but he
also played a significant and important part in supporting the work of the ISG
in other areas of its activity and had provided sound scientific advice to Defra,
particularly on its vaccine research programme.
John Bourne
July 2003
5
2. RECOMMENDATIONS.
2.1 Badgers.
2.1.1 BCG may be of value to protect badgers but before a field trial of BCG
can be put in place it is essential to await the outcome of vaccine protection
studies that are currently being carried out on a population of housed wild
badgers in the Republic of Ireland (RoI). We advise that even if a degree of
protection is shown in these studies that success in the field cannot be
guaranteed and that a field trial would inevitably have to be put in place and
designed on a large scale and continue for an extended time period, in order
to demonstrate its effect on the incidence of TB in cattle.
2.1.2 It will also be necessary to await the outcome of the RBCT in order to
obtain essential epidemiological data on TB in the badger and the impact of
badger culling on cattle TB before deciding on whether or not to proceed with
a field trial.
2.1.3 A field vaccine for badgers will need to be delivered as an oral bait.
Priority needs to be given to development of oral/respiratory delivery systems
that are effective in stimulating protective immune responses without capture
of badgers.
2.1.4 There is additional preparatory work that could be undertaken in order
to enable a field trial to be in place as soon as badger vaccine protection and
field trial data become available. We recommend that oral bait formulation
studies be continued, and that field studies be initiated on bait uptake and bait
targeting in badgers and the level of bait uptake by non-target species
including cattle.
2.2 Cattle.
2.2.1 BCG is the only currently available vaccine candidate that could be
considered for practical use. Experimental challenge of vaccinated cattle has
demonstrated very variable protection of up to 70%, as judged by reduction in
pathology, but lower levels of protection against establishment of infection.
Field trials have generally provided poor protection. It is our view that BCG in
its present form would not provide an effective cattle vaccine and that cattle
vaccination could only be considered when an improved vaccine is available.
2.2.2 It will be imperative to maintain the current effort on development and
testing of vaccines, which relates to both cattle, including neonates, and
badgers, with emphasis on testing in the target species (cattle). The well
developed and effective international collaborations with scientists working on
vaccines for both animal and human TB must be maintained and built on.
2.2.3 We also recommend studies on the oral sensitisation of cattle with BCG
and on the effect of vaccinating already infected animals particularly with
respect to lesion development.
6
2.2.4 We recommend that greater priority be given to developing improved
diagnostic tests for both cattle and badgers.
2.3 Other.
2.3.1 A large body of data on BCG safety in a number of wildlife species,
based on laboratory experimentation, already exists. We recommend that an
extensive literature search is carried out to collate these data.
7
3. BADGER VACCINES.
3.1 Introduction.
3.1.1 In its report of 1997, the Kreb's Committee recommended1 that a
research programme aimed at developing a vaccine against tuberculosis for
use in cattle should be implemented, although the option of developing a
vaccine for use in wildlife (badgers) should also be retained. A vaccine
targeted at badgers would not be required to protect individual badgers
against TB, but would need to reduce transmission to cattle. Thus a vaccine
which reduces the severity of the disease and/or reduces shedding of the
bacteria from infected badgers could have the desired effect of reducing
transmission to cattle. Of course, such a vaccine would have the additional
requirement of being safe, both for the target species (badgers) and for nontarget species including domestic animals, wildlife and humans (Appendix 1).
In principle developing a wildlife vaccine may be regarded as a more realistic
and less long-term option than developing a cattle vaccine. However, it
should be noted that, implementing a field trial to measure the effect of a
wildlife vaccine on TB in cattle presents considerable challenges, and cannot
be done quickly. Moreover, while there is reasonable evidence that virtual
elimination of badgers has been shown to have an impact on TB in cattle, the
influence of reducing the numbers of infected badgers and/or the severity of
disease in affected badgers on the risk of TB in cattle is not known. Thus, any
decision to proceed towards a field trial of a vaccine targeted at badgers (or
other wildlife species) should await the outcome of the ongoing RBCT. We do
however advise that preparatory work is put in place to inform on matters such
as bait uptake and improved vaccine formulations, and thus prepare for the
possibility of a trial.
3.2 Epidemiological considerations and vaccination strategies.
3.2.1. Developing and testing a vaccine for badgers remains a considerable
undertaking. Even with an appropriate vaccine candidate, many hurdles
remain, and even if these hurdles are overcome, there can be no guarantee of
success. The development of a vaccine strategy targeted at badgers would
need to address the following issues:
3.2.1.1 The expected efficacy of the vaccine, as determined by experimental
protection studies.
3.2.1.2 The extent of the badger population to be covered and the optimal
area of coverage required to have a measurable impact on the disease in
cattle.
3.2.1.3 The route of delivery of the vaccine would need to be easy and
inexpensive, and while providing the maximum possible take-up rate in
badgers, it should avoid immunisation of non-target species and particularly
cattle.
8
3.2.1.4 How would a badger vaccine be used in the field? What are the
frequency and duration of vaccine application that would be required. What
proportion of badgers would eat the bait? What is the duration of immunity?
3.2.2
Given the extent of the TB problem in cattle, it is likely (assuming
current studies confirm that badgers are an important source of infection) that
vaccination would need to be applied over large areas to have a significant
impact on the problem. The rapid turnover of the badger population and the
fact that vaccination is unlikely to confer complete protection also means that
a vaccine would need to be administered at regular intervals (probably at least
annually) over a prolonged period of time. While trapping of badgers in order
to administer vaccine by injection may be justifiable under certain
circumstances (e.g. to deal with small, well-circumscribed pockets of disease),
it would be impractical for the more extensive application of vaccination that is
required to address the problem. Such a vaccination programme would
require an oral vaccine that could be delivered in the form of a bait.
3.2.3 There is currently insufficient knowledge of the epidemiology of the
disease in badgers and the route and frequency of transmission to cattle, to
produce simulation models for predicting the level of vaccine efficacy and
determining the optimal vaccination strategy required to interrupt transmission
to cattle (Appendix 2). While the RBCT will provide useful epidemiological
data, quantitative information on a number of parameters relating to
transmission of infection, which would be particularly useful for model
construction, are extremely difficult to obtain. For these reasons the only
realistic way of determining whether or not a vaccine (even if effective in
badgers) has an impact on TB in cattle is to conduct a field trial to measure
the effect of vaccination on the incidence of cattle herd breakdowns. The
limitations in producing precise mathematical models for TB in badgers also
make it impossible, at present, to predict the long-term impact of vaccination
on TB in the badger population, and whether or not it might be possible to
achieve eradication in local populations of badgers.
3.2.4 Considering the current situation regarding vaccine candidates, the only
vaccine which is currently available and which is likely to be available within
the medium term is the human vaccine, BCG (Bacille Calmette-Guerin). BCG
was developed during the early part of the 20th Century. It was derived from a
strain of virulent Mycobacterium bovis which became attenuated following
prolonged passage in laboratory culture medium. BCG was introduced as a
human vaccine on a large scale during the second half of the 20th Century and
is currently one of the most extensively used vaccines available (Appendices
3 and 4).
3.2.5 Unfortunately, it has now become evident that the efficacy of BCG
against the major form of TB in humans is extremely variable, ranging from
0% to approximately 80% in different trials. The basis for this variability is not
fully understood. BCG has been tested in experimental conditions in a wide
variety of animal species, both for efficacy against TB and for possible
virulence (Appendices 3 and 4). This extensive testing of BCG in a wide
variety of mammalian species has failed to reveal any substantive evidence
9
that the organism can cause disease (Appendix 3). At the same time, most
species which have been used in experimental efficacy studies have been
found to exhibit some level of protection against challenge with virulent M.
tuberculosis or M. bovis.
3.2.6 The most relevant information on the potential of BCG to protect wildlife
against M. bovis infection, and interrupt transmission to cattle comes from
work carried out (Appendix 5) in New Zealand (NZ). In NZ the Brushtail
possum is a major wildlife reservoir for M. bovis infection. In preliminary
experimental studies, BCG administered to Brushtail possums by a variety of
routes, including orally, gave low level protection against experimental
infection with M. bovis. Subsequently a field study was carried out in which
vaccinated and unvaccinated control possums were released into a study
area and the amount of TB in the possum population was monitored for 2
years. The results, which because of inadequate experimental design are
difficult to interpret, confirmed that BCG gave some protection to possums
against M. bovis infection in this field situation although the effects on cattle
TB could not be measured. Thus, these limited studies are the only grounds
for considering trialing BCG for protection against TB in badgers. However,
even with evidence of significant protection in badgers, it would be difficult to
predict how this translates to protection of cattle. Therefore, it would be
critical to design a trial to measure the impact of badger vaccination on TB in
cattle.
3.3 Towards a trial of BCG vaccination of badgers.
3.3.1 Given that there is some available evidence to suggest that BCG might
have a rôle in the vaccination of badgers, the Sub-Committee felt it would be
useful to document the steps required in developing a field trial protocol. In
many ways this represents a ‘best case scenario’. Given the widespread use
of BCG in the human population and the considerable background information
on its safety in many species and optimal modes of administration, gaining
approval to implement a field trial is likely to be considerably more
straightforward than would be the case for a completely novel vaccine.
3.3.2 Regulatory considerations.
3.3.2.1 The fact that BCG has been so widely used in man, and has been
extensively studied for efficacy and toxicity in a large number of wildlife and
domestic species, means that many of the steps involved in authorising its
use in field trials will be considerably less demanding than would be the case
for a completely novel vaccine formulation. The probable steps required for
authorisation have been set out (Appendix 6).
3.3.2.2 As part of the regulatory requirements for the use of BCG as a wildlife
vaccine, it would be necessary to demonstrate safety and efficacy against the
target species under laboratory conditions (see below); this would mean
obtaining uninfected badgers from the wild for experimental purposes. The
legal aspects of the Badger Act on the procurement of badgers for research
purposes (see below) have been described (Appendix 7). It would also be
10
necessary to demonstrate safety in a number of non-target species that might
be exposed to the vaccine. Evidence of safety could include information from
previously published studies. In addition to the requirements under the Home
Offices Animals (Scientific Procedures) Act of 1986, there may also be issues
related to the procurement of protected species for these purposes.
3.3.3 Scientific Considerations.
3.3.3.1 Regarding experimental infection and vaccination studies, although
some preliminary work has been carried out on looking at immune responses
in badgers vaccinated with BCG, and on experimental infection of badgers,
more work is required to demonstrate proof of principle of protection. Such
work would require a source of uninfected badgers and facilities for
accommodating experimental badgers, including Category 3 containment
facilities. The types of experiments that would be required are set out
(Appendix 5), and include a need to establish the effect of BCG vaccination
not only when administered prior to infection but also when given to already
infected animals. The implications for establishing experimental badger
facilities are discussed (Appendix 8). Establishing experimental badger
facilities would have major financial and logistical implications, particularly as
Containment Level 3 facilities would be required.
3.3.3.2 An alternative option would be to make use of the information
generated at the experimental badger facility in the RoI. The RoI facility has
been explicitly established with a view to carrying out experimental infection
and vaccinology studies. Good collaborative links already exist between UK
groups (VLA) and the RoI group. A compromise strategy would be to have
limited experimental facilities available in the UK to carry out vaccine dosage,
vaccine delivery and purely immunological studies, but to rely on the RoI
group to carry out the experimental protection studies. It is our view that
duplication of the facilities is not currently justified. However since the RoI
research programme is designed to address their own needs and their animal
holding capacity is limited, their priorities may diverge from those required in
the UK. Thus, there may be a need to review this policy in future.
3.3.3.3 Considering the delivery of BCG to badgers, the only practical means
of delivering a vaccine to badgers on a wide scale, is by the oral route.
Methods that combine oral and aerosol delivery are in development. In
general much larger doses are required for immunisation by the oral route as
opposed to delivery by injection. Although initial experimental work on the
effects of immunisation with BCG is likely to involve delivery by injection to
provide proof of principle, considerable research will be required to determine
the optimal procedures for oral immunisation. A limitation of both oral and
parenteral vaccine strategies is the difficulty of vaccinating pre-emerging cubs
below ground and preventing early transmission of infection from adults in the
same sett (pseudo-vertical transmission).
3.3.3.4 Regarding the diagnosis of TB in badgers, currently available badger
diagnostic tests lack sensitivity. Improved tests would be extremely valuable
and could be used to support epidemiological studies on the extent and
11
distribution of TB in badgers and also to develop a range of vaccination
strategies. For example it has been suggested that a potential vaccination
strategy for TB in badgers would be to target vaccination around infected
badger social groups, communities or local populations, coupled to the
coincidental culling of infected animals. Such a strategy would require a
highly sensitive, ‘cage-side’ diagnostic test which could be performed on living
badgers; if applied along with vaccination on more than one occasion, the test
would also need to distinguish between vaccinated and infected animals.
However, even if this strategy was practical, it would need to be applied over
a large number of local sites to have a significant impact on TB in cattle and
thus would be extremely costly. Nevertheless, an improved diagnostic test
that distinguished infected from vaccinated animals would also be of value for
larger-scale vaccination programmes using baited vaccines, by allowing the
effect of vaccination to be monitored in samples of vaccinated animals
(Appendix 9).
3.4 Field trials.
3.4.1 Following successful experimental proof of principle in laboratory
conditions, it would then be necessary to carry out a field trial. Some of the
requirements of a field trial to test efficacy of BCG in badgers have been set
out (Appendix 10 and 11). It is worth noting that it would be essential to
design a badger vaccine trial which would enable the impact on TB incidence
in cattle to be measured. This would be the major constraint in determining
the location, size and duration of the trial. Some indication of these factors
could be deduced from the on-going RBCT. As with a vaccine field trial, the
culling trial is measuring the impact on the incidence of TB in cattle of an
intervention from wildlife; thus one might anticipate that a vaccine trial would
need to be of a scale similar to that of one of the three treatments within the
culling trial. Surveying of badger setts would be required for delivery of
vaccine baits, but once completed vaccination could be applied rapidly.
However, because several years of vaccination may be required to have
maximal effect on TB in the badger population, the effects of vaccination of
badgers on TB transmission to cattle are likely to take longer to have an effect
than badger culling (Appendix 2). The statistical approach would be similar to
that described for the RBCT (ISG 2nd Annual Report2).
3.5 Support studies.
3.5.1 In addition to the work described above, the ability to carry out an
effective vaccine trial in badgers will depend on a number of additional areas
of research support. These include:
3.5.1.1 Research on vaccine delivery. For large scale vaccination of
badgers, oral delivery of vaccine will be the only practical option. Research to
identify appropriate baits and optimal doses of vaccine, and methodologies to
measure bait uptake will be required (Appendix 11).
3.5.1.2 Immunological monitoring of effective immunisation of badgers. No
information is available on the responses induced following administration of
12
BCG to wildlife in the form of an oral bait. It would be necessary, prior to a
trial, to carry out experimental studies of immune responses induced following
oral vaccination, in order to identify responses that can be used as markers to
evaluate “vaccine take” (i.e., that the vaccine has successfully induced an
immune response similar to that seen under experimental conditions) in
samples of vaccinated badgers (Appendix 9).
3.5.1.3 The effect of exposure of non-target species to an oral vaccine. The
method of vaccine delivery employed must avoid, as far as possible, uptake of
bait by non-target species including domestic animals, wildlife and humans.
The potential effect of vaccine uptake by the oral route in these species must
also be considered.
3.6 Constraints on carrying out a vaccine field trial for badgers.
3.6.1 The cost and staff resource required to carry out the scientific studies
prior to the field trial, the field trial itself, and the necessary support work is
likely to be high. An estimate of costs of surveying for badger setts and bait
application can be made from costs of the RBCT. An estimate of the cost of
vaccination and the potential financial benefits that could result from
vaccination should be possible when the method and frequency of vaccine
administration are better defined. However, an accurate cost/benefit analysis
could only be carried out after a field trial was completed.
3.6.2 A trial is likely to be lengthy as well as costly. It should be stressed that
demonstration of vaccine efficacy under experimental conditions is no
guarantee of effectiveness under field conditions and vaccination alone may
not solve the problem. As a consequence the implementation of other control
measures must not be relaxed.
3.6.3 Uptake of baited vaccine by cattle could potentially result in false
positive tuberculin tests. While there is some evidence that oral vaccination of
cattle with BCG does not result in skin-test conversion, this would need to be
investigated thoroughly with the precise vaccine formulation used in the trial.
3.6.4 Other constraints to consider would be farmer compliance, interference
with field operations and the practicality of baiting large areas of the
countryside.
4. CATTLE VACCINES.
4.1 Introduction.
4.1.1 The requirements of a vaccine which targets cattle are somewhat
different from those which target wildlife (Appendices 12 and 13).
Operationally, delivering a vaccine to cattle would be much easier since it
would be possible to deliver the vaccine by injection to individual animals,
guaranteeing widespread coverage of the target species. Operational
considerations aside however, a vaccine for cattle poses considerable
difficulties. A cattle vaccine would not only have to reduce substantially
13
transmission from infected to uninfected animals but also prevent the
establishment of persistent infection. None of the vaccines that have been
tested so far for effectiveness against bovine TB, are efficient at preventing
persistent infection. Of greater concern for the use of cattle vaccination is the
likelihood that a wildlife reservoir of TB infection will persist in the environment
and vaccinated cattle, even if fully protected, might respond immunologically
when exposed to natural infection from this wildlife source. These animals
might react positively to the skin test, or any other immunological test that
might be used for diagnosis, and so with current control policy trigger a herd
breakdown.
4.1.2 Vaccination of cattle against TB would require either a vaccine that is
compatible with the diagnostic assay currently used for herd testing, or
changes in control policies that would allow the use of alternative vaccine
strategies. An over-riding consideration in introducing any new vaccine
strategy would be that it did not compromise protection of human health.
Thus, development of a successful vaccine strategy targeting cattle is likely to
require both significant scientific advances for the development of novel
candidate vaccines and diagnostics, and new approaches to disease control.
4.2 The current situation regarding vaccine candidates.
4.2.1 As discussed above, the only vaccine that is likely to be available for
use in the field over the next few years is BCG. Although vaccination of cattle
with BCG has been shown to reduce the severity of pathology following
challenge with virulent M. bovis, a significant proportion of the vaccinated
animals continue to harbour viable bacteria and have visible pathological
lesions (Appendix 12). Moreover, animals vaccinated with BCG give a
positive reaction in the tuberculin skin test, and hence cannot be distinguished
from infected animals. Thus, current research activities aimed at generating
novel candidate vaccines should be continued, but in the short term
vaccination of cattle does not present a viable option.
4.3 Potential use of vaccination of cattle in the longer term.
4.3.1 Successful vaccination of cattle is likely to require significant scientific
developments and changes to strategies for control (Appendix 14). For the
last 50 years control of bovine TB in the UK and the rest of Europe has relied
on herd testing to identify and remove infected animals. This strategy was
originally adopted with the aim of eradicating the disease. The only available
vaccine, BCG, was not sufficiently effective for vaccination to be considered
as a primary strategy to achieve eradication, and BCG could not be used in
conjunction with herd testing because of interference with interpretation of the
skin test. Looking to the future, development of new diagnostics and vaccines
might allow alternative control strategies incorporating vaccination to be
considered.
4.3.2.1 Vaccination in conjunction with an alternative diagnostic test. Leaving
aside the issue of vaccination, there is a need to improve the sensitivity of the
diagnostic assay used in herd testing. Substantial research effort, funded by
14
Defra, is currently being devoted to the development of TB-specific interferongamma (IFN-γ) assays incorporating defined M. bovis antigens. As with the
skin test, the IFN-γ assay measures the immunological response to M. bovis;
however using state-of-the-art genomic analysis it has been possible to
identify antigens which are present in M. bovis but absent in environmental
mycobacteria and also absent in BCG. Thus, such an assay is likely to be
more specific in defining TB infection than the existing skin test. In the short
term, it is envisaged that such assays could be used in conjunction with the
skin test to improve the efficiency of herd testing. It is likely that an IFN-γ
assay with similar or superior sensitivity to that of the skin test will be
developed over the next few years. If sensitivity can be achieved along with a
high level of specificity, serious consideration should be given to replacing the
skin test with the IFN-γ assay as the primary diagnostic assay for herd testing.
Such a laboratory-based assay would allow improved standardisation of TB
testing and require only one farm visit per test (as compared to two at
present).
4.3.2.2 A diagnostic assay based on the use of defined M. bovis antigens
would also potentially allow the use of vaccines that did not contain the
antigens used in the diagnostic assay. For example, many of the candidate
diagnostic antigens are absent from BCG but present in wild-type M. bovis, so
using such a test should differentiate between infection with M. bovis and
vaccination with BCG. Thus, either live attenuated or sub-unit vaccines could
be considered. However, as discussed elsewhere (see 4.1.1), the diagnostic
assay would not only need to distinguish infected from vaccinated animals but
also infected from vaccinated immune animals that have been exposed to
challenge with M. bovis. The latter might be difficult to achieve but is
amenable to experimental investigation.
4.3.3 Vaccination without herd testing. Current resources for control of TB
are focused on identification of animals once they have become infected with
the causative organism. If wildlife is confirmed as a major source of infection
and if measures to control infection in wildlife prove to be impractical,
unacceptable or ineffective, this control strategy will have a limited impact on
the problem and will continue to consume a large amount of resource. An
alternative, though radical approach would be to use vaccination of cattle as
the primary means of control in affected regions, dispense with routine herd
testing and focus resources on detection of infected carcasses in
slaughterhouses coupled with a ban on the consumption of raw milk. Such a
strategy would require a highly effective vaccine, which reliably prevents
systemic infection and substantially reduces pathology and bacterial
excretion. The principal aim would be to protect human health, by reducing
bacterial excretion to a level that poses negligible risk to humans in contact
with the live animal and limits pathology to avoid lesions that would lead to
condemnation of the carcass at post mortem, slaughterhouse, inspection.
This approach would require a vaccine with a protective effect superior to that
of BCG.
4.3.4 An advantage of vaccine development in cattle is that any vaccine
candidate considered suitable for field use can be tested rigorously for
15
efficacy under experimental conditions. The logistics of undertaking a field trial
are also more straightforward than for badgers, in that large numbers of
animals can be vaccinated rapidly and the impact of vaccination on the
incidence of disease can be measured directly. However, in the case of a
vaccine applied along with a new diagnostic test, information on the
performance of the diagnostic test under field conditions would be required
before proceeding with a vaccine trial. Trials of vaccines intended for use in
the absence of herd testing would need to incorporate close monitoring of
animals destined for slaughter.
4.3.5 These new vaccination strategies are dependent on advances in
diagnostics and vaccine development and would require rigorous
experimental and field-testing of the candidate vaccines before they could be
implemented. Legislative changes would also be required to allow new TB
control policies to be adopted. Nevertheless, in view of the uncertainty
concerning the impact of other approaches to improving control of bovine TB,
we consider that the options for vaccination of cattle need to be retained. In
any event, much of the work on testing vaccine candidates is relevant to both
badgers and cattle. Unlike the situation regarding development of badger
vaccines, experimental bovine models for characterising TB allowing rapid
testing candidate vaccines in natural target species are already in use in the
UK.
5. REFERENCES.
1. Krebs, J.R (1997). Bovine Tuberculosis in Cattle and Badgers. MAFF
Publications, PB3423, London.
2. An Epidemiological Investigation into Bovine Tuberculosis (1999). Second
Annual Report of the Independent Scientific Group on Cattle TB. MAFF
Publications, PB4870, London.
16
APPENDIX 1.
EPIDEMIOLOGICAL INVESTIGATIONS INTO BOVINE TB – THE
POTENTIAL FOR THE USE OF VACCINES IN CATTLE AND WILDLIFE.
John Bourne
ISG, Location 105, 1A Page Street, London SW1P 4PQ
1. INTRODUCTION.
1.1 The ISG in co-operation with Defra has put in place a range of studies to
gain more information on the epidemiology of TB in both cattle and wildlife
since it is our view that only through this knowledge can sustainable control
policies be developed.
1.2 Full details of the scientific approach taken and the research now in
place, which includes vaccine research, can be found in the Group’s reports to
Ministers (2000, 2001).
1.3 The use of vaccines in either cattle or badgers remains a potential policy
option, although we regard this option as offering prospects only in a long
term context and also caution that success cannot be guaranteed. The
demands of an acceptable cattle vaccine are particularly severe since it would
need both to prevent the establishment of persistent infection and to eliminate
transmission. Additionally, it should not give a positive reading in the
tuberculin skin test since this would confuse the regular herd testing
procedure and create serious regulatory problems. However, an additional
concern about the use of cattle vaccination in Great Britain relates to the
strong likelihood that a wildlife reservoir of TB infection will persist in the
countryside environment, and exposure of cattle protected by a successful
vaccine to this source of infection would result in immunological responses
which may compromise the skin test.
1.4 Any diagnostic test based upon detecting an immune response would
need therefore to distinguish immune responses generated following infection
from those elicited following challenge of a protected vaccinated animal. This
would be difficult to achieve. In addition, to being highly sensitive such a test
would have to have a high level of specificity for it to be acceptable, since
false positive reactions would trigger a herd breakdown control response.
1.5 Nonetheless, we support continuation of the cattle vaccine research and
its co-ordination with human TB research, since new technologies are
continually developing which may be applicable to cattle vaccine
development. Experimental infection of cattle with TB also provides a model
of the natural disease, which will provide information on the immunology and
pathogenesis of bovine TB relevant to vaccine development for both cattle
and badgers and also to the development of improved diagnostics.
17
1.6 By contrast with the cattle situation, vaccination of wildlife would require a
less demanding vaccine since, although widespread coverage would be the
target, protection of each individual animal would not be essential. The
primary rôle of a wildlife vaccine would be to reduce the severity of disease in
the target species and the consequent rate of transmission to cattle.
However, a wildlife vaccine would only be effective in controlling TB in cattle if
most cattle TB infections derived from wildlife, a point that at present is in
doubt.
1.7 If an effective vaccine was available for wildlife, the logistics of
vaccinating a badger population in the wild presents enormous challenges.
The effectiveness of vaccination is likely to be greatly influenced by the route
of administration, but there are practical constraints on which route can be
employed; oral vaccination is likely to be the preferred route for use in the
badger but by this route it may be difficult to achieve a protective immune
response.
1.8 If the strategy of badger vaccination is to be seriously pursued,
experimental facilities to conduct pathogenesis and vaccination challenge
studies would have to be made available. This will necessitate sourcing TBfree badgers and possibly rearing offspring that can be used for experimental
studies in disease secure high containment facilities. A more demanding
requirement will be to validate the potential vaccine in the field and to
determine how its success would be measured particularly as we currently
have no reliable rapid live test for TB infection in badgers. A further
consideration is the possibility of transmission of a wildlife vaccine to other
wildlife, domestic animals, man and also to cattle, and the impact that that
might have on tuberculin testing in cattle.
1.9 While there is strong pressure from some groups for successful
vaccination of cattle or badgers to be considered as the preferred strategy
there are many difficult issues to be addressed if this policy is to be pursued.
1.10 The purpose of the present exercise is to consider these issues and to
assist the ISG in further advising Ministers on the requirements for pursuing
the vaccination strategy.
1.11 There are two issues to consider, namely a badger vaccine and a cattle
vaccine.
2. BADGER VACCINE.
2.1 We must consider the factors that could influence the impact of
vaccination and these are listed below.
2.1.1 The contribution badgers make to bovine TB.
2.1.2
The extent of reduction in transmission to cattle achieved by
vaccination.
18
2.1.3 The pattern of disease in badger populations, including prevalence,
clustering, the rôle of super-excretors, the proportion of badger populations
that can be vaccinated or need to be vaccinated and cycles of infection.
2.1.4 The value of simple modelling.
2.2.1 Regarding vaccine candidates, BCG must be considered as it available
from established sources, it is cheap, its safety in man has been established,
it has been shown to influence disease in badgers and protect possums and it
would allow a fast-track time-frame.
2.2.2 New vaccine candidates must be considered as research is on-going,
but their time-frame is unknown.
2.3 The protective activity of candidate vaccines must be established. An
immune effect and some protection can be demonstrated following
intradermal vaccination of badgers with BCG, but effects on bacterial
excretion and transmission has not been studied in detail and duration of
immunity has not been determined. Pathogenesis / protection studies are
required to provide information on protective potential. The following need to
be considered.
2.3.1 The sourcing TB-free badgers.
2.3.1.1 The number of badgers required per year.
2.3.1.2 Should we use wild or captive badgers?
2.3.1.3 The need to establish a breeding colony.
2.3.1.4 The size and fecundity of captive badgers.
2.3.1.5 Badger genetic variability.
2.3.1.6 Ethical considerations must be considered.
2.3.1.7 English Nature licensing must be investigated.
2.3.2 The facilities for experimental work on badgers must be considered.
2.3.2.1 Disease containment would be an HSE responsibility.
2.3.2.2 The Home Office licensing requirements must be adhered to.
2.3.3 Experimental models must be considered.
2.3.3.1 We should consider an infectious disease and challenge model.
2.3.3.2 Immune reagents should be investigated; some are now available.
19
2.3.3.3 Previous exposure to M. bovis or environmental mycobacteria should
be considered.
2.3.4 The costs and time frame must be examined.
2.4 The route of vaccine delivery must be investigated. Oral, might be
preferable but might not immunise; aerosol is logistically difficult, but would
injection be logistically impossible?
2.5 Field trial validation must be investigated. How are protective effects of
vaccination on disease in badgers and cattle measured?
2.5.1 Current live tests to diagnose TB in the badger or other wildlife have low
sensitivity; if sensitive tests were available, a large scale trial would be
required to evaluate the impact on badger TB (is there dependence on
prevalence?).
2.5.2 To measure the effect on cattle TB herd breakdowns would necessitate
a field trial of similar scale and time-frame to the ongoing culling trial.
2.5.3 Interaction with environmental mycobacteria should be investigated.
3. CATTLE VACCINE.
3.1 The potential value must be investigated.
3.1.1 This would require a highly effective vaccine.
3.1.2 We should investigate a differential diagnostic test that distinguishes
infected animals from vaccinated animals, including successfully vaccinated
animals exposed to challenge.
3.1.3 EU legislation and trade issues must be examined.
3.2 Vaccine candidates must be examined.
3.2.1 Is BCG sufficiently effective?
3.2.2 New vaccine candidates must be examined - research is already
ongoing.
3.2.3 The time frame must be considered.
3.3 The protective activity of candidate vaccines should be established.
3.3.1 Some experimental facilities are available; is there a requirement for
more?
20
3.3.2 Experimental challenge models should be established.
3.3.3 Are immune reagents available?
3.3.4 Relevant pathogenesis studies are now ongoing.
3.3.5 Rapid testing of promising vaccine candidates and diagnostic tests
would be required.
3.4 Regarding vaccine delivery, easy administration by a variety of routes
must be examined.
3.5 A field trial will need evaluation.
3.5.1 The design should be conventional.
3.5.2 The effect on cattle TB breakdowns should be measurable.
3.5.3 Are diagnostic tests on live animal available?
3.5.4 A differential test is required; infected/vaccinated, and vaccinated
animals following field challenge?
3.5.5 The effect of environmental mycobacteria must be examined.
4. GENERAL (APPLICABLE TO BOTH CATTLE AND WILDLIFE).
4.1 Safety.
4.1.1 The impact on the food chain is important.
4.1.2 Environmental contamination, excretion, the effect on other wildlife and
domestic animals must be examined.
4.1.3 The compatibility with TB testing should be evaluated.
4.1.4 The experimental work needs to incorporate an evaluation of safety.
4.1.5 The time frame, costs and facilities must be considered.
4.2 Regarding registration / legislation:
4.2.1 Different for a Non GMO or GMO-based vaccine.
4.2.2 EU registration / legislation must be followed.
4.2.3 Time frame and cost must be considered.
21
4.2.4 VMD and industry input must be considered.
4.3 An economic and cost/benefit analysis should be undertaken, and who
pays?
4.4 Other considerations are:
4.4.1 Political acceptability.
4.4.2 To be effective will vaccination of wildlife have to be complemented by
culling?
4.4.3 We must consider the New Zealand control model.
4.4.4 We must consider the opportunities to be gained from collaboration with
other workers.
4.4.5 Southern Ireland (badger studies) will be relevant.
4.4.6 New Zealand (possum studies) will be relevant.
4.4.7 Do we need to wait for culling Trial data / results before advising on the
commitment of significant expenditure?
4.4.8 The public perception of food products from vaccinated cattle must be
considered.
4.4.9 The long term production of disease susceptible populations must be
considered.
22
APPENDIX 2.
BADGER VACCINATION:
CONSIDERATIONS
ECOLOGICAL
AND
EPIDEMIOLOGICAL
Rosie Woodroffea and Christl Donnellyb
a. Department of Wildlife, Fish and Conservation Biology, University of
California, One Shields Avenue, Davis, CA95616-8751, USA. b. Department
of Infectious Disease Epidemiology, Imperial College School of Medicine, St.
Mary's Campus, Norfolk Place, London, W2 1PG
1. INTRODUCTION – AIMS OF A VACCINATION PROGRAMME.
1.1 In judging the likely effectiveness of a badger vaccination programme, it is
important to bear in mind precisely what such a programme might be
expected to achieve. Administration of vaccines might have one or two
possible impacts on individual badgers, leading to different population effects
and, potentially, to different impacts on cattle exposure to M. bovis. First,
vaccination might be intended to render badgers immune to M. bovis infection.
This ‘classical’ effect of vaccination could be expected to control (and, given
sufficient coverage and efficacy, ultimately to eradicate) M. bovis infection in
the badger population, hence reducing exposure of cattle to M. bovis.
Alternatively, and less optimistically, administration of vaccines might be
intended to reduce bacterial shedding by infected badgers. This effect – a
more realistic expectation of BCG vaccination – could also reduce exposure of
cattle (and other badgers) to infection. Reducing bacterial shedding might
contribute to local eradication of infection; however it might also contribute to
disease control even if eradication is not achieved, and is therefore worthy of
consideration in its own right.
2. IF VACCINATION PROMOTES IMMUNITY: ERADICATING TB FROM
BADGER POPULATIONS.
2.1 Many infectious diseases have been successfully eradicated by use of
vaccination programmes. The eradication of rabies from populations of red
foxes (Vulpes vulpes) on mainland Europe through oral vaccination is a
frequently cited success story (e.g. Artois et al., 2001).
2.2 Understanding how vaccine-induced immunity leads to the eradication of
infection demands an understanding of basic epidemiology. Pathogens can
persist in host populations only if each infected host, on average, infects one
or more susceptible hosts. If the average number of new hosts infected per
case (termed R0 in a fully susceptible population) drops below one, then the
pathogen population will die out. Persistence, then, requires a supply of
susceptible hosts. By inducing immunity in hosts that have not been naturally
infected, vaccination reduces the supply of susceptible hosts available to the
pathogen. If a high enough proportion of hosts is rendered immune through
vaccination, the average number of new hosts infected per case can be forced
23
below one, and the pathogen will die out. The higher R0, the greater the
proportion of hosts that must be vaccinated to achieve eradication. Estimation
of R0 is therefore vital to determine the proportion of hosts that must be kept
immune through vaccination in order to achieve eradication.
2.3 Eradication of TB infection from closed badger populations is clearly
theoretically possible. However, several technical barriers make it unlikely
that eradication could be achieved at present.
2.3.1 The only vaccine currently available – BCG – has not been shown to
confer immunity to experimental challenge with M. bovis. Twelve badgers
vaccinated with BCG in captivity showed immune responses to vaccination
(Stuart et al., 1988). However, when seven of these were subsequently
challenged by intradermal injection of M. bovis they did become infected
(though they lived longer, and shed fewer bacteria), than did three
unvaccinated controls (Stuart et al., 1988), although it is not clear to what
extent experimental intradermal infection mimics natural exposure. It is
possible that reduced bacterial excretion by infected but vaccinated badgers
could reduce transmission and help to control the disease; however, in the
absence of any data on TB transmission routes among badgers, and on how
bacterial excretion influences infectiousness, it is impossible to make
quantitative predictions.
2.3.2 Estimation of the proportion of animals to be vaccinated requires an
estimate of R0.
This requires basic epidemiological data which are,
unfortunately, not currently available for TB in badgers. Existing models (e.g.
White & Harris, 1995; Smith et al., 1995) do predict population density and
group size thresholds for the persistence of TB in badgers. Unfortunately
these models largely fail to capture the observed distribution of infection
(disease persists in much lower-density populations than predicted). This
suggests either that some component of disease dynamics, such as social
perturbation effects (Swinton et al., 1997) or infection from alternative host
species, is important in the natural system but missing from the base models,
or that models have been incorrectly parameterised, due for example to the
sparse data available from a limited number of badger studies. In either case,
these models currently have limited predictive value but data generated by the
randomised badger culling trial (RBCT) may lead to the use of more accurate
parameter values of similar models, and may allow estimation of the
proportion of badgers that would have to be made immune to TB to reduce
transmission rates below the required threshold. Such estimates would then
need to be combined with measures of vaccine efficacy to allow approximate
calculation of the vaccine coverage required to achieve eradication. In the
absence of reliable data on either TB transmission rates within badger
populations, or vaccine efficacy, it is impossible to know whether the bait
uptake rates (and hence the potentially achievable vaccination coverages)
reported in Appendix 11 are acceptably high.
2.3.3
Classical disease eradication through vaccine-induced immunity
requires vaccinating individual hosts before they are exposed to infection. If
initial exposure occurs in young cubs that have not yet emerged from the sett,
24
it would be virtually impossible to vaccinate prior to exposure. Hughes et al.
(1996) suggest that cubs might be vaccinated through regurgitation of baits by
their mothers, but, since regurgitation has been recorded only very rarely, this
possibility remains speculative. Pre-exposure vaccination might become
possible several years into a vaccination campaign, if transmission rates could
be reduced such that animals were first exposed at a later age; however it is
not possible to predict whether or when this might be possible.
2.3.4 While driving the average number of new hosts infected per case below
one will eradicate infection eventually (in the absence of reinfection from
outside sources), the process may be slow in a disease with a long infectious
period. Given the longevity of badgers, the time course of eradication might be
“guesstimated” to take more than a decade, and possibly longer.
2.3.5 Badgers are not the only species that becomes infected with TB. If
badgers are the only major reservoir host for TB, then eradication of TB from
badger populations could be expected to lead to disappearance of the
infection from other wildlife species (as well as from cattle), just as rinderpest
disappeared from African ungulate populations when it was eradicated from
cattle (Plowright, 1982). Vaccination cover might be suspended at that point.
However, badgers’ rôle in maintaining TB infection in multi-host systems is
currently unknown; thus it would probably be necessary to maintain
vaccination coverage in the long term to avoid re-infection from other wildlife
hosts, or from cattle.
3 IF VACCINATION REDUCES BACTERIAL SHEDDING: REDUCING
CATTLE EXPOSURE.
3.1 As an alternative to TB eradication, vaccination of badgers might be used
to reduce bacterial shedding and, hence, exposure of cattle (and other
badgers) to M. bovis. BCG might fulfil this more limited rôle but the potential
effectiveness of such an approach cannot be predicted; ultimately, the only
way to assess this would be to trial it over statistically meaningful numbers of
farms but a cautious approach to this possibility would be warranted since:
3.1.1 The quantitative effect of vaccination on bacterial shedding is not well
established (Stuart et al., 1988); more captive studies would be needed to
further evaluate this.
3.1.2 Data are not currently available to determine how TB risk to cattle
reflects bacterial shedding by badgers (or even TB prevalence in badgers).
Hence it is currently impossible to know what level of shedding might be
deemed sufficient to reduce cattle exposure.
4 OTHER CONCERNS ABOUT VACCINATING BADGERS.
4.1 The points raised above suggest that, at present, there can be little shortterm expectation of successfully controlling cattle TB by vaccinating badgers,
irrespective of the aim of the vaccination programme. Several other concerns
about these approaches also deserve attention.
25
4.1.1 What proportion of cattle TB cases originate in badgers? At present,
the proportion of cattle TB cases originating in badgers is unknown. Hence, it
is impossible to predict what proportion of cases might be prevented by
vaccination. General models suggest that vaccination is likely to control
infection more slowly and less effectively than culling (Barlow, 1996) although
this would depend upon the completeness and effectiveness of vaccination
compared with that of culling. Hence, as a first approximation, one might
expect vaccination to be less effective than culling, unless the social
disruption caused by culling greatly increases transmission rates (Swinton et
al., 1997). Results of the RBCT and associated research on social disruption,
should therefore help to provide a more informed picture of the possible
impacts of badger vaccination on cattle TB, and thus permit a closer
approximation of the potential cost-effectiveness of this approach.
4.1.2 How can the effects of vaccination be measured? Given the paucity of
data on TB transmission between badgers and to cattle, and the consequent
difficulties of building predictive models, at present not even the vaguest
estimate of the effectiveness of badger vaccination could be achieved without
a field trial. However, since general models suggest that vaccination is likely
to control infection more slowly and less effectively than culling (Barlow,
1996), a vaccination trial would need to be of comparable scale, and probably
greater duration, than the ongoing RBCT. Such a trial would require a very
substantial investment of time and funding, with (in contrast to culling) not
even anecdotal evidence to suggest a likely effect. Such an investment might
be better delayed until ongoing studies provide better “guesstimates” of the
possible effectiveness of badger vaccination in influencing cattle TB.
4.1.3 Safety concerns. Several delivery methods have been considered for
badger vaccines (Appendix 11). However, remote delivery – using oral baits
or a combination of intranasal aerosol and conjunctival installation as used in
possums (Appendix 3) – is favoured, given the costs, difficulties, and variable
effectiveness of capturing badgers (Hughes et al., 1996). Such remote
delivery methods have the potential to expose other wildlife and – of perhaps
greater concern – cattle to TB vaccine. Cattle vaccinated by accident in this
way could be expected to react to the tuberculin test; hence badger
vaccination has the potential to generate spurious and bogus ‘breakdowns’
that could be extremely costly. The risks of such events need to be assessed
carefully, since poorly designed or poorly implemented delivery systems could
have the potential to make the situation worse rather than better.
5. CONCLUSIONS AND RECOMMENDATIONS.
5.1 The points discussed above indicate great uncertainty about the potential
benefits of vaccinating badgers against TB. Using available data, it is
currently impossible to predict, even in the vaguest way, whether vaccination
might be expected to prove beneficial, ineffective, or damaging. While
vaccination could reduce cattle exposure to M. bovis, poorly designed or laxly
implemented delivery methods have the potential – through accidental
vaccination of cattle – to cause as many TB incidents in cattle as they prevent.
26
One firm conclusion can be drawn: vaccinating badgers is not a ‘quick fix’ that
could be implemented outside the RBCT with any expectation of effectiveness
in the short or medium term.
5.2 These discussions highlight the fact that many of the concerns about the
potential effectiveness of badger vaccination stem from lack of data on the
transmission of TB among badgers, and between badgers and cattle. Some
of the necessary data will be provided by the ongoing RBCT and associated
research. Hence, the outcome of the trial might inform expectations of the
potential success of any vaccination programme and the extent to which
vaccinating badgers might potentially influence cattle TB. In addition, the trial
will provide much-needed data on TB epidemiology in badger populations that
would help in the design of vaccination programmes. However even with trial
data we will still lack some important information on transmission.
5.3 Given (i) a lack of confidence in the possible effectiveness of badger
vaccination in controlling cattle TB; (ii) the cost and timescale of the field trial
that would be necessary to evaluate the effectiveness of this measure; and
(iii) the expectation that data from the ongoing RBCT, and associated
research, will provide better estimates of what might be achievable, and how
that might best be achieved, I recommend that field trials of badger
vaccination are not to be carried out at this point, but that the situation be reassessed when results of the RBCT and other work become available.
6. ACKNOWLEDGEMENTS.
6.1 I would like to thank Sir David Cox for epidemiological advice during the
preparation of this Appendix.
7. REFERENCES.
Artois, M., Delahay, R., Guberti, V., Cheeseman, C. (2001). Control of
infectious diseases of wildlife in Europe. Veterinary Journal, 162, 141-152.
Barlow, N.D. (1996). The ecology of wildlife disease control: simple models
revisited. Journal of Applied Ecology, 33, 303-314.
Hughes, M.S., Neill, S.D., Rogers, M.S. (1996). Vaccination of the badger
(Meles meles) against Mycobacterium bovis. Veterinary Microbiology, 51,
363-379.
Plowright, W. (1982). The effects of rinderpest and rinderpest control on
wildlife in Africa. Symposia of the Zoological Society of London, 50, 1-28.
Smith, G. C., Richards, M. S., Clifton-Hadley, R. S., Cheeseman, C. L. (1995).
Modelling bovine tuberculosis in badgers in England: Preliminary results,
Mammalia, 59, 639-650.
27
Stuart, F.A., Mahmood, K.H., Stanford, J.L., Pritchard, D.G. (1988).
Development of diagnostic tests for, and vaccination against, tuberculosis in
badgers. Mammal Review, 18, 74-5.
Swinton, J., Tuyttens, F., Macdonald, D. W., Nokes, D. J., Cheeseman, C. L.
Clifton-Hadley, R. (1997). A comparison of fertility control and lethal control of
bovine tuberculosis in badgers: the impact of perturbation induced
transmission. Philosophical Transactions of the Royal Society, 264, 1-13.
White, P. C. L., Harris, S. (1995). Bovine tuberculosis in badger (Meles
meles) populations in Southwest England: the use of a spatial stochastic
simulation model to understand the dynamics of the disease. Philosophical
Transactions of the Royal Society of London, Series B, 349, 391-413.
28
APPENDIX 3.
BCG VACCINATION OF WILDLIFE.
Glyn Hewinson
Veterinary Laboratories Agency, New Haw, Addleston, Surrey KT15 3NB
1. INTRODUCTION.
1.1 This appendix reviews current knowledge on the use and efficacy of BCG
in wildlife species. It concentrates on the use of BCG in possums, ferrets and
badgers although subcutaneous vaccination with between 104 to 107 cfu BCG
has also been shown to confer significant protection against infection and
disease in domesticated deer (Griffin et al, 1999).
2. BCG VACCINATION IN POSSUMS.
2.1 Challenge Model.
2.1.1 Two models have been developed for the evaluation of vaccines in
possums. The first consists of an intratrachael inoculation of 100 - 1000 cfu of
M. bovis (Aldwell et al, 1995 a & b). In this model lesions are confined to the
lungs and lymph nodes of the thorax, except in the advanced stage of disease
(Cooke et al, 1999). However, disease progression is more rapid than
observed for natural infection and possums develop severe pneumonia six to
eight weeks after challenge. More recently a low dose aerosol challenge
model has been developed using an aerosol-generating chamber in which a
dose of 104 cfu in the nebuliser produces eight to fifteen primary lesions
resulting in a more natural time scale for disease progression (Skinner et al,
2001). In an attempt to develop a natural challenge model, vaccinated and
non-vaccinated possums were housed with possums that had been
experimentally infected with M. bovis using the intratrachael challenge model.
In these experiments transmission of disease was highly variable with
infection rates for in-contact possums ranging from 10% to 60%. This level of
variation prevented interpretation of the protection results (Skinner et al, 2001;
Corner, 2001).
2.2 BCG vaccination.
2.2.1 A number of vaccination studies have been undertaken in possums
using BCG which have demonstrated a significant level of protection to
experimental challenge. These studies have also indicated that the route of
vaccination affects the protective efficacy achieved. In all of these studies
vaccination has not prevented animals from developing tuberculous lesions
but has conferred a significant reduction in the dissemination of M. bovis to
the spleen and liver. Vaccination with BCG has also been shown to influence
the immunopathology associated with M. bovis challenge. In comparison with
the predominantly necrotic lesions present in non-vaccinated animals, the
29
lung lesions in vaccinated animals are mostly granulomas with minimal
necrosis and few acid fast bacilli (Aldwell et al, 1995a). Vaccination with BCG
might be expected to be more efficacious against natural infection where the
challenge is less stringent, the possums less stressed and where the course
of infection is longer. A recent field trial of BCG vaccination in possums
suggests that this may be the case (see below).
2.2.2 In the first BCG vaccination study, groups of possums were vaccinated
with 106 cfu BCG by the subcutaneous, intratrachael and intragastric routes of
vaccination (Aldwell et al, 1995a).
Subcutaneous and intratrachael
vaccination resulted in a marked reduction in the severity of tuberculosis
compared with that observed in the non-vaccinated controls and animals
vaccinated intragastrically. Intragastric vaccination gave no protection against
experimental intratrachael challenge with M. bovis.
2.2.3 In a second study designed to compare the efficacy of different routes
of infection likely to be of use in the field, possums vaccinated intranasally by
aerosol spray or by the subcutaneous route with 106 cfu BCG gave greater
levels of protection against challenge compared to animals vaccinated orally
with 108 cfu BCG (Aldwell et al, 1995b). In order to determine whether the
lack of efficacy of oral vaccination was due to degradation of BCG in the
stomach, the levels of protection against tuberculosis were compared
between possums vaccinated with 108 cfu BCG intraduodenally and those
vaccinated with the same sized inoculum via the intragastric route (Buddle et
al, 1997). The animals vaccinated via the intragastric route had a 100-fold
reduction in bacterial burden in the lungs and increased lymphocyte
responses to PPD-B indicating that protection of live BCG from degradation in
the stomach should improve efficacy.
2.3 Duration of protection.
2.3.1 One of the key requirements for vaccination of wildlife is that protection
should be long lasting. In a recent study in captive possums, animal were
vaccinated with a single dose of approximately 1 x 105 cfu of BCG by
intranasal aerosol and challenged by intratrachael instillation of M. bovis 2, 6
or 12 months after vaccination (Corner et al, 2001). Vaccination induced
moderate protection from challenge as determined by a decrease in
pulmonary lesions and dissemination to body lymph nodes with intervals of 2
or 6 months between vaccination and challenge but a lower level of protection
was observed when the interval was increased to twelve months.
2.4 Effect of Multiple doses of BCG.
2.4.1 Recently a vaccination regime combining intranasal aerosol and
conjunctival instillation (total inoculum: 3 x 107 cfu BCG) has been used to
study the effect of repeated doses on the protective efficacy of BCG in
possums (Corner et al, 2002a). In these experiments captive possums were
vaccinated either 12 times at weekly intervals, twice at 6-weekly intervals or
once. Protection was greatest in the group vaccinated 12 times indicating that
protection could be enhanced if vaccinations were repeated at weekly
30
intervals while no benefit or detriment resulted from revaccination after longer
intervals (1-2 months).
2.5 Field trial of BCG in Possums.
2.5.1 To date one field trial using BCG has been completed in New Zealand
(Corner et al, 2002b). A population of possums in which M. bovis infection
was endemic within a 56 hectare site was vaccinated with 3 x 106 cfu BCG by
a combination of intranasal aerosol and conjunctival instillation. Possums
were revaccinated on average every 5 months and the population was
monitored bimonthly over 2 years by capture and release. Over the 2 years
300 possums were recruited to the study, with 149 being allocated to the
vaccination group. There were significantly fewer cases of tuberculosis in the
vaccinated (4 cases) than in the unvaccinated group (13 cases; p=0.023).
The vaccine efficacy was 69%.
2.5.2 Although the results are encouraging it is important to note that there
were a number of limitations in the design and conditions that occurred during
the study. The number of incident and prevalent cases at each trapping
session declined progressively during the study. No new cases of TB were
detected in the last 8 months of the study. This may have been caused by a
steady decline in the population of the site over time due to a culling operation
in the area surrounding the site. This encouraged dispersal of juvenile
possums away from the site and prevented recruitment of juveniles from the
surrounding area. At the conclusion of the study the susceptible population
on the site was 25% of the long term mean population. At this density the
transmission of infection appeared to be reduced. In an attempt to increase
the statistical power of the study and elevate the incidence of disease in the
population, possums experimentally infected with M. bovis of a unique
molecular profile were released onto the site. However, this did not result in
any additional cases of TB.
2.6 Formulations for oral delivery of BCG.
2.6.1 A number of encouraging studies using novel oral bait formulations for
BCG have been performed in New Zealand (Aldwell et al., 2003b Bryce
Buddle, personal communication). Although, BCG cultures delivered orally or
intragastrically were relatively ineffective, BCG delivered intraduodenally or
intragastrically with an ant-acid medication induced protection against an
experimental challenge (Buddle et al. 2002). These encouraging results
demonstrate that BCG could be effective if it was protected from degradation
in the stomach. BCG encapsulated in a lipid matrix (Aldwell et al., 2003a) has
been fed to possums and resulted in significant protection against an
experimental aerosol challenge with M. bovis (Aldwell et al., 2003b).
Currently a dose response trial is in progress to determine how much BCG is
required in oral bait to induce optimal protection (Bryce Buddle, personal
communication).
2.7 Vaccines other than BCG.
31
2.7.1 The very high susceptibility of possums to M. bovis infection and limited
protection of possums against experimentally-induced infection provides
opportunities to identify tuberculosis vaccines that are more effective than
BCG. In one study, killed Mycobacterium vaccae mixed with live BCG and
administered intranasally induced significantly greater protection than BCG
alone (Skinner et al., 2002). In another study, vaccination with two newly
derived attenuated M. bovis strains induced a higher degree of protection than
that seen with BCG (Buddle et al., 2002).
3. BCG VACCINATION IN FERRETS.
3.1.1 The route of transmission of M. bovis to ferrets is usually by ingestion
through the scavenging of infected carrion. Consequently an oral M. bovis
challenge model has been used to assess the efficacy of BCG in ferrets. In
this model ferrets are infected orally with 5 x 106 cfu by feeding with infected
lung tissue (Qureshi et al, 1999; Cross et al, 2000). The outcome of challenge
is determined twenty weeks after challenge by autopsy, histology and
bacterial culture. This route of infection gives rise to progressive disease with
lesions primarily in the mesenteric lymph nodes where the bacterial burden is
highest and also in the head region lymph nodes. The pathology observed in
this model mimics natural infection in the ferret.
3.2 BCG Vaccination Studies.
3.2.1 In a recent study ferrets were orally vaccinated with two doses of 5 x
108 cfu live BCG incorporated into dietary meat administered 4 weeks apart
(Qureshi et al, 1999). Although oral vaccination did not prevent infection,
significant manifestations of protection were observed most notably a
reduction in the bacterial burden, incidence and severity of TB in the head
lymph nodes. Interestingly, blood from only 2/9 vaccines gave tuberculin
specific lymphocyte responses suggesting that systemic immune responses
may have been less important than local immunity in mediating protection in
this study. Subcutaneous vaccination of ferrets with 5 x 106 cfu BCG between
the shoulder blades also induced protection against oral challenge but again
did not prevent infection (Cross et al, 2000). In this case protection was
characterised by a significant reduction in bacterial burden, the prevention of
gross lesions in the mesenteric lymph nodes and reduced bacterial spread to
thoracic lymph nodes. In contrast, to the favourable results in possums,
vaccination by intraduodenal inoculation of 5 x 107 cfu BCG was not effective
in reducing disease (Cross et al, 2000). Both subcutaneous and intraintestinal vaccination with BCG induced tuberculin-specific lymphocyte
reactivity.
4. BCG VACCINATION IN BADGERS.
4.1 Introduction.
32
4.1.1 The early observation that badgers may survive for a number of years
after natural or experimental infection (Mahmood et al., 1987; Newell et al,
1997) suggests that they are not especially susceptible to M. bovis infection.
Preliminary studies of the badger immune response to experimental infection
led to the conclusion that badgers exhibit an immune spectrum during
tuberculosis akin to other mammalian species (Thorns and Morris, 1983).
More recent studies on the pathology and immunology of tuberculous badgers
suggest that they are capable of mounting a vigorous cell-mediated immune
response even when heavily infected and that they can contain infection,
possibly for several years (Newell et al, 1997; Gavier-Widen et al, 2001).
4.2.1 Protocols for the experimental infection of badgers with M. bovis have
been developed at VLA in previous studies (Pritchard et al, 1988; Mahmood et
al, 1987). Two groups of four badgers were challenged with either 103 or 104
M. bovis either intradermally or intratracheally. Two animals thus received
each dose/route combination. The intratracheal challenge route failed to lead
to tuberculosis in all cases and their immunological responses were the same
as the control, uninfected animals. The four intradermally challenged animals
all developed miliary tuberculosis accompanied by positive skin test and
increases in lymphocyte transformation and anti-mycobacterial antibodies.
These studies highlighted the need to develop an improved challenge model
for badgers.
4.3 Development of a badger challenge model in the Republic of Ireland.
4.3.1 Development of an experimental M. bovis challenge model for badgers
has started at the Badger Research and Observation Complex (BROC) facility
in Abbotstown. In the first instance, groups of uninfected badgers held in the
BROC facility were challenged intratracheally with M. bovis over a range of
doses (ca. 100 – 10,000 cfu). After a set interval (15 weeks), all animals were
sacrificed and the presence and extent of infection determined at post
mortem. Lung lesions were observed in all animals receiving 10,000 cfu.
This challenge dose of M. bovis is now being used to infect further groups of
badgers in order to determine the reproducibility of the model and to examine
the progression of disease over time. This will be measured immunologically,
physiologically and pathologically by serial necropsy. VLA is providing
support for the immunological aspects of this study through a Defra funded
project.
4.4 BCG vaccination.
4.4.1 In a previous study performed at VLA, Stuart et al. (1988) reported the
protective effect of BCG against M. bovis in badgers. An intradermal
inoculation of 106 cfu of BCG was found to be non-pathogenic, was not
excreted by the badgers and was not transmitted to in-contact animals. There
was an increase in LTT response but no skin-test reaction or antibody
increase in all vaccinated badgers. When seven of these badgers were
subsequently challenged intradermally with 104 M. bovis, between 5 and 25
33
months after vaccination, the LTT response tended to fall and the antibody
response rose. Skin-test responses became positive. The vaccinated
badgers were shown to live longer, shed fewer tubercle bacilli and their
inoculation sites healed more rapidly after challenge than a group of three
control badgers. Thus, although only small numbers of badgers were
involved, cell-mediated immunity did seem to be enhanced by BCG
vaccination, leading to prolonged survival of the badgers and delayed
excretion of tubercle bacilli.
4.4.2 In a recent study in the Republic of Ireland, the immunological
responses were measured in a resident population of badgers following
subcutaneous vaccination with BCG (Southey et al, 2001). Three doses of
vaccine were administered 1 cm above right ear. An initial dose of 5 x 104 cfu
BCG was followed 17 weeks later with a boost of 5 x 104 cfu and a second
boost of 5 x 105 cfu at week 30. Cellular immune responses were only
observed after the third dose of BCG (at week 42) and were characterized by
lymphocyte blastogenic responses to PPD-B. Antibody responses to MPB83
(the Brock Test) were minimal. This study highlighted the need to optimise
the dose and route of BCG vaccination for badgers before further field
evaluation could be performed. It is clear that the testing of BCG in badgers is
lagging some way behind that in possums and ferrets, not least because of
the lack of facilities to perform such work.
5. POST-EXPOSURE VACCINATION.
5.1 Vaccination of badgers in the field will inevitably result in the vaccination
of many badgers that have already been infected with M. bovis and have
clinical or subclinical disease. It is possible that the ensuing immune
response to vaccination may result in exacerbation of the disease (the Koch
phenomenon).
This might have two effects.
First, if post-exposure
vaccination exacerbates disease it might result in increased spread of
infection. Second, vaccination might reveal occult disease which could
confound interpretation of a field trial since the number of TB cases in the
vaccinated population would be selectively increased compared to that in the
untreated population.
5.2 A number of post-exposure experiments have been performed in mice
using BCG (Turner et al, 2000; Moreira et al., 2002). When administered to
mice already infected with M. tuberculosis a single dose of BCG did not
exacerbate disease nor effect the bacillary loads in the organs of the infected
mice. Neither did it have a therapeutic effect on the pre-existing infection.
However, repeated BCG vaccination of infected mice resulted in exacerbation
of the granulomatous response with detrimental pathologic changes in the
lungs. The effect became more prolonged and severe if the vaccine was
given twice or three times (at 15 day intervals) although there was no effect on
the bacillary load in the lungs (Turner et al., 2000).
5.3 Exacerbation of TB following post-exposure vaccination with BCG has not
been reported for any other species including man. “There have not been
reports of significant harm associated with boosters or revaccination with BCG
34
or harm associated with BCG vaccination of tuberculin skin test positive
individuals with latent TB." (Egsmore, 1968).
6. CONCLUSIONS.
6.1 Although BCG does not induce sterilising immunity in possums, ferrets or
badgers, it has been shown to induce a marked reduction in pathology,
disease, bacterial burden and haematogenous dissemination of M. bovis. The
only recorded field trial of BCG in possums has indicated that an efficacy of
69% can be achieved with repeated doses of BCG.
6.2 To date the published data suggest that subcutaneous and aerosol
vaccination might be more effective than oral vaccination for BCG and that
further work is required to produce formulations which protect BCG from the
stomach acids. However, recent data have shown that some oral bait
formulations under development in New Zealand may be as effective as
subcutaneous vaccination, at least in possums. In humans, oral BCG
vaccination required much larger doses (ca. 3,000 times the dose) and was
hence more expensive. It also proved difficult to control the effective dose
with oral administration as some viable bacteria were inactivated in the
stomach and many passed right through the intestinal tract. If this were the
case in badgers oral vaccination would increase the risk of exposure of
sentinel animals including domestic livestock and other wildlife.
7.
REQUIREMENTS FOR DEVELOPMENT OF BCG VACCINATION
REGIMES FOR BADGERS.
7.1 Facilities for badger vaccination experiments.
7.2 M. bovis challenge model for badgers including studies on pathogenesis
and kinetics of the immune response.
7.3 Optimised dose of BCG for use in badgers.
7.4 Proof of principle experiments to show that BCG can give demonstrable
protection against M. bovis challenge in badgers and reduce bacterial
excretion.
7.5 Safety data for BCG in badgers using a single dose, 10 x overdose, and
a repeated dose.
7.6 Determination of duration of protective immunity and effect of boosting.
7.7 Development of effective systems for oral delivery of BCG to badgers.
7.8 Development of immunological assays to monitor field vaccination studies
(including differential diagnostic assays to distinguish protected from infected
badgers).
35
7.9 In addition to the above there may be a requirement to demonstrate that
BCG does not exacerbate disease in pre-infected badgers.
8. ACKNOWLEDGEMENTS.
8.1 Bryce Buddle, Leigh Corner, Frank Aldwell and Eamonn Gormley
provided unpublished data and information.
9. REFERENCES.
Aldwell F.E., Keen D.L., Stent V.C., Thomson A., Yates G.F., de Lisle G.W.,
Buddle B.M. (1995a). Route of BCG administration in possums affects
protection against bovine tuberculosis. NZ vet J, 43, 356-359.
Aldwell F.E., Pfeffer A., DeLisle G.W., Jowett G., Heslop J., Keen D.,
Thomson A., Buddle B.M. (1995b). Effectiveness of BCG vaccination in
protecting possums against bovine tuberculosis. Res Vet Sci., 58, 90-5.
Aldwell F.E., Tucker I.G., de Lisle G.W., Buddle B.M. (2003a). Oral delivery of
Mycobacterium bovis BCG in a lipid formulation induces resistance to
pulmonary tuberculosis in mice. Infect Immun., 71, 101-8.
Aldwell F.E., Keen D.L., Parlane N.A., Skinner, M.A., de Lisle G.W., Buddle
B.M. (2003b). Oral vaccination with Mycobacterium bovis BCG in a lipid
formulation induces resistance to pulmonary tuberculosis in brushtail
possums. Submitted for publication.
Buddle, B. M., Skinner M. A., Wedlock D. N., Collins D. M., de Lisle G. W.
(2002). New generation vaccines and delivery systems for control of bovine
tuberculosis in cattle and wildlife. Vet. Immunol. Immunopathol., 87, 177-185.
Buddle B.M., Aldwell F.E., Pfeffer A., de Lisle G.W. (1994). Experimental
Mycobacterium bovis infection in the brushtail possum (Trichosurus
vulpecula): pathology, haematology and lymphocyte stimulation responses.
Vet Microbiol., 38, 241-54.
Buddle B.M., Aldwell F.E., Keen D.L., Parlane N.A., Yates G., de Lisle G.W.
(1997). Intraduodenal vaccination of brushtail possums with bacille CalmetteGuerin enhances immune responses and protection against Mycobacterium
bovis infection. Int J Tuberc Lung Dis., 1, 377-83.
Cooke M.M., Buddle B.M., Aldwell F.E., McMurray D.N., Alley M.R. (1999).
The pathogenesis of experimental endo-bronchial Mycobacterium bovis
infection in brushtail possums (Trichosurus vulpecula). NZ vet J., 47 187-192.
Corner L.A., Buddle B.M., Pfeiffer D.U., Morris R.S. (2001). Aerosol
vaccination of the brushtail possum (Trichosurus vulpecula) with bacille
Calmette-Guerin: the duration of protection. Vet Microbiol., 81,181-91.
36
Corner L.A.L. 2001. Natural transmission of bovine tuberculosis in captive
brushtail possums (Trichosurus vulpecula). In Bovine tuberculosis in brushtail
possums (Trichosurus vulpecula): Studies on vaccination, experimental
infection and disease transmission. PhD Thesis, Massey University, New
Zealand.
Corner L.A., Buddle B.M., Pfeiffer D.U., Morris R.S. (2002a). Vaccination of
the brushtail possum (Trichosurus vulpecula) against Mycobacterium bovis
infection with bacille Calmette-Guerin: the response to multiple doses. Vet
Microbiol., 84, 327-36.
Corner L.A., Norton S., Buddle B.M., Morris R.S. (2002b). The efficacy of
bacille Calmette-Guerin vaccine in wild brushtail possums (Trichosurus
vulpecula). Res Vet Sci., 73, 145-52.
Cross M.L., Labes R.E., Mackintosh C.G. (2000). Oral infection of ferrets with
virulent Mycobacterium bovis or Mycobacterium avium: susceptibility,
pathogenesis and immune response. J Comp Pathol., 123,15-21
Cross M.L., Labes R.E., Griffin J.F., Mackintosh C.G. (2000). Systemic but
not intra-intestinal vaccination with BCG reduces the severity of tuberculosis
infection in ferrets (Mustela furo). Int J Tuberc Lung Dis., 4, 473-80
Egsmore, T. (1968). The effect of BCG vaccination in naturally infected
tuberculin-positive individuals. Scand. J. Resp. Dis. 49,123-140.
Gavier-Widen D., Chambers M.A., Palmer N., Newell D.G., Hewinson R.G.
(2001). Pathology of natural Mycobacterium bovis infection in European
badgers (Meles meles) and its relationship with bacterial excretion. Vet Rec.,
148, 299-304.
Griffin J.F., Mackintosh C.G., Slobbe L., Thomson A.J., Buchan G.S. (1999).
Vaccine protocols to optimise the protective efficacy of BCG. Tuber Lung
Dis., 79, 135-43.
Mahmood K.H., Rook G.A.W., Stanford J.L., Stuart F. A., Pritchard D.G.
(1987). The immunological consequences of challenge with bovine tubercle
bacilli in badgers (Meles meles). Epidemiology and Infection, 98, 155-163.
Moreira A.L., Tsenova L., Aman M.H., Bekker L.G., Freeman S., Mangaliso
B., Schroder U., Jagirdar J., Rom W.N., Tovey M.G., Freedman V.H., Kaplan
G. (2002). Mycobacterial antigens exacerbate disease manifestations in
Mycobacterium tuberculosis-infected mice. Infect Immun. 70, 2100-7.
Newell D.G., Clifton-Hadley R.S., Cheeseman C.L. (1997). The kinetics of
serum antibody responses to natural infections with Mycobacterium bovis in
one badger social group. Epidemiology and Infection, 118, 173-80.
37
Pritchard D.G., Stuart F.A., Brewer J.I., Mahmood, K.H. (1987). Experimental
infection of badgers (Meles meles) with Mycobacterium bovis. Epidemiology
and Infection, 98, 145-154.
Qureshi T., Labes R.E., Cross M.L., Griffin J.F., Mackintosh C.G. (1999).
Partial protection against oral challenge with Mycobacterium bovis in ferrets
(Mustela furo) following oral vaccination with BCG. Int J Tuberc Lung Dis., 3,
1025-33.
Skinner, M. A., Keen D. L., Parlane N. A., Yates G. F., and Buddle B. M..
2002. Increased protection against bovine tuberculosis in the brushtail
possum (Trichosurus vulpecula) when BCG is administered with killed
Mycobacterium vaccae. Tuberculosis 82,15-22.
Skinner M.A., Wedlock D.N., Buddle B.M. (2001). Vaccination of animals
against Mycobacterium bovis. Rev Sci Tech, 20, 112-32
Southey A., Sleeman D.P., Lloyd K., Dalley D., Chambers M.A., Hewinson
R.G., Gormley E. (2001). Immunological responses of Eurasian badgers
(Meles meles) vaccinated with Mycobacterium bovis BCG (bacillus calmette
guerin). Vet Immunol Immunopathol., 79,197-207.
Stuart F.A., Mahmood K.H., Stanford J.L., Pritchard D.G. (1988).
badgers. Mammalian Review, 18, 74-75.
Thorns C.J., Morris J.A. (1983). The immune spectrum of Mycobacterium
bovis infections in some mammalian species: a review. Veterinary Bulletin,
53, 543-550.
Turner J., Rhoades E.R., Keen M., Belisle J.T., Frank A.A., Orme I.M. (2000).
Effective preexposure tuberculosis vaccines fail to protect when they are
given in an immunotherapeutic mode. Infect Immun. 68, 1706-9.
38
APPENDIX 4.
BCG IN WILD-LIFE AND DOMESTIC LIVESTOCK; VIRULENCE AND
EFFICACY.
Jo Colston (deceased)
National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7
1AA
1. INTRODUCTION.
1.1 Extensive testing of virulence was carried out by Calmette and his
colleagues during their development of BCG in the early part of the 20th
century. In addition to this there has been extensive work carried out in wildlife or domestic livestock to investigate protective efficacy or immunogenicity
of BCG, rather than virulence; these studies allow us to draw some
conclusions about the virulence of BCG in these species. Calmette and
colleagues also carried out experiments in which large doses of BCG were
administered to animals which were already infected with M. tuberculosis;
because of the potential importance of these studies, these have been
included in the discussion (see section 3).
2. EXPERIMENTS ON THE VIRULENCE OF BCG CARRIED OUT BY
CALMETTE AND COLLEAGUES.
2.1 Cattle.
2.1.1
In Calmette and Guerin’s original work, 100mg of BCG was
administered intravenously to cattle. The recipients were reported to have
developed a “typhoid-like” disease (Le seul effet de cette injection massive est
de provoquer une maladie generale d’allure typhique, qui guèrit spontanement
après 15 a 20 jours de fievre, sans produire la moindre lesion folliculair), but
all recovered and remained healthy.
2.2 Guinea pigs.
2.2.1
Guinea pigs given 5-10mg of BCG intradermally or 3-5mg
intraperitoneally remained healthy. 50-100mg administered into the stomach
resulted in lymph node swelling but again the animals remained healthy.
2.3 Rabbits.
2.3.1 1-5mg BCG injected sub-cutaneously had no effect on the health of the
rabbits. Intravenous injection of 100mg also had no effect.
2.4 Dogs.
2.4.1 A single 4Kg dog was given 0.5mg BCG intravenously, followed five
days later with 1mg by the same route, and three months later 10mg
39
intraperitoneally. The dog remained healthy in spite of a slightly elevated
temperature after the second and third injection. A post mortem examination
carried out six months after the last injection revealed no gross lesions, but
intact mycobacteria were detectable.
2.5 Monkeys.
2.5.1 A Macaque cynomolgus was given 2mg of BCG intraperitoneally, and
four months later a further intraperitoneal injection of 4mg. The animal
remained healthy, and there was no evidence of tuberculosis on post mortem
examination.
2.6 Horses.
2.6.1 One horse was given 10mg BCG intravenously; the horse developed a
slight fever 12 days later lasting for 6 days. A second horse received 100mg
intravenously; this animal developed temperature oscillations between 39.5oC
and 40oC for two weeks. The animal lost appetite, developed rapid breathing
and a high pulse rate. There was evidence of pulmonary congestion between
seven and eight days, but by six weeks the animal had fully recovered.
Another horse was given 200mg intravenously and sacrificed two weeks later.
Mycobacteria could be found in lymphoid tissue, but there was no evidence of
tuberculosis-like lesions.
3. STUDIES ON EFFICACY AND IMMUNOGENICITY OF BCG.
3.1 With the exception of the work by Calmette et al, most of the work which
has involved exposing wild-life or domestic livestock to BCG, has been carried
out to investigate protective efficacy or immunogenicity, rather than virulence.
Nevertheless, these studies do allow us to draw some conclusions about the
virulence of BCG in these species. The information set out below summarises
research on vaccination of different species of animals with BCG.
3.2 Cattle.
3.2.1 The original work of Calmette (see Section 2) would have involved
doses of more than 1010 BCG. More recently doses have ranged from 104 to
108 viable BCG, usually given subcutaneously. One study (Buddle et al,
1995) involved intratracheal vaccination. Virtually all of these studies reported
some level of protection in animals which were subsequently challenged with
virulent M.bovis, although this appeared to wane after approximately 5 years
(Bergeen, 1977). With the exception of the report by Calmette and Guerin
(see 2.1.1), there have been no reports of adverse affects following the
administration of BCG.
3.3 Deer.
3.3.1 Various experiments have been carried out in which BCG-vaccinated
deer have been challenged with M.bovis BCG; dosage has ranged from 5 x
104 – 5 x 108 viable bacteria (Griffin et al, 2001; Miller et al, 1999; Slobbe et
40
al, 1999; Hook et al, 1996). As with cattle vaccination, all of these studies
reported some level of protection and there were no reports of adverse affects
from the vaccination.
3.4 Possums.
3.4.1 Possums have been vaccinated with BCG by a variety of routes,
including subcutaneous, aerosol and intraduodenal (Aldwell et al, 1995;
Buddle et al, 1997). One study involved a combination of intranasal aerosol
and conjunctival instillation. No adverse effects of vaccination have been
reported. In all experiments, there was a reduction in disease severity in the
BCG vaccinated animals following challenge with viable M.bovis.
3.5 Ferrets.
3.5.1 BCG has been given orally to ferrets, followed by oral challenge with
virulent M.bovis. There was significant reduction in gross lesions, and in
culture and acid fast positive lymph nodes in the vaccinated groups. No
adverse side effects of vaccination were reported (Qureshi et al, 1999).
3.5.2 In another series of experiments, ferrets were vaccinated with live BCG
via subcutaneous injection or intra-duodenal inoculation.
Only the
subcutaneous route was effective in reducing disease (Cross et al, 2000).
3.6 Badgers.
3.6.1 Numbers of experimental studies have been carried out on vaccination
of badgers with BCG (Stuart et al, 1988; Southey et al, 2001). Generally the
route of administration has been intradermal or subcutaneous. No adverse
effects have been reported and the experiments reveal an increase in cellmediated immunity against M.bovis.
3.7 Rabbits.
3.7.1 Tuberculosis in rabbits is claimed to resemble human TB more closely
than TB in other common laboratory animals. Immunisation of rabbits with
BCG has been carried out by a number of workers (Lurie et al, 1952;
Dannenberg et al, 2001). BCG was usually administered intradermally using
106 – 107 viable bacilli. No adverse affects were reported and significant
levels of protection against subsequent challenge with M.bovis observed.
3.8 Guinea pigs.
3.8.1 Guinea pigs have been widely used for experimental tuberculosis
studies, and there are many reports of vaccination with BCG (e.g. Chambers
et al, 2000). There are no reports demonstrating that BCG can cause
progressive infections or have adverse side effects.
3.9 Mice.
41
3.9.1 Mice are the most commonly used experimental animals for testing
vaccination against tuberculosis. BCG does not cause progressive infections
in these animals.
4.
ADMINISTRATION
TUBERCULOSIS.
OF
BCG
TO
ANIMALS
INFECTED
WITH
4.1 Calmette and colleagues carried out a number of studies in which large
doses of BCG were administered to animals already infected with M. bovis.
Their general conclusion was that this did not produced aggravation of the
tuberculosis (L’introduction de bacilles bilies, meme a fortes doses plusieurs
fois repetees, dans l’organisme des animaux deja tuberculises ne produit
aucune aggravation de la maladie).
4.2 A PPD-positive cow was given 10mg of BCG intravenously, followed nine
days later with 50mg, again intravenously. The animal was sacrificed and
subjected to post mortem examination two and a half months later. Two
small, caseous lung lesions were found, along with a number of calcified
lesions in mediastinal lymph nodes; however these were considered to be old
lesions, and there was no evidence of recent tuberculosis.
Similar
experiments carried out with guinea pigs and rabbits failed to reveal evidence
of aggravation of the disease.
5. CONCLUSIONS.
5.1 Extensive testing of BCG in a variety of mammalian species has failed to
reveal any evidence that the organism can cause disease or can exacerbate
pre-existing tuberculosis. Many of these tests were carried out with very large
doses of BCG given by a variety of different routes. However, it should be
noted that lack of virulence of BCG is related to the immunological status of
the host. Thus people with congenital defects in type 1 cytokines or their
receptors may develop a disseminated, lethal BCG infection. Thus individual
animals which are immunosuppressed, or species with more primitive immune
systems could be highly susceptible to BCG infection.
6. REFERENCES.
Aldwell F.E., Keen D., Stent V.L.C. et al. (1995). Route of BCG administration
in possums effects protection against bovine tuberculosis. New Zealand Vet.
Rec., 43, 356-359.
Bergeen S.A. (1977) Incidence of tuberculosis in BCG vaccinated and control
cattle in relation to age distribution in Malawi. Br. Vet. J., 133, 490-494.
Buddle B.M., Keen D., Thomson G. et al. (1995). Protection of cattle from
bovine tuberculosis by vaccination with BCG by the respiratory or
subcutaneous route, but not by vaccination with killed Mycobacterium vaccae.
Res. Vet. Sci., 59, 10-16.
42
Buddle B.M., Aldwell F.E., Keen D., et al. (1997). Intraduodenal vaccination
of brushtail possums with bacille Calmette-Guerin enhances immune
responses and protection against Mycobacterium bovis infection. Int. J.
Tuberc. & Lung Dis., 1, 377-383.
Chambers M.A., Williams A., Gavier-Widen, D. et al. (2000). Identification of
a Mycobacterium bovis BCG auxotrophic mutant that protects guinea pigs
against M. bovis and hematogenous spread of Mycobacterium tuberculosis
without sensitisation to tuberculin. Infect. Immun., 68, 7094-7099.
Cross M.L., Labes R.E., Griffin J.F.T., Mackintosh C.G. (2000). Systemic but
not intra-intestinal vaccination with BCG reduces the severity of tuberculosis
infection in ferrets (Mustelo furo). Int. J. Tuberc. & Lung Dis., 4, 473-480.
Calmette A., Boquet A., Negre L. (1921). Contributions a letude du bacille
tuberculeux bilie Extrait des Annales de l’Institut Pasteur. Septembre 1921,
Tome XXXV.
Dannenberg A.M., Bishai W.R., Parrish N. et al. (2001). Efficacies of BCG
and vole Bacillus (Mycobacterium microti) vaccines in preventing clinically
apparent pulmonary tuberculosis in rabbits: a preliminary report. Vaccine, 19,
796-800.
Griffin J.F.T., Chinn D.N., Rodgers C.R., Mackintosh C G. (2001). Optimal
models to evaluate the protective efficacy of tuberculosis vaccines.
Tuberculosis, 81, 133-139.
Hook S., Griffin F., MacKintosh C., Buchan G. (1996). Activation of an
interleukin-4 mRNA-producing population of peripheral blood mononuclear
cells after infection with Mycobacterium bovis or vaccination with killed, but
not live, BCG. Immunology, 88, 269-274.
Lurie M.B., Zappasodi P., Cardona-Lynch E., Dannenberg A.M. (1952). The
response to the intracutaneous inoculation of BCG as an index of native
resistance to tuberculosis. J. Immunol., 68, 369-387.
Miller L.A., Johns B.E., Elias D.J., Killian G.J. (1999). Oral vaccination of
white-tailed deer using a recombinant Bacillus Calmette-Guerin vaccine
expressing the Borrelia burgdorferi outer surface protein A: prospects for
immunocontraception. Am. J. Rep. Imm., 41, 279-285.
Qureshi T., Labes R.E., Cross M.L., et al. (1999). Partial protection against
oral challenge with Mycobacterium bovis in ferrets (Mustelo furo) following
oral vaccination with BCG. Int. J. Tuberc. & Lung Dis., 3, 1025-1033.
Slobbe L., Lockhart E., O’Donell M.A., et al. (1999). An in vivo comparison of
bacillus Calmette-Guerin (BCG) and cytokine-secreting BCG vaccines.
Immunology, 96, 517-523.
43
Southey A., Sleeman D.P.S., Lloyd K., et al. (2001).
Immunological
responses of Eurasian badgers (Meles meles) vaccinated with Mycobacterium
bovis BCG (bacillus Calmette-Guerin). Vet. Immunol. Immunopath., 79, 197207.
Stuart F.A., Mahmood K.H., Stanford J.L., Pritchard D.G. (1988).
badgers. Mammalian Rev., 18, 74-75.
44
APPENDIX 5.
PROTOCOLS FOR THE DEVELOPMENT AND EVALUATION OF BCG
VACCINATION AGAINST M. BOVIS INFECTION IN BADGERS.
Glyn Hewinson and Mark Chambers
1. INTRODUCTION.
1.1 Vaccinating badgers against infection with M. bovis is one possible
strategy with which to break the transmission of tuberculosis, by reducing the
burden of infection within the badger population and the level of shedding of
the bacterium by infected individuals.
1.2 In Appendix 3 was outlined a number of steps that would be required for
the development of BCG vaccination regimes for badgers. The main purpose
of the study would be to provide proof of principle that BCG can protect
against a stringent challenge with M. bovis and to determine the level of
protection conferred by BCG in this model. Previous studies in other wildlife
species have shown that, to date, the optimum level of protection for BCG has
been achieved by subcutaneous vaccination (Appendix 3). Therefore it would
be prudent to provide proof of principle that BCG can protect against M. bovis
infection in badgers using this route of vaccination before embarking on the
development of formulations and delivery systems for oral vaccination. The
aim of this Appendix is to discuss the development of protocols to achieve this
goal.
2. M. BOVIS CHALLENGE MODEL FOR BADGERS INCLUDING STUDIES
ON PATHOGENESIS AND KINETICS OF THE IMMUNE RESPONSE.
2.1 The first objective would be to develop an M. bovis challenge model for
badgers. The optimum dose for intratrachael challenge is being determined in
the Republic of Ireland (RoI) by titrating doses of M. bovis (10, 100, 1000 cfu).
The kinetics of the immune response and shedding during infection are being
measured and pathology will be defined by post mortem examination.
2.2 The second objective would be to define the variation in the parameters
that would be used for measuring protection against M. bovis challenge in this
model. This would ensure that a minimum number of animals were used for
subsequent vaccination and challenge studies.
2.3 Ideally, the experimental design would include a badger group size of
between twelve and twenty animals. At least two pre-bleeds should be taken
for each badger. The dose of M. bovis given would be determined from the
experiments performed in RoI outlined above (2.1). All badgers would be kept
12-18 weeks after challenge or until they showed severe clinical signs of
disease. A full post mortem would be carried out on each animal and
45
pathology, histopathology and cfu in lung, lymph nodes and other tissues
would be determined. Pathology scores would be determined for lungs and
lymph nodes using scoring systems developed for the bovine model of M.
bovis infection.
2.4 The clinical markers to assess disease progression would be weight,
haematology, blood biochemistry, survival, clinical signs (include lymph node
enlargement).
2.5 Regarding immune markers of disease progression, badgers would be
sampled at two to three-weekly intervals and tested for the following:
2.5.1 Serum IgG response (using the Brock Test, MAPIA/Lateral flow assays
and Dachs ELISA; Appendix 9).
2.5.2 IgA response in tracheal aspirates and serum.
2.5.3 Lymphocyte transformation assay (Appendix 9) using PPD-M, PPD-A
and specific M. bovis antigens that are present in M. bovis and absent from
BCG (e.g. ESAT-6 and CFP10).
2.5.4 IFNγ ELISA and ELISPOT using PPDM, PPDA, ESAT-6, CFP10 and
other antigens that might be useful in determining disease progression
(Appendix 9).
2.6 Shedding of M. bovis would be detected by culturing urine, faeces and
tracheal aspirates and by PCR.
2.7 The information gathered as a result of this experiment would be used to
determine which parameters would be useful in determining protective
efficacy, the variation in these parameters and hence the group size required
for subsequent vaccination and challenge experiments.
3. PROOF OF PRINCIPLE EXPERIMENTS TO SHOW THAT BCG CAN
GIVE DEMONSTRABLE PROTECTION AGAINST M. BOVIS CHALLENGE
IN BADGERS AND REDUCE BACTERIAL EXCRETION.
3.1 Group size for a BCG vaccination and challenge experiment would be
determined from the data obtained from the experiment outlined in 2. It should
be noted that groups of six cows were sufficient to demonstrate 80 %
‘protection’ (i.e. reduction in lesions) in BCG vaccinated animals compared to
controls. This is the minimum group size that could demonstrate a statistically
significant protective effect in cattle.
3.2 It is suggested that a commercial preparation of BCG that is licensed in
GB (i.e. BCG Copenhagen; see Appendix 6) be used at a dose that has been
efficacious for a wide range of species i.e. 106 cfu (Appendix 3).
3.3 Shedding of BCG prior to M. bovis challenge would be detected by
culturing urine, faeces and tracheal aspirates and by PCR.
46
3.4 Immune responses of vaccinated badgers would be monitored as
described in section 2.5 above.
3.3 It is suggested that there would be a rest between BCG vaccination and
M. bovis challenge of ca. 8 weeks in the first instance.
3.4 The challenge experiment would be carried out as described in Section 2
above.
47
APPENDIX 6.
VACCINES FOR THE CONTROL OF BOVINE TUBERCULOSIS:
COMMERCIAL
PRODUCT
DEVELOPMENT
AND
REGULATORY
APPROVAL.
Steve Houghton
Hoechst Roussel Vet Ltd., Walton Manor, Walton, Milton Keynes, MK7 7AJ
1. INTRODUCTION.
1.1 The expertise necessary to develop and license commercial TB vaccines
lies with animal health companies collaborating with research institutes or
laboratories. A commercial company involved in the development of vaccines
will seek to make a return on investment whilst at the same time having to
comply with regulatory requirements. This involves compliance with Good
Manufacturing Practice (GMP) for production, Good Laboratory Practice
(GLP) for experimental studies and Good Clinical Practice (GCP) for field
studies.
2.
PROJECT EVALUATION: HOW COMPANIES CHOOSE WHAT
PRODUCTS TO DEVELOP.
2.1 In deciding what projects to progress, the following are taken into
consideration:
2.1.1 The market. How many countries are involved and how widespread is
the disease? What is the likely uptake of the vaccine (prohibition or
prescription for use by control policies?), what are the manufacturing costs
and anticipated selling price?
2.1.2 Technological feasibility. How likely is it that a useful vaccine can be
developed?
2.1.3 Product profile. This sets the objectives for the project which primarily
involves defining the following:
2.1.3.1 Type of vaccine: live, inactivated whole cells, subunit, extract,
recombinant etc.
2.1.3.2 Adjuvant (usually only for inactivated vaccines).
2.1.3.3 Dosage regimen.
2.1.3.4 Method and route of application (by injection, oral etc).
2.1.4 Production methods/costs.
48
2.1.4.1 The more complicated the production process, the higher the costs. It
is easier to predict the costs of a simple process, similar to established
methodology.
2.1.4.2 The vaccine strain(s), notably the history (particularly with respect to
culture conditions and TSE), and any IP issues are essential to address early
on.
2.1.5 Consumer concerns. The release of live strains with potential zoonotic
implications and perhaps the release of Genetically Modified Organisms
(GMOs) as live vaccine strains in particular will undoubtedly present problems
with consumer and regulatory acceptance.
3. RESEARCH AND DEVELOPMENT OF CANDIDATE TB VACCINES.
3.1 A successful project team is multidisciplinary consisting of R&D,
Marketing, Registration, QA, QC and Production personnel throughout the
duration of the development.
3.1.1
First and foremost Transmissible Spongiform Encephalopathy
compliant production master and working seeds must be established and the
method of production of the vaccine defined, otherwise all subsequent studies
might be invalidated.
3.1.2
A validated, consistent, method of production is essential.
Fermentation, culture conditions etc must be set. Culture media used at all
stages of manufacture have to comply with Transmissible Spongiform
Encephalopathy guidelines of the Committee for Veterinary Medicinal
Products.
An initial stage of vaccine development is undertaken with
candidate vaccines prepared to a documented method and used to inoculate
animals in challenge studies to evaluate efficacy and safety. This phase may
also involve dose ranging. Data on vaccine stability are required and are
initiated as soon as possible in development.
3.1.3 The seeds have to be tested for identity and purity. The maximum and
minimum titre (for live vaccines) of the final product is set. If a range of titres
is specified for the product, all efficacy studies are carried out using minimum
titre and all safety studies at maximum titre.
3.1.4 Safety studies are carried out under GLP conditions and conducted in
the most susceptible category of animal (e.g. neonates, pregnant) and
include:
3.1.4.1 Safety of a single dose.
3.1.4.2 Safety of a repeated dose.
3.1.4.3 Safety of a 10 times (live) or double (inactivated) overdose.
3.1.4.4 Reversion to virulence (live).
49
3.1.4.5 Persistence and shedding (live).
3.1.4.6 Numbers of the order of 5/6 per group are usually sufficient.
3.1.5 Efficacy studies are carried out under experimental conditions and
include studies which will enable the product claims to be substantiated
involving:
3.1.5.1 Efficacy of the recommended dose regime, including onset of
immunity, duration of immunity, booster vaccination.
3.1.5.2 Efficacy in the face of maternal antibodies (if given to neonates).
4. PRACTICAL CONSIDERATIONS IN TB VACCINE DEVELOPMENT.
4.1 An animal health company partner. Studies are not relevant for
registration unless they involve the product manufactured in a manner
representative of full-scale manufacture.
4.2 Target species only. Evaluation of vaccine candidates in guinea pigs or
other laboratory animals may or may not be relevant to target species
efficacy, but is certainly not acceptable as the only efficacy model. An early
decision on which vaccine candidate is chosen and then work in the target
species using the stated dose by the chosen route of application is key. Any
amount of efficacy or safety in laboratory animals is at best supporting data
and cannot replace studies in the target species(badgers or cattle).
4.3 Live GMO. In addition to centralised licensing, it would need to be
registered with the Health and Safety executive (HSE) for contained release
during development and deliberate release into the environment when in use
commercially.
4.4.1 GMOs. These must be developed in containment facilities and licensed
via the centralised system with the involvement of all 15-member states in the
process. However, countries for which the product is intended can be
nominated and those countries, where use of the product is prohibited by local
control policies, can prevent national approval.
4.4.2 Centralised registration applies to not just live GMOs but also any
material produced by a recombinant process - therefore even if the vaccine is
inactivated or a sub-unit protein the same rules apply.
4.5 Field Trials. These can only be carried out in the UK under an Animal
Test Certificate (ATC) according to GCP although trials could be done
elsewhere. An ATC application requires data on quality and safety in the form
of a dossier, but not efficacy. However as the definitive evidence of efficacy is
by experimental challenge, field studies would be expected to provide
supporting data at best for efficacy, and to confirm safety under field
conditions.
50
5. BCG.
5.1 From all the studies conducted so far BCG is the only realistic vaccine
candidate currently available.
5.2 BCG is a licensed product for humans in the UK, therefore there are no
significant zoonotic implications.
5.3 Adopting this vaccine for use in badgers or cattle is likely to save years in
development time. Collaboration and consent of the manufacturer would be
necessary.
5.4 For badgers the oral route in bait is likely to be the method of application
of choice. Efficacy and stability work would be necessary to develop this.
5.5 Ecology and the Environment. For any product a key part of the dossier
is the assessment (called the ecotoxicity section) of impact on the
environment and spread to other species. This assessment method is clearly
described in regulatory guidelines and involves key studies of the vaccine and
its stability. There is a wealth of published data on the safety and efficacy of
BCG in numerous species, including man, cattle and laboratory animals and
some in badgers.
6. REGULATORY STEPS.
6.1 The sequence involved depends on which of a number of options
provides the best route:
6.1.1 Article 8 of Directive 2001/82/EC. As there is no licensed vaccine for
animals it is possible (but, vide infra) that the human BCG vaccine could be
used in badgers and cattle to combat a disease emergency, and the EU
commission informed of this action. Given the current levels of TB in GB this
route should not be ignored and for a badger vaccine this may be the ideal
route to pursue as long as data on stability in bait can be developed. For
cattle, tuberculin testing is required by Directive 64/432 and evidence that
BCG does not interfere with this test would be necessary. However it is
unlikely that TB in cattle would constitute a disease emergency and oral
administration of BCG to badgers would not be a direct correlate of the use of
BCG in other species and is unlikely to be approved without data to support
it’s likely efficacy.
6.1.2 Cascade. Where there is no licensed product available, a veterinary
surgeon may be permitted to administer to a small number of animals on a
particular holding “a product authorised for human beings”. For badgers and
selected cattle herds this would be acceptable. The same issues as in 6.1.1
above would apply but it is unlikely that this would be considered an option for
justifying the use of BCG in badgers. The key point is that the animals are
under the care of the prescribing veterinary surgeon, which is unlikely to
apply to wildlife. This point is also relevant to 6.1.1.
51
6.1.3.1 Marketing Authorisation (MA) for BCG in Badgers. The sequence is
laid out in Table 1 for badgers but as essentially the Quality section of the
dossier would be provided by the licensed manufacturer(s) this would save
considerable time in development. Published data and new studies would
provide data for the safety and efficacy sections of the dossier. This would
lead to a national marketing authorisation in the UK which could then be
mutually recognised in Ireland or other interested Member States.
Table 1- MA for BCG for Badgers.
- Agreement with licensed manufacturer.
- State product specification and profile, develop delivery system.
- Develop challenge model.
- Establish dose giving adequate efficacy in preliminary titration studies.
With minimum effective dose perform further challenge studies.
Support with published data.
- Single dose, overdose, repeated dose studies in Badgers to GLP.
- Compile dossier including safety and efficacy and quality data from
manufacturer.
- Submit to VMD for Animal Test Certificate – i.e. field trials on a limited
scale.
- Complete Quality, Safety, Efficacy sections of dossier in EU format
and submit to VMD.
- Validation, followed by Questions from VMD Biologicals Committee.
Following satisfactory answers, Veterinary Product Commission
consulted before MA granted subject to resolution of outstanding points.
6.1.3.2 It is estimated that the procedure in Table 1 would take approximately
4-5 years providing there are no bottlenecks in animal availability or major
technical problems.
6.1.3.3 The development of a novel TB vaccine (i.e. not BCG) would require
a considerable amount of additional work. The early development and
screening of candidate vaccine components and formulations, and
establishing production and quality test methodologies in particular, would
probably add at least another 2 to 3 years to the programme.
7. CONCLUSIONS.
The provision of any vaccine to aid the control of Bovine TB, whether for use
in cattle or badgers, would be most likely achieved by a close collaboration
between a vaccine manufacturer and research institutes (perhaps several)
from the beginning. Co-ordination of research activities to provide the science
necessary to underpin the development programme, particularly with respect
to novel vaccines, is essential. From manufacturing, vaccine development
and probably regulatory/consumer acceptance perspectives, the use of BCG
in badgers is the option that would be quickest to market.
52
APPENDIX 7.
ISSUES RELATING TO THE PROCUREMENT OF BADGERS FOR
VACCINE RESEARCH.
Chris Cheeseman, Des Delahay & Gavin Wilson
CSL Woodchester Park, Nympsfield, Stonehouse, Glos, GL10 3UJ
1. INTRODUCTION.
1.1 Captive badgers will be required for experimental research related to the
development of a TB vaccine for badgers. Consequently badgers will need to
be procured from the wild by live trapping.
2. GENERAL.
2.1 Badgers are social animals and therefore cannot be housed individually in
captivity on a long-term basis. However, although housing singly is not
desirable for welfare reasons, housing in pairs or groups will have implications
for cross-infection between individuals in the course of the vaccination
studies. Advice will be required from the relevant immunologists and
statisticians on the desired characteristics of badgers to be procured for
vaccine research, as this will influence the strategy for their capture. Are
badgers to be kept in pairs? If so what age and sex distribution is required?
Alternatively, will it be possible to house whole social groups? Will the
badgers be required to come from locations of varying history of exposure to
M. bovis?
3. AGE AND SEX.
3.1 There is likely to be a requirement for the sample of procured badgers to
have a particular age and sex structure. One scenario is that badgers are
held in pairs. In order to minimise disruption to existing social groups from
which badgers are being removed, a small number of individuals should be
taken. A maximum removal of one male and one female could probably be
sustained by a normal group of five to eight individuals, as this is a minimal
increase over the natural background mortality rate of approximately 30% per
annum. However, this approach will require trapping of many setts in order to
procure sufficient badgers, which will be labour intensive. There may be limits
to the months when trapping can be carried out, to avoid the breeding season.
It is obviously undesirable to bring pregnant females into captivity and
lactating females cannot be removed from their cubs. It may also be
necessary to carry out bait-marking surveys in the areas of interest to
determine social group territories.
3.2 The intention only to partially deplete social groups to avoid disruption
carries with it the need to assess group size, age and sex composition. For
example, it would not be desirable to remove two badgers from a group of
less than say five individuals. A possible alternative to this, if there were
53
appropriate facilities to house them, would be to capture whole social groups.
In this scenario, trapping could be condensed, as the required number of
badgers would be more quickly reached after fewer trap-events. As they are
social animals, it may be less stressful (see Sections 8.1.3 and 9) for badgers
if kept together as a group (see Section 8).
3.3 Advice received from people with experience of keeping captive badgers
suggests that it may not matter how pairs are mixed according to sex or even
social group origin. However, it is important to introduce them together,
monitor the situation and be prepared to separate them again if conflict
occurs. In order to overcome the potential problems of keeping pairs of adults
together, it may be better to remove animals from the wild as cubs, as they
settle into captivity much better than adults. The experience of badger
rehabilitation centres is that cubs of both sexes mix well, but they do exhibit a
behavioural change in the autumn where they spend much of their time trying
to escape. This period coincides with the time of year that cubs in the wild
become independent and disperse.
4. ESTABLISHING DISEASE STATUS.
4.1 Presumably known infected animals will be required as well as those of
TB-free status. There are two available approaches to establishing the TB
status of badgers; ELISA blood testing, and culturing of clinical samples.
ELISA results can be returned in a matter of hours, but culturing takes several
weeks. In theory, ELISA tests could be carried out on badgers held in holding
cages in the field, to help establish disease status. Sensitivity and specificity
issues must be considered when planning to use such techniques. If TB
positive badgers are required, a single trap-side ELISA may be performed in
the field. The high specificity of the test would allow identification of positive
animals, which could then be removed to the laboratory. For disease free
badgers, confirmation of negative status by repeat ELISA (see Forrester et al
2001) and clinical sampling could only be achieved in captivity. Consideration
may have to be given to the quarantine of individuals until their disease status
is confirmed.
5. PROCURING KNOWN NEGATIVE BADGERS FROM DISEASE FREE
AREAS.
5.1 Although it is not possible to guarantee that procured badgers come from
areas where infection is definitely absent, there are areas of the country
where there is no history of infection in either badgers (although insufficient
sample sizes may be a factor) or cattle. Targeting these areas would provide
the best chance of obtaining disease free badgers. These areas would
however be outside TB hotspots if this is an important consideration (see
“Genetic considerations”). Confirmation of the disease-free status of these
badgers could be achieved by repeat ELISA testing, plus clinical sampling.
54
6. PROCURING KNOWN POSITIVE BADGERS.
6.1 The best chances of identifying infected animals is in a population which
has been subject to sequential sampling, such as the situation that exists at
Woodchester Park. It follows therefore that the most efficient approach may
be to set up such study areas well in advance of the requirement for procured
badgers.
6.2 One possible scenario is that target setts are trapped repeatedly until
sufficient animals of the desired disease status are caught. Badgers could be
blood tested in the field at capture. The high specificity of the ELISA test
means that any animal testing positive is highly likely to be infected. Positive
individuals could be taken into captivity, where further testing could be carried
out to confirm disease status. Culture of clinical samples from these badgers
would also help confirm disease status. At the time of the initial capture, all
badgers could be clinically sampled and given permanent identification marks.
Culture of clinical samples from all badgers would provide a further
opportunity to identify infection in animals not identified by the initial ELISA
test. Any additional positive individuals could be selected in subsequent
trapping operations.
7. PROCURING KNOWN TB NEGATIVE BADGERS FROM HOT SPOTS.
7.1 Procurement of known negative badgers from the same genetic stock as
the known positive badgers may be required, which would involve capturing
them in TB hot spots. The limitations of current TB diagnostic techniques will
mean that it would be difficult to obtain disease-free badgers from these areas
with a high level of confidence.
8. SELECTING WHOLE SOCIAL GROUPS.
8.1 An alternative approach to selecting a small number of badgers from
many social groups would be to catch as many badgers as possible from a
smaller number of groups, i.e. removal of entire groups if possible. The
advantages of this would be the following.
8.1.1 Less trapping would have to be carried out to reach the numbers of
badgers required.
8.1.2 The badgers would be captive therefore it would be easier to carry out
repeated culture tests, and if necessary repeat ELISA tests.
8.1.3 The whole social group would be kept together, which might reduce
stress to the target individuals.
8.2 However, this may be impractical due to the requirements of housing
several badgers together. It should be noted that a current proposal allows for
badgers to be held in captivity in pairs at a new facility (see Appendix 8). It
55
should also be noted that removal of badger from the wild by cage trapping is
not 100% effective.
9. STRESS - WILD ANIMALS IN CAPTIVITY.
9.1 Experience suggests that there is a great deal of individual variation in
how easily badgers accept captivity. In general, cubs seem better at settling
into captivity than adults. Adults tend to spend more of their time and energy
attempting to escape, and sometimes never settle completely. If they are to
be held in pairs, the chances of them accepting each other are increased if
they are introduced to their accommodation at the same time. Some badgers
in captivity may remain intolerant of each other. This does not seem to be
determined by whether they came from the same or different social groups, or
whether they are males or females. Therefore there is likely to be an element
of trial or error in successfully housing badgers in pairs.
9.2 The exact design of the accommodation needs to be considered carefully.
The stress levels of the animals may affect their immune response. Therefore
it will be very important to house the badgers in a way which reduces stress
as much as possible. Before committing to the construction of a large number
of enclosures, it may be worth considering a small-scale pilot study to
establish a successful design for the accommodation (see Appendix 8,
Section 6).
10. GENETIC CONSIDERATIONS.
10.1 Preliminary work suggests that the levels of genetic variability are very
similar between trial areas. No such information is available for non TB hotspot areas. Also, it is as yet unknown what implications differences in genetic
variability between areas would have for the immune response, or TB
pathogenicity in badgers. Therefore genetic composition is an issue which
cannot currently be resolved, and it is assumed that it will not be a
consideration for badger procurement.
11. LEGAL CONSIDERATIONS.
11.1 Under the Protection of Badgers Act 1992, the killing or taking of
badgers and/or interference with their setts is prohibited. Section 10 of the
Act, however, makes provision for the issue of licences for specific purposes
to carry out otherwise unlawful activities against badgers and their setts.
Section 10(1) of the Act provides for the licensing of certain activities,
including the killing or taking of badgers, and interference with setts, for
scientific or educational purposes, or for the conservation of badgers. English
Nature is the licensing authority for licences issued under this Section.
11.2 In addition, the Act provides an exemption to the above offences for the
purpose of doing anything which is authorised under the Animals (Scientific
Procedures) Act 1986 e.g. experimental procedures approved under licence
to advance biological or behavioural knowledge.
56
11.3 One part of the Crown is, strictly speaking, unable to apply to another
part of the Crown for a licence and it may be a Crown laboratory that would
wish to carry out the research. In circumstances such as these it is usual for
Crown staff to operate within the spirit of the law, and should a "licence" prove
necessary, to submit an "application" and to comply with the conditions
attached to any "licence" subsequently issued.
12. SECURITY CONSIDERATIONS.
12.1 Removal of animals from the wild for experimental purposes will attract
the attention of animal rights activists, both in the field and at the captive
facility. Consideration should be given to the possibility of procuring badgers
from a secure, perhaps Ministry of Defence, site.
13. REFERENCE.
Forrester G.J., Delahay R.J., Clifton-Hadley R.S. (2001). Screening badgers
(Meles meles) for Mycobacterium bovis infection by using multiple
applications of an ELISA. Veterinary Record, 149, 169-172.
14. BIBLIOGRAPHY.
Pope and Burke, preliminary report 6th March 2002. Report to Defra.
57
APPENDIX 8.
FEASIBILITY AND COSTS FOR PROVIDING ACCOMMODATION FOR
BADGERS.
1. INTRODUCTION.
1.1 Work with badgers infected with bovine tuberculosis would require
containment at Level 3. Appropriate containment is also required to protect
local farming interests. As the work would require animals to be maintained in
captivity for an extended period particular attention needs to be paid to their
welfare and the conditions under which they would be held.
1.2 Given the containment and animal welfare considerations of this work a
new facility would be required. Existing secure facilities are available which
include sufficient open ground to accommodate a new unit while providing
access to trained animal technicians and scientists.
2. STANDARDS.
2.1 To comply with Level 3 containment and Home Office Procedures the
facilities must meet the following standards.
2.1.1 All rooms must be maintained to an air pressure negative to the
atmosphere.
2.1.2 Extracted air must be filtered by a HEPA (high efficiency particulate
absorption) filter.
2.1.3 Liquid waste should be discharged via a sealed and leak-proof drainage
system into an impermeable holding or treatment enclosed tank within the
designated area.
2.1.4 All areas must be sealable to permit disinfection.
2.1.5 An autoclave must be available within the facilities and all bedding,
animal waste and bodies must be autoclaved before disposal.
2.1.6 When undertaking procedures, such as post mortem, a class 1
microbiological safety cabinet is required; the exhaust must go into the room
extract system via a HEPA filter.
2.1.7 A dedicated staff changing area is required.
3. SERVICES.
3.1 Under The Animal (Scientific Procedures) Act 1986 all services should be
installed in such away that they are either buried within the fabric of the
building or clear of wall surfaces. Maintenance required to any services might
disturb the animals. Therefore the design for services such as lighting must
58
be accessible from outside the holding area. All holding areas should have
temperature and relative humidity control, which are carefully maintained.
The temperature should be within the range appropriate for the species and
the relative humidity would be maintained at 55%. Ventilation should provide
sufficient air of an appropriate quality and reduce the levels and spread of
odours, dust and infection; in order to comply with this recommendation 15-20
air changes per hour distributed throughout the holding area should be
adequate. No procedures or euthanasia must be performed in the normal
holding areas where animals are housed, i.e. there must be an adequate area
provided to carry out these.
4. HOLDING AREA.
4.1 These requirements mean that infected badgers will need to be kept in an
enclosed facility with no access to outdoor or grass runs. There is currently
no available information on the welfare requirements of badgers to be kept
under such containment conditions for an extended period of time. However,
working on the assumption of two animals to be kept in each enclosure, and
from experience with other species, it is suggested a holding area of 4.5m x
10m be an appropriate minimum. This area should be concrete floored with
steel walls. Within this area the animals would be kept on a deep litter system
and be provided with nest boxes.
4.2 A series of such enclosures would require access through a central
corridor leading to a procedures room, post mortem area, autoclave facility
and changing area. The area would require secure drainage.
5. COSTS.
5.1 Commercial construction of Category 3 facilities costs approximately
£4,400 per square meter. Adding 15% to the floor area for corridors and
circulation and each enclosure built to existing standards would involve a cost
of £227,700. Such area-based costs might be higher than necessary given
the large enclosed spaces required by the animals and should be viewed as a
maximum. It might be possible to use cheaper alternatives or modular preconstructed units although these would require further investigation. A low
end cost of £3,000 per square meter might be a minimum in these
circumstances producing a cost of £155,250 per enclosure. The central
procedures, autoclave, post mortem and changing areas would have an
additional cost of approximately £440,000.
No
Enclosures
each
containing
two badgers
10
25
50
Cost of
Enclosures at
£4,400 per
m2
Cost of
Enclosures at
£3,000 per
m2
£2,277,000
£5,692,500
£11,385,000
£1,552,500
£3,881,250
£7,762,500
59
Cost of
Central
Facilities at
£4,400 per
m2
£440,000
£440,000
£440,000
Total price
range
£2.25-2.72m
£4.32-6.13m
£8.20-11.82m
5.2 In addition to the capital costs of construction there would also be staff,
veterinary consultancy and running costs associated with the facilities.
Approximate annual costs are outlined below.
No
Enclosures
each
containing
two badgers
10
25
50
Staff Costs
Veterinary
Costs
Running
Costs
Total
£40,000
£60,000
£85,000
£2,000
£2,500
£3,000
£30,000
£75,000
£150,000
£72,000
£137,500
£238,000
5.3 Holding animals in existing facilities while checking disease status would
not change the above costs; these are largely determined by the number of
simultaneous challenges that are required, not by how long the animals are
held. If animals were to be held for a brief period to check disease status and
then for up to a year in category 3 for the challenge work, there would be a
slight saving in time, but not a significant one. Using holding pens would also
raise issues of soil contamination, risking infection of subsequent animals and
the surrounding environment.
5.4 These costings contain a number of uncertainties that require further
investigation before reliance can be placed on the figures. In particular the
standard of building required to provide containment at reasonable cost, and
the conditions under which animals should be held to ensure their welfare
both require further investigation. It is suggested that two lines of enquiry are
needed to explore the options.
6. FURTHER ENQUIRY.
6.1 Firstly, there is limited information and expertise on keeping badgers
under such conditions. A pilot study would be required to identify suitable
protocols to maximise the health and welfare of animals. This would use
uninfected badgers to obviate the need for containment. It is suggested
holding two pairs of badgers in enclosures modified from existing low
containment facilities. This pilot study should be carried out for 12 months to
develop protocols for the following.
6.1.1 Optimum space requirements for housing.
6.1.2 Routine and experimental handling.
6.1.3 Food presentation and suitable sources of food.
6.1.4 Types of bedding and nesting material required.
6.1.5 Presentation of bedding and nesting material.
6.1.6 Water presentation.
60
6.1.7 Benefits of environmental enrichment.
6.1.8 To assess whether the badgers health and welfare is optimised,
badgers would regularly be weighed and inspected for injury and behaviour
monitoring would be conducted using standard techniques e.g. 24 hour time
budgets once a month. Faecal cortisol levels would be measured weekly to
provide an independent measure of stress.
6.1.9 It is anticipated that such a study would cost around £100,000 and
could be completed in 15 months.
6.2 Secondly there is a need to explore the methods of containment and
associated costs. As described earlier the typical cost of £4,400 per m2 for
Category 3 containment might not be applicable to this situation. A study to
assess the practicality and cost of other options such as pre-constructed
modular units is needed before accurate designs and costings could be
produced. It is suggested a contract to a building and containment specialist
contractor would be needed to explore the available options and it is
anticipated a cost of £20,000 would be made for such work.
61
APPENDIX 9.
IMMUNOLOGICAL ASSAYS TO SUPPORT THE DEVELOPMENT AND
EVALUATION OF A VACCINE AGAINST BADGER TUBERCULOSIS.
Glyn Hewinson and Mark Chambers
1. INTRODUCTION.
1.1 One of the stumbling blocks to vaccine development for badgers is the
paucity of available immunological reagents that might be used to assess
‘vaccine take’ and to monitor M. bovis infection and vaccine efficacy in the
field. Over the past few years a number of immunological assays have been
developed for badgers. The purpose of this appendix is to review the assays
that are already available, to describe those that are in development and to
outline how each assay might be used in a vaccine development and
evaluation programme.
2. PROPOSED USES FOR IMMUNOLOGICAL ASSAYS.
2.1 Sensitive and specific detection of M. bovis infection in the target
population.
Test
Rationale
ELISA for serological response to M. The existing Brock Test ELISA detects
bovis-specific antigen(s).
IgG antibody against a single antigen,
MPB83, with a sensitivity of ca. 45%.
Adding further M. bovis specific
antigens has improved sensitivity to ca.
55% without a loss in specificity
(Kampfer et al., 2003; Greenwald et al.,
2003).
Lymphocyte
(LTA)
transformation
assay Measures T cell responses to either
vaccination or infection. More sensitive
than Brock Test (Dalley et al., 1999).
High performance and operational
IFNγ ELISA with PPD-M and PPD-A, or ease based on experience of
analogous test for cattle.
antigen(s) specific to TB complex.
Improved detection of M. bovis
infection has been reported using a
combination of cellular and humoral
assays (Griffin and Buchan, 1994).
Above tests used in combination.
62
2.2 Assessment of vaccine ‘take’.
Test
Rationale
As for 2.1 plus IFNγ ELISPOT assay.
Use of an IFNγ ELISPOT assay would
allow assessment of the magnitude of
the memory response generated by
vaccination (e.g. Vordermeier et al.,
2002).
IgA ELISA
Detection of IgA against M. bovis
antigens would be especially useful for
detecting mucosal immune responses.
2.3 Assessment of vaccine efficacy.
Test
Rationale
LTA or IFNγ ELISA using antigen(s)
present in M. bovis but not in vaccine
(e.g. ESAT-6 and CFP10, in the case
of vaccination with BCG).
Recent
results
in
cattle
have
demonstrated that, following BCG
vaccination, protected animals could be
differentiated from those that were
developing disease (Vordermeier et al.,
2002) using this approach.
ELISA for serological response to M. Absence of seroconversion to MBB83
amongst vaccinated animals could
bovis-specific antigen(s).
indicate control of infection or disease
progression, since BCG vaccinated
animals do not mount a serological
response against this antigen (Southey
et al., 2001).
2.4 ‘Trap-side’ diagnosis.
Test
Lateral flow-format serological assay.
Rationale
Seropositive badgers are at greatest
risk of shedding M. bovis (Chambers et
al., 2002, Clifton-Hadley et al., 1995).
This assay would allow detection of
‘super excretors’ within 15 minutes of
capture.
63
3. PROGRESS MADE ON TEST DEVELOPMENT: AVAILABLE ASSAYS.
3.1 Lymphocyte transformation assay.
3.1.1 A comparative lymphocyte transformation assay (LTA) has been
developed using bovine and avian tuberculin as antigen to detect cellmediated responses in M. bovis-infected badgers (Dalley et al., 1999). Todate the sensitivity of the comparative LTA is 91%. This compares favourably
with the sensitivity of 50% for the existing indirect ELISA assay for the
detection of tuberculous badgers (the Brock Test – see below). However, the
ELISA test gives a greater specificity (92% compared with 89% for the
comparative LTA). Preliminary evidence suggests that for the comparative
LTA, the blood cannot be stored overnight prior to testing as this procedure
reduces the specificity of the assay to approximately 57%, although the
sensitivity remains at approximately 86%.
3.2 Brock Test (indirect ELISA for detecting IgG antibodies against MPB83).
3.2.1 The only validated immunological test for the detection of tuberculosis
in the badger is the Brock Test. This is an indirect ELISA for a serological
response to MPB83, a 26 KDa protein antigen expressed by M. bovis
(Goodger et al., 1994; Hewinson et al. 1997). Evaluation of the Brock Test for
the detection of M. bovis infection in badgers gave the predictive value of a
positive test result of 67.5% and the predictive value of a negative test of
84.6%. The sensitivity of the test was significantly higher in animals with
gross tuberculous, which suggested the Brock Test may be useful for the
detection of badgers most likely to be excreting M. bovis (Clifton-Hadley et al.,
1995). The sensitivity of the test at the population level was 72.9%, compared
with 40.7% at the level of the individual animal, suggesting the test could also
be used to determine the burden of disease, at least for a population of
badgers.
3.2.2 The serological responses in 102 badgers from social groups in
Woodchester Park have been examined where M. bovis infection has been
endemic since 1985. These responses were compared with culture from
faeces, urine, tracheal aspirates and bite wound swabs taken from these
animals whilst alive. The majority of culture-positive badgers excreted M.
bovis intermittently over the period of study. As a result, there was only a
27.5% chance of detecting an infected badger by culturing M. bovis from
clinical samples. In contrast, a positive ELISA result correctly predicted
68.2% of badgers with a history of excreting M. bovis. In the absence of
alternative live tests for the badger, the Brock Test indirect ELISA should be
more valuable than culture for measuring the effect of vaccination on reducing
the number of badgers at risk of transmitting tuberculosis (Chambers et al.,
2002).
3.2.3 In addition, animals vaccinated with BCG Pasteur do not mount a
serological response to MPB83 (Southey et al., 2001) and so the Brock test
could be used to detect M. bovis infected animals within a BCG vaccinated
population.
64
3.3. Indirect ELISA for detecting IgA antibodies against MPB83.
3.3.1 Monoclonal antibodies against badger IgA have been raised and used
to develop an indirect ELISA for detecting IgA antibodies against MPB83 in
badgers. Preliminary data suggest that IgA responses can be detected in
tracheal aspirates and sera of M. bovis infected animals.
3.4 Multi-Antigen Print ImmunoAssay (MAPIA).
3.4.1 The existing serological ELISA test (Brock Test) looks for an antibody
response to a single mycobacterial antigen, MPB83, and has low sensitivity
for surveillance purposes (Clifton-Hadley et al., 1995). Recent work using a
technique known as Multi-Antigen Print ImmunoAssay (MAPIA) (Lyashchenko
et al, 2000), identified a proportion (16%) of M. bovis culture-positive badgers
that were negative by Brock Test but seropositive for their recognition of other
M. bovis-specific antigens. This study suggests that modifying the Brock Test
by incorporating a suitable cocktail of mycobacterial antigens results in
enhanced test sensitivity (Greenwald et al., 2003).
3.5 Lateral flow-format seroassay.
3.5.1 The technology involved in the MAPIA approach described above is
readily amenable to conversion to a lateral flow-format assay, in which a small
volume (5 - 10µl) of serum is placed on a ‘wand’ onto which the target
antigens are bound. Within 5 to 10 minutes a colour-change indicates firstly,
that the test has worked, and secondly whether the test serum contains IgG
(or IgA) antibodies to any of the target antigens.
3.5.2 Preliminary results from 178 badgers (Greenwald et al., 2003) showed
that a lateral flow-format gave enhanced sensitivity and specificity over the
Brock Test and MAPIA-based assay (sensitivity 53% vs 47% vs 49%;
specificity 95% vs 89% vs 88%, respectively).
3.5.3 Although a lateral flow test is unlikely to have a sensitivity much beyond
55%, it is the only test that could be performed ‘badger-side’ and should
preferentially detect those animals at greatest risk of shedding M. bovis
(Chambers et al., 2002). Such a test would enable a ‘cull or vaccinate’ test
strategy to be adopted in the field, should this be an option.
3.6. Multi-antigen BrockTest (the Dachs® ELISA; Kampfer et al., 2003). The
protocol used for the Dachs® TB-ELISA is essentially the same as used in the
Brock Test. The antigens used for the Dachs® TB-ELISA are MPB83,
MPB70, CFP10 and 16 kD antigen. In a preliminary evaluation of the test
(Kampfer et al., 2003), the Dachs® TB-ELISA gave higher sensitivity (a 33%
improvement) than the Brock Test at the same specificity. These preliminary
results suggest that serodiagnosis of badger TB can be enhanced with the
new test. However, analysis of more sera with the Dachs® TB-ELISA is
required to reduce the confidence intervals to confirm its improved
65
performance over the Brock Test; which was originally evaluated on nearly
two thousand sera (Clifton-Hadley et al., 1995).
4. PROGRESS MADE ON TEST DEVELOPMENT: ASSAYS UNDER
DEVELOPMENT.
4.1 IFNγ ELISA.
4.1.1 Badger interferon-gamma (IFNγ) has been cloned and sequenced.
Badger IFNγ was found to be most similar to canine IFNγ, with 88% aminoacid identity. Rabbits have been immunised with DNA encoding badger IFNγ
and the resulting polyclonal antiserum demonstrated specificity for native
badger IFNγ by intracellular staining and flow cytometry analysis of badger
lymphocytes stimulated with PMA (Phorbol myristate acetate) and ionomycin.
4.1.2 At least 20 monoclonal antibodies have been generated that specifically
recognise badger IFNγ, as demonstrated by flow cytometry on mitogenstimulated badger lymphocytes. These antibodies are being systemically
evaluated in pair-wise combinations for their performance in the sandwich
ELISA.
4.1.3 A prototype sandwich ELISA has been produced that detects the
presence of badger IFNγ. However, the test requires further optimisation as
the sensitivity is currently too low to be of practical use. Blood from badgers
experimentally infected with M. bovis in the Republic of Ireland (RoI) will be
used for this purpose.
4.1.4 The IFNγ assay is not anticipated to be available and validated until
March 2005.
4.2 IFNγ ELISPOT.
4.2.1 Evaluation of a cross-reactive commercial ELISPOT kit for canine IFNγ
(R&D Systems) lacked the required sensitivity and reproducibility for use in
badgers. A promising prototype ELISPOT for badger IFNγ has been
produced using a combination of monoclonal antibodies generated against
badger IFNγ. However, this assay requires further optimisation.
5. USE OF M. BOVIS SPECIFIC ASSAYS TO DISCRIMINATE BETWEEN
VACCINATED, INFECTED AND VACCINATED BUT INFECTED ANIMALS.
5.1 Analysis of cellular immune responses in cattle following M. bovis
challenge has demonstrated that proliferative T cell and IFN-γ responses
towards the M. bovis specific antigen ESAT-6 (whose gene is absent from
BCG) were generally low in vaccinated animals, but high in all non-vaccinated
calves. Importantly, the amount of ESAT-6 specific IFN-γ measured by ELISA
after M. bovis challenge, but not the frequency of responding cells, correlated
positively with the degree of pathology found 18 weeks after infection.
However, diagnostic reagents based on antigens not present in BCG, like
66
ESAT-6 and CFP-10, were still able to distinguish BCG vaccinated/diseased
animals from BCG vaccinated animals without signs of disease (differential
diagnosis). These results suggest that the determination of ESAT-6 specific
IFN-γ, whilst not a direct correlate of protection, constitutes a useful prognostic
immunological marker predicting both vaccine efficacy and disease severity
(Vordermeier et al., 2002). Preliminary data generated using the LTA assay
suggest that T cells from infected badgers also recognise these antigens.
Blood from badgers experimentally infected with M. bovis in the RoI will be
used for further evaluation of M. bovis specific antigens in T cell assays.
6. REFERENCES.
Chambers M.A., Pressling W.A., Cheeseman C.L., Clifton-Hadley R.S.,
Hewinson R.G. (2002). Value of existing serological tests for identifying
badgers that shed Mycobacterium bovis. Vet. Microbiol., 86, 183-189.
Clifton-Hadley R.S., Sayers A.R., Stock M.P. (1995). Evaluation of an ELISA
for Mycobacterium bovis infection in badgers (Meles meles). Vet. Rec., 137,
555-558.
Dalley D., Chambers M.A., Cockle P., Pressling W., Gavier-Widen D.,
Hewinson R.G. (1999). A lymphocyte transformation assay for the detection
of Mycobacterium bovis infection in the Eurasian badger (Meles meles). Vet.
Immunol. Immunopathol., 70, 85-94.
Goodger, J., Nolan, A., Russell, W.P., Dalley, D.J., Thorns, C.J., Stuart, F.A.,
Croston, P., Newell, D.G. (1994). Serodiagnosis of Mycobacterium bovis
infection in badgers: development of an indirect ELISA using a 25 kDa
antigen. Vet. Rec., 135, 82-85.
Greenwald R., Esfandiari J., Lesellier S. Houghton R., Pollock J.., Aagaarde
C., Andersen P., Hewinson R.G., Chambers M.A., Lyashchenko K. (2003).
Development of a Lateral-Flow Immunoassay for Rapid Detection of
Mycobacterium bovis Infection in Badgers (Meles meles). Diagnostic
Microbiology and Infectious Disease. In press.
Griffin J.F., Buchan G.S. (1994). Aetiology, pathogenesis and diagnosis of
Mycobacterium bovis in deer. Vet. Microbiol., 40, 193-205.
Hewinson R.G., Michell S.L., Russell W.P., McAdam R.A., Jacobs W.R. Jr.
(1996). Molecular characterization of MPT83: a seroreactive antigen of
Mycobacterium tuberculosis with homology to MPT70. Scand J Immunol. 43,
490-9.
Kampfer S., Dallet D., Hewinson R.G., Chambers M.A., Singh, M. (2003).
Multi-Antigen ELISA Test for Enhanced Diagnosis of Badger TB. Vet Record.
In press.
67
Lyashchenko K.P., Singh M., Colangeli R., Gennaro M.L. (2000). A multiantigen print immunoassay for the development of serological diagnosis of
infectious diseases. J. Immmunol. Methods, 242, 91-100.
Southey A., Sleeman D.P., Lloyd K., Dalley D., Chambers M.A., Hewinson
R.G., Gormley E. (2001). Immunological responses of Eurasian badgers
(Meles meles) vaccinated with Mycobacterium bovis BCG (bacillus calmette
guerin). Vet. Immunol. Immunopathol., 79, 197-207.
Vordermeier H.M., Chambers M.A., Cockle P.J., Whelan A.O., Simmons J.,
Hewinson R.G. (2002). Correlation of ESAT-6-specific gamma interferon
production with pathology in cattle following Mycobacterium bovis BCG
vaccination against experimental bovine tuberculosis. Infect. Immun. 70,
3026-32.
68
APPENDIX 10.
REQUIREMENTS OF A FIELD TRIAL TO TEST BCG IN BADGERS.
Ivan Morrison
Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter
Bush, Roslin, Scotland EH25 9RG
1. INFORMATION REQUIRED BEFORE UNDERTAKING A TRIAL.
1.1 The following information would be highly desirable not only to justify a
field trial with BCG but also to facilitate design of the trial and interpretation of
the results. Some of this information might be available from the literature, but
much of it would need to be generated from experimental studies.
1.1.1 Optimal dose and route of administration of BCG to achieve protection.
1.1.2 A reliable method to measure vaccine uptake, if administered remotely
in bait.
1.1.3 Whether or not excretion of BCG occurs following vaccination.
1.1.4 Risk of uptake by, or transmission to, other species and potential
pathogenic effects.
1.1.5 Level of protection obtained, in terms of reduced disease and bacterial
excretion.
1.1.6 Types of immune responses induced by infected and BCG-vaccinated
badgers, including immune responses that distinguish infected from
vaccinated animals.
2. PARAMETERS THAT NEED TO BE MONITORED IN A TRIAL.
2.1 Essential parameters.
2.1.1 Badger population density and structure. This can only be estimated on
the basis of survey data. It would be needed at outset to determine where
vaccine baits should be laid and also needed during the course of a trial to
ensure that the badger population does not change radically.
2.1.2 The rate of vaccine uptake. Methods would need to be tested and
validated prior to a trial; this need only be done on a sample of badgers.
2.1.3 The incidence of cattle herd breakdowns.
2.1.4 Environmental impact. One would need to assess possible infection of
other species with BCG and any potential deleterious effects. Ideally this
69
needs to be done prior to starting a trial; it could perhaps be done as a risk
assessment based on information from experimental studies or it might
require field experiments prior to a trial.
2.2 DESIRABLE PARAMETERS.
2.2.1 Immunological evidence of vaccine take. This would be dependent on
assays that detect vaccine-induced immune responses similar to those
detected in experimentally vaccinated badgers; it need only be done on a
sample of badgers.
2.2.2 Prevalence of infection in the badger population. This would be
dependent on having an assay that detects infected animals and distinguishes
them from vaccinated uninfected animals; it need only be done on a sample of
animals.
3. A TWO-PHASE OR SINGLE-PHASE TRIAL?
3.1 The success of any vaccination of badgers would ultimately be measured
by whether or not it had an impact on the incidence of cattle herd breakdowns.
Vaccination trials must therefore be conducted in areas where there is a high
incidence of breakdowns. However, even in high incidence areas, such as
those included in the current culling trial, the annual incidence of herd
breakdowns is only about 10%. As each trial area (i.e. each individual
member of a triplet) contains on average about 100 herds, vaccination of
badgers would need to be applied over a large area to encompass sufficient
numbers of breakdowns each year to measure the impact of the vaccine.
Moreover, since the badger population takes 2-3 years to turn over, a
substantial impact on TB in the badger may not be achieved until the
population has received two or three annual vaccinations and, because of the
lag between cattle becoming infected and detection of infection by testing, any
effect on cattle herd breakdowns might not be apparent for a further year.
Based on these assumptions, it is unlikely that meaningful information on the
impact of badger vaccination on cattle herd breakdowns could be obtained
without undertaking a relatively large scale trial over at least a four year
period.
3.2 For similar reasons, a small-scale trial is also unlikely to yield reliable
information on the effect of vaccination on prevalence of TB in the badger,
(even assuming there were reliable assays to diagnose TB in the live animal).
The prevalence of TB in most populations of badgers is probably less than
10%, it can vary considerably between local social groups and can also show
cyclical variation over a period of several years. As discussed above, two or
three years of vaccination might be required to have an impact on TB in the
badger. Therefore, large numbers of badgers would need to be vaccinated
and monitored by trapping and blood sampling over a prolonged period of
time to obtain meaningful data. In any event, current assays for detection of
infection by one-off sampling of live badgers have limited sensitivity and
specificity and the likelihood and time-scale for developing such assays is
uncertain.
70
3.3 For these reasons, it would be preferable to proceed directly to a largescale trial aimed primarily at examining the impact of vaccination on TB in
cattle, assuming that the experimental studies provided evidence of efficacy.
The precise design of the trial would depend on the area that would need to
be covered to include the numbers of herd breakdowns required. This might
be either a single large site or multiple sites, as in the current culling trial, with
appropriately matched control sites. Indeed, the control areas, and possibly
also the reactive areas (depending on the results), in the current culling trial
might be suitable for such a trial.
3.4 However, there may be a need for limited scale, short-term experiments
in the field to examine the feasibility of particular aspects of the trial, e.g.
assessment of environmental risks, measurement of vaccine uptake or
assessment of vaccine take.
71
APPENDIX 11.
VACCINATION OF BADGERS AGAINST BOVINE TB: THE ECOLOGICAL
CONSIDERATIONS.
Chris Cheeseman, Des Delahay & Gavin Wilson
CSL Woodchester Park, Nympsfield, Stonehouse, Glos, GL10 3UJ
1. INTRODUCTION.
1.1 Vaccination of wildlife presents particular challenges related to the
ecological characteristics of the target population. The efficacy of the vaccine
will be a product of the rates of uptake and immunisation that are achieved.
Understanding the practical constraints imposed by ecological factors is
essential for the development of an effective vaccine and a successful
strategy for its delivery.
1.2 This appendix describes the potential influence of badger social
organisation, population dynamics and the epidemiology of Mycobacterium
bovis infection on the development and execution of any future vaccination
programme, and discusses options for vaccine delivery strategies.
2. BADGER SOCIAL ORGANISATION AND POPULATION DYNAMICS.
2.1 In order to establish an effective vaccine delivery programme it is
necessary to estimate the size and distribution of the target population (which
may relate to either the number of badgers or their setts). Consequently,
vaccination of badgers would require information on population density, social
organisation and demographic structure (particularly if age or sex biased
disease transmission occurs, e.g. pseudo-vertical transmission). In addition,
information on population turnover rates (fecundity, mortality and
emigration/immigration) would be required to determine the frequency of
application that would ensure a fixed proportion of the population was always
vaccinated.
2.2 Badger density varies widely throughout the UK, from less than a single
animal / km2 in marginal habitats to more than 25 / km2 in optimal habitats
(Wilson et al., 1997). The density of badgers in the TB cattle hotspot areas of
South West England is probably medium to high, perhaps typically varying
between 6-15 adults / km2 based on the presence of 1-2 social groups of
moderate size / km2. However, it is likely that in many of these areas current
population density is below carrying capacity as a result of previous culling
operations. It will be necessary to assess the size of target populations for
vaccination, and the methodology employed will depend on the proposed
scale of operations. Current Defra funded projects are investigating the
development of methods to estimate badger abundance.
2.3 Badger social organisation varies between populations. In undisturbed
medium and high-density populations, badgers live in social groups and
72
collectively maintain territories. Although badgers may use several setts
within the group territory, much activity is concentrated at the main sett. This
stable pattern of social organisation allows the delineation of a target area for
vaccination that is ecologically meaningful.
2.4 However, this stable pattern is disrupted to varying degrees in lower
density and disturbed populations. Consequently, a more dynamic social
system (e.g. more movement between groups and sett-sharing) may exist in
populations that have been subjected to badger culling operations in the past.
However, there is currently insufficient data on the social structure of
disturbed populations to fully assess the likely implications for vaccination
strategies. The demographic and epidemiological consequences of badger
culling are the subject of another current Defra funded project. Nevertheless,
evidence from studies of culled populations suggests that in the absence of
further major disruption, numbers might have reached carrying capacity and a
more stable social structure might have returned in many such areas by the
time a vaccination strategy was employed. Following complete removal of 11
social groups (60 adults and yearlings, 11 cubs in total) from the high density
Woodchester Park population it took 10 years for population density and
social organisation to return to pre-cull levels (Cheeseman et al., 1993).
Following the incomplete removal of eight social groups (29 badgers in total)
in a lower density population at North Nibley, the disruption of social group
organisation was largely limited to the first year post-BRO and density
returned to pre-cull levels after only three years (Tuyttens et al., 2000 a & b).
2.5 Any vaccination strategy would need to be sustained over a protracted
period of time and the interval between repeated applications would be
determined by the rate of turnover of individuals in the population. Disease
eradication could probably only be achieved over several decades (White &
Harris, 1995; Smith et al., 2001). Fecundity, mortality, immigration and
emigration determine population turnover rates.
2.6 Female badgers do not usually reproduce until they are two years old.
However, although the majority of females mate and produce blastocysts, in
many populations only a relatively small proportion produce litters. In badgers
examined from South West England only 44% of females implanted
(Cresswell et al., 1992). In high density populations (e.g. Woodchester Park)
more females per social group produce litters than in lower density
populations where suppression by dominant females is thought to be
resource-related (Woodroffe & Macdonald, 1995). However, within high
density areas the number of successful pregnancies (i.e. cubs weaned) might
decrease as the number of adult females per group increases (Woodroffe &
Macdonald, 1995). Generally, only one litter (typically of 2-3 cubs) is
produced per social group each year. This gives an annual productivity of 0.5
to 0.8 cubs per badger in the UK (Smith, 2002). Cub mortality rates are high
and variable (Cresswell et al., 1992; Rogers et al., 1997). Mortality rates of
uninfected adults are more constant: 0.30 and 0.24 per year for males and
females respectively (Wilkinson et al., 2000). This gives a per capita mortality
rate of about 0.5 (Smith, 2002).
73
2.7 Rates of immigration into stable badger populations and those that are
recovering from culling operations will influence the time scale for vaccine
deployment on all but the largest of areas (e.g. at a regional level). In high
density populations rates of movement of badgers between social groups are
relatively low (Cheeseman et al., 1988a; Rogers et al., 1998). However, rates
of movement within populations that are recovering from culling might be
higher (Cheeseman et al., 1993; Tuyttens et al., 2000b).
2.8 Consequently, the intrinsic growth rate (r) of badger populations is
relatively low; approximately 0.24 to 0.30 per year for moderate to high
density populations (Anderson & Trewhella, 1985; Smith, 2002). Rates of
population turnover need to be considered in conjunction with vaccine uptake
rates in order to determine the optimal strategy for repeated applications.
3. THE EPIDEMIOLOGY OF TB IN BADGER POPULATIONS.
3.1 The distribution of infected badgers is spatially clustered. Social groups
with endemic infection can be adjoined by groups where infection is absent
(Cheeseman et al., 1988b; Delahay et al., 2000a). Also, the prevalence of
infection might vary considerably both within and between badger populations,
and over time (Cheeseman et al., 1981; Cheeseman et al., 1985; Delahay et
al., 2000a). However, as there is currently no reliable, cost-effective and
practical technique for accurately identifying such patterns, it might not be
possible to target vaccine delivery accordingly.
3.2 Evidence from Woodchester Park suggests that the prevalence of
infection in the badger population might not bear any linear relationship with
density (Cheeseman et al., 1989; Rogers et al., 1999). However, no
concurrent data exists on both badger density and TB prevalence from other
sites. Mathematical models suggest that a threshold of about 8 badgers per
social group is required for maintenance of infection over the moderate to
long-term (i.e. up to 30 years) in a population (Smith et al., 1995).
3.3 Evidence from the Woodchester Park study suggests that the greatest
risks of infection to cattle may be posed by a relatively small proportion of the
population, consisting of persistently infectious animals (Cheeseman &
Mallinson, 1981; Delahay et al., 2000a). Infected individuals can live for
several years and breed successfully whilst excreting bacilli (Clifton-Hadley et
al., 1993; R. Delahay, unpublished data). As the distribution of infected
individuals can also be highly aggregated within populations, this argues for a
spatially broad-based strategy for vaccination, since small foci of infection
cannot be adequately identified. It is possible that a proactive campaign
involving broad scale application of a vaccine could reach a high proportion of
the target population. However, if small foci of infectious animals were missed
(perhaps reflected in the persistence of local cattle breakdowns), then smallerscale, reactive applications of vaccine could be used to target these ‘problem
areas’. Delivery of a vaccine over an extensive area might be best achieved
by deployment of baits, whereas trapping and injection could be useful in
intensive localised operations.
74
3.4 It is not yet known whether badgers can naturally mount an effective
immune response to M. bovis capable of protecting against the development
of disease and excretion of bacilli. There is some evidence from the
Woodchester Park study, of a transient sero-positivity to M. bovis in badger
cubs. However, it is unclear whether this is the result of maternally derived
antibodies or prior exposure (Newell et al., 1997; Chambers et al., in press).
Nevertheless, in the majority of badgers that exhibited transient sero-positivity
as cubs, M. bovis could not be isolated from clinical samples during later life
(R. Delahay & G. Wilson, unpublished data). Both Newell et al. (1997) and
Chambers et al. (2002) reported that Western blotting may identify serum
antibodies that are correlated with prolonged culture negativity in later life.
However, at present there is insufficient information on the true immune status
(cellular immunity in particular) of these animals to predict the likely effects of
a vaccine.
3.5 It would also be important to consider what the effect of potential vaccines
would be on individuals that were already infected. If cubs are infected at an
early age by females (e.g. pre-weaning and/or pre-emergence from the sett)
then this would probably make it impossible to deliver a vaccine to them prior
to infection. However, in order for a badger vaccine to reduce the incidence of
TB in cattle it might only need to reduce the severity of disease rather than
protect against infection. It might be possible to reduce the rate of
transmission from badgers to cattle by either stopping or decreasing the
excretion of bacteria in infectious badgers. However, if the vaccine had no
effect on infected individuals, then this would suggest the necessity of
frequent follow up vaccination campaigns to prevent these animals from
causing new cases.
4. VACCINE DELIVERY.
4.1 The most likely options for successful delivery of a vaccine to wildlife are
by injection, by an aerosol spray, by ingestible bait or by an orally
administered bait with the capacity to deliver an aerosol to the respiratory
tract. The likelihood of successful immunisation resulting from each potential
delivery route will depend on the characteristics of the vaccine. For example
some vaccines might not survive passage through the gastro-intestinal tract.
The survival of the vaccine in the environment and its likely effects on nontarget species would also influence the choice of delivery vehicle. The pattern
of vaccine deployment would influence the proportion of the population that
could be reached, and this in combination with the immunisation rate would
determine the overall efficacy of the vaccine.
4.2 Delivery of a vaccine by injection would require the capture of badgers.
Cage trapping is unlikely to be more than 80% efficient and would often be
much lower (see Tuyttens et al., 1996), could be biased towards particular
age and sex classes, would be extremely labour intensive over an extended
area and would be prone to interference from objectors. In addition, capture
related stress in trapped badgers could potentially adversely affect the
immune response. However, administration by injection would eliminate the
problems associated with non-target species and survival of the vaccine in the
75
environment. Capture of animals would also allow a specific dose to be
delivered to each individual by a chosen route, and provide accurate data on
numbers vaccinated. In addition, if a suitable ‘badger-side’ diagnostic test
was available then vaccination could be combined with selective culling of
infected individuals. Modelling studies suggest that as culling is more
effective in eradicating disease from the badger population than vaccination, a
combined strategy (of culling and ring vaccination for example) would be likely
to be more efficacious than vaccination alone (Smith et al., 2001).
Alternatively, vaccination by injection could be employed as a fall-back
strategy in specific problem areas, as an adjunct to bait delivery.
4.3 Badger setts are relatively conspicuous structures that could be used to
target delivery of a vaccine. Delivery of bait into the setts themselves would
limit opportunities for exposure to non-target species. Identification of setts for
bait delivery would require labour intensive surveys much like those already
carried out in treatment areas for the Randomised Culling Trial. Main setts
can often be identified (although not always with certainty), but at any given
time some badgers are also likely to be occupying other setts. Also, rates of
movement between setts might be higher in areas that have been the subject
of some disturbance in the past (Tuyttens et al., 2000b) and might change
seasonally. It is likely therefore, that in order to maximise uptake, bait would
have to be delivered to all ‘active’ setts within the target area over a period of
several days, and that re-surveying for active setts would be required before
each subsequent application.
4.4 Bait uptake rates in carnivores have been monitored throughout Europe
and North America as part of strategies to control wildlife rabies by
vaccination. Bait uptake rates can be influenced by a variety of environmental
factors, including prevailing weather conditions, the availability of natural
foods and season. It might also take sometime for populations of ‘bait naïve’
animals to become accustomed to a novel food source, so uptake might
improve with repeated applications.
4.5 The strategy of bait delivery to badgers would need to minimise the
opportunity for a few animals to monopolise the vaccine. This is also the aim
when carrying out studies of badger social organisation with marked bait. In
this case bait containing plastic markers is placed in badger setts and also
distributed in the immediate proximity of the holes at bait points under stones
and logs. This maximises the opportunity for all occupants of the sett to take
bait, protects it from the elements and reduces opportunities for exposure to
non-target species (Delahay et al., 2000b). Such a strategy could also be
employed to deliver a bait containing a vaccine.
4.6 In a field trial in Cork, Republic of Ireland, chocolate-coated gelatine
capsules containing dead Mycobacterium vaccae were added to peanut and
syrup baits placed in shallow pits near sett entrances (McCarthy, 1993). To
date, only limited work has been carried out on bait uptake rates by badgers
and the results have been variable. Southey et al., (2001) reported rates of
bait uptake by badgers that varied widely between sites (between 20 and 82
%), and suggested that uptake by non-targets, weather conditions, time of bait
76
deployment and the local availability of natural foods might have been
influential.
4.7 The strategy might need to minimise exposure of non-target species to
baits, if the vaccine was likely to have any pathological effects, or if uptake
rates in the target population could be adversely affected. Placing baits in
badger setts would reduce exposure to non-target species, but cannot
eliminate it as some mammals (e.g. foxes, rabbits, rats, mice and, in rarer
cases, otters) might also be resident.
4.8 A bait that would be taken orally (whether or not it contains an
effervescent component) would need to be highly palatable to badgers. In
bait preference tests, a formulation consisting of plant and animal protein, fish
oil, a synthetic polymer and coated in chocolate was readily accepted by
captive badgers (O’Callaghan, 1996). Scented attractants could also be used
to improve bait uptake (e.g. synthetic fermented egg in fox baits).
4.9 It is important that the vaccine had no detrimental effects if taken several
times by the same badger, as this would be extremely difficult to avoid. If
delivery of a specific dose was required, then this would seriously constrain
the options for use of an oral bait and could arguably rule it out. However, it
might be possible to use the principles of conditioned taste aversion (CTA) to
limit bait uptake by individuals. This would involve incorporating a CTA agent
in each bait, to induce nausea in any animal that consumed it. Work on foxes
and ferrets carried out by CSL suggests that this could induce a short-term
aversion to consuming further similar baits (G. Massei, unpublished data).
Trapping and injection would allow each captured animal to receive a known
dose and if these animals were marked in some way then re-dosing could be
avoided.
4.10 Monitoring rates of bait uptake during vaccination operations would be a
substantial undertaking, and would be likely to only be possible on a relatively
small sub-sample of the population. The development of a potentially
effective bait delivery strategy would require research on uptake rates with
respect to variations in season, weather, habitat and badger density.
4.11 In New Zealand, vaccine delivery trials have been undertaken using a
mechanical device that sprays an aerosol at possums visiting a bait station .
Using this approach in badgers would require the development of suitable
technology, the vaccine would need to remain viable during storage in the bait
station and suitably prepared for reliable aerosolisation. However, automated
vaccine delivery systems could be prone to mechanical failure and it might be
difficult to monitor numbers receiving the vaccine. It is likely that a large
number of such devices would be required and it is not clear how delivery of a
specific dose and avoidance of multiple dosing could be assured, but it might
be possible to substantially reduce exposure of non-target species by such a
method.
4.12 Once a vaccine candidate and delivery route were identified then firstorder estimates of its effectiveness in the badger population could be obtained
77
from modelling studies. Following experimental dose-response and challenge
studies on captive badgers, field trials would be required to monitor the
immune responses in vaccinated and control animals in the wild, and the
effects of vaccination on patterns of disease prevalence. A field trial would
also provide the only measure of the efficacy of a badger vaccine in reducing
TB breakdown rates in cattle.
5. CONCLUSIONS.
5.1 It is difficult to judge the relative importance of many of the ecological
factors described in this appendix, in the absence of information on the
properties of the candidate vaccines.
5.2 The characteristics of the vaccine (e.g. persistence in the environment,
effects on non-targets, duration of protection afforded) would also influence
the optimal strategy for delivery.
5.3 Characteristics of an ideal vaccine might be that it provides long-term
protective immunity and some therapeutic value for infected animals at a
range of doses, whilst being safe in non-targets that could be delivered in an
oral bait.
5.4 Successful delivery of a vaccine to wild badger populations throughout
the TB affected areas of England and Wales, would be likely to be aided by
their typical organisation into social groups based around relatively
conspicuous communal setts.
5.5 At present, an orally delivered bait appears to be the most practical option
for vaccination (see Annex). However, the limited studies undertaken to date
suggest that rates of bait uptake could vary widely (e.g. G. Smith, unpublished
data; Southey et al., 2001), so further work would be required to identify
optimal strategies.
5.6 Potentially promising strategies include annual broad scale application of
a vaccine followed by localised, intensive, follow-up vaccination operations in
‘problem areas’, and vaccination in combination with selective culling.
5.7 Field studies on the effects of a vaccine in wild badgers would require one
or more populations for which the prevalence of infection, social organisation
and demographic characteristics were already known.
6. REFERENCES.
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Chambers M.A., Pressling W.A., Cheeseman C.L., Clifton-Hadley R.S. &
Hewinson, R.G. (2002). Value of existing serological tests for identifying
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Cheeseman C.L., Jones G.W., Gallagher J. & Mallinson P.J. (1981). The
population structure, density and prevalence of tuberculosis (Mycobacterium
bovis) in badgers (Meles meles) from four areas in south-west England.
Journal of Applied Ecology, 18, 795-804.
Cheeseman C.L. & Mallinson P.J. (1981). Behaviour of badgers (Meles
meles) infected with bovine tuberculosis. Journal of Zoology, 194, 284-289.
Cheeseman C.L., Little T.W.A., Mallinson P.J., Page R.J.C., Wilesmith J.W. &
Pritchard D.G. (1985). Population ecology and the prevalence of tuberculosis
in badgers in an area of Staffordshire. Mammal Review, 15, 125-135.
Cheeseman C.L., Cresswell W.J., Harris S. & Mallinson P.J. (1988a).
Comparison of dispersal and other movements in two badger (Meles meles)
populations. Mammal Review, 18, 51-59.
Cheeseman C.L., Wilesmith J.W., Stuart F.A. & Mallinson P.J. (1988b).
Dynamics of tuberculosis in a naturally infected badger population. Mammal
Review, 18, 61-72.
Cheeseman C.L., Wilesmith J W. & Stuart F.A. (1989). Tuberculosis: the
disease and its epidemiology in the badger, a review. Epidemiology and
Infection, 103, 113-125.
Cheeseman C.L., Mallinson P.J., Ryan J. & Wilesmith J.W. (1993).
Recolonisation by badgers in Gloucestershire. In Hayden, T. J. (ed.). The
Badger, 78-93. Royal Irish Academy, Dublin.
Clifton-Hadley R.S., Wilesmith J.W. & Stuart F.A. (1993). Mycobacterium
bovis in the European badger (Meles meles): epidemiological findings in
tuberculous badgers from a naturally infected population. Epidemiology and
Infection, 111, 9-19.
Cresswell W.J., Harris S., Cheeseman C.L. & Mallinson P.J. (1992). To breed
or not to breed: an analysis of the social and density-dependent constraints on
the fecundity of female badgers (Meles meles). Philosophical Transactions of
the Royal Society of London Series B, 338, 393-407.
Delahay R.J., Langton S., Smith G.C., Clifton-Hadley R.S. & Cheeseman C.L.
(2000a). The spatio-temporal distribution of Mycobacterium bovis (Bovine
Tuberculosis) infection in a high density badger (Meles meles) population.
Journal of Animal Ecology, 69, 428-441.
Delahay R.J., Brown J.A., Mallinson P.J., Spyvee P.D., Handoll, D., Rogers,
L.M. & Cheeseman C.L. (2000b). The use of marked bait in studies of the
territorial organisation of the European badger (Meles meles). Mammal
Review, 30, 73-87.
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McCarthy J. (1993). The badger vaccination trial in West Cork: Progress
report. In Hayden, T. J. (ed.). The Badger, 181-188. Royal Irish Academy,
Dublin.
Newell D.G., Clifton-Hadley R.S. & Cheeseman C.L. (1997). The kinetics of
serum antibody responses to natural infections with Mycobacterium bovis in
one badger social group. Epidemiology and Infection, 118, 173-180.
O’Callaghan W. (1996). Responses of badgers and other mammals to
different food flavours. National University of Ireland, Cork, Ireland.
Rogers L.M., Cheeseman C.L., Mallinson P.J. & Clifton-Hadley R. (1997).
The demography of a high density badger (Meles meles) population in the
west of England. Journal of Zoology, 242, 705-728.
Rogers L.M., Delahay R.J., Cheeseman C.L., Langton S., Smith G.C. &
Clifton-Hadley R.S. (1998). Movement of badgers (Meles meles) in a high
density population: individual, population and disease effects. Proceedings of
the Royal Society Lond. B., 265, 1-8.
Rogers L.M., Delahay R.J., Cheeseman C.L., Smith G.C. & Clifton-Hadley
R.S. (1999). The increase in badger (Meles meles) density at Woodchester
Park, south-west England: a review of the implications for disease
(Mycobacterium bovis) prevalence. Mammalia, 63, 183-192.
Smith G.C., Richards M.S., Clifton-Hadley R.S. & Cheeseman C.L. (1995).
Modelling bovine tuberculosis in badgers in England: preliminary results.
Mammalia, 59, 639-650.
Smith G.C., Cheeseman C.L., Clifton-Hadley R.S. & Wilkinson D. (2001). A
model of bovine tuberculosis in the badger Meles meles: an evaluation of
control strategies. Journal of Applied Ecology, 38, 509-519.
Smith G.C. (2002). The role of the badger (Meles meles) in rabies
epizootiology and the implications for Great Britain. Mammal Review, 32, 1326.
Southey A.K., Sleeman D.P., Prendergast J., O’Sullivan R.F.O. & Mulcahy
M.F. (2001). Use of biomarkers to assess the feasibility of delivering a
vaccine to badgers (Meles meles). Journal of Zoology, 253, 133-139.
Tuyttens F.A.M., Macdonald D.W., Delahay R. J., Rogers L.M., Mallinson P.J.,
Donnelly C. A. & Newman C. (1996). Differences in trappability of European
badgers Meles meles in three populations in England. Journal of Applied
Ecology, 36, 1051-1062.
Tuyttens F.A.M., Delahay R.J., Macdonald D.W., Cheeseman C.L., Long, B. &
Donnelly C.A. (2000a). Spatial perturbation caused by a badger (Meles
meles) culling operation: implications for the function of territoriality and the
80
control of bovine tuberculosis (Mycobacterium bovis).
Ecology, 69, 815-828.
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Tuyttens F.A.M., Macdonald D.W., Rogers L.M., Cheeseman C.L. & Roddam
A.W. (2000b). Comparative study on the consequences of culling badgers
(Meles meles) on biometrics, population dynamics and movement. Journal of
Animal Ecology, 69, 567-580.
White P.C.L. & Harris, S. (1995). Bovine tuberculosis in badger (Meles
meles) populations in south-west England: an assessment of past, present
and possible future control strategies using simulation modelling.
Philosophical Transactions of the Royal Society of London B, 349, 415-432.
Wilkinson D., Smith G.C., Delahay R.J., Rogers L.M., Cheeseman C.L. &
Clifton-Hadley R S. (2000).
The effects of bovine tuberculosis
(Mycobacterium bovis) on mortality in a badger (Meles meles) population in
England. Journal of Zoology, 250, 389-395.
Wilson G., Harris S. & McLaren G. (1997). Changes in the British badger
population, 1988 to 1997. Peoples Trust for Endangered Species.
Woodroffe R. & Macdonald D.W. (1995). Female/female competition in
European badgers (Meles meles): effects on breeding success. Journal of
Animal Ecology, 64, 12-20.
ANNEX TO APPENDIX 11.
STAFF TIME REQUIRED FOR A STRATEGY BASED ON DELIVERY OF
VACCINE IN BAIT.
1. This example assumes that the strategy will involve two applications of bait
each year in the proximity of all the active badger setts in the target area.
2. Initially the area would need to be surveyed for all badger setts, in the
same manner as was carried out for each treatment area in the randomised
badger culling Trial.
Between applications, follow-up surveys (directly
comparable to the re-surveys carried out in proactive treatment areas of the
Trial) would be required to identify any changes in sett use that may have
taken place. The resource requirements for survey work in Trial areas are
already known.
3. Experience at Woodchester Park suggests that one fieldworker with a
Land Rover and driving access to within several meters, can feed bait at
about 8-10 main setts each day. On average this will involve the placing of
25-30 individual baits in shallow pits covered with large stones. For the
purposes of bait-marking studies, feeding continues for 8-10 consecutive
days, although if each badger only needed to consume a single bait then this
period could probably be shortened for vaccine delivery.
81
APPENDIX 12.
VACCINATION OF CATTLE WITH BCG TO PROTECT AGAINST
INFECTION WITH MYCOBACTERIUM BOVIS.
John Pollock
Veterinary Sciences Div, DARDNI, Stormont, Belfast BT4 3SD
1. INTRODUCTION.
1.1 This appendix seeks to trace the sequence of the main events in almost a
century of attempts to develop cattle vaccines for bovine tuberculosis. Within
that broad aim, the main areas of focus have been selected to be of relevance
to the present need to assess potential strategies to address the ongoing
problem with this disease.
1.2 Considerable numbers of studies have been performed in several
countries and have been based generally on the use of Bacillus Calmette
Guérin (BCG). Some studies have been constructed as experimental
investigations, others as field trials of various magnitudes. Some have been
reported in detail as carefully designed studies with adequate controls, others
less so. This variation must be acknowledged when considering the
relevance of individual studies to the current situation and the overall potential
of vaccination. To that end, this appendix attempts to rationalise:
1.2.1 The problems the investigators were attempting to solve and the
background.
1.2.2 Any flaws now apparent which may limit the strength of the conclusions.
1.2.3 The details of the vaccination strategy which was used.
1.2.4 The protocols by which vaccine efficacy was assessed.
1.2.5 The outcome and the conclusions which were reported.
1.3 In a number of the studies which have been reviewed, particularly the
more historical ones, some of these details are difficult to ascertain. However,
with the benefit of previous reviews in this area (Francis, 1958; Zuckerman,
1980; O’Reilly and Daborn, 1995; Skinner et al., 2001; Buddle, 2001), it is
usually possible to fit each study into a perspective of how opinions and ideas
have changed with time.
2. IDEAL FEATURES OF A VACCINE FOR BOVINE TUBERCULOSIS.
2.1 It is apparent that the ideal features of a vaccine to combat bovine
tuberculosis depend on the prevailing conditions, including economics and
disease prevalence. For example, the requirements of a vaccine to improve
the situation in the early part of the 20th Century are likely to have been very
82
different from present requirements. Around 100 years ago, knowledge of the
pathogenesis of the disease was in its infancy. At that time, up to a third of all
cattle were infected with tuberculosis, and there had been little attempt to deal
with the situation. Currently in the U.K., however, statutory programmes for
eradication have been in place for decades and have greatly decreased
disease prevalence.
Additionally, it is become accepted that wildlife
reservoirs may play a significant rôle in the maintenance of bovine
tuberculosis in particular areas (as reviewed by Krebs, 1997).
2.2 Within recent years, several authors have considered the features
required of a vaccine to effectively address bovine tuberculosis in developed
countries, like U.K. and New Zealand, where there are potential wildlife
reservoirs of infection (badgers and possums, respectively). In such a
situation, the vaccine could be targeted towards either cattle or wildlife, and
the profile of the vaccine will be different in each situation.
2.3 Within a programme to control tuberculosis in domestic animals, the aim
of a vaccine for wildlife species is, essentially, to prevent spread of infection to
cattle.
To that end, such a vaccine need not necessarily prevent
establishment of infection in the target animal, but must prevent excretion of
bacilli (Newell and Hewinson, 1995). It has been considered that a badger
vaccine should reduce the number and infectiousness of animals with active
tuberculosis, but that it is not a concern if vaccinated animals have persistent
low levels of infection (Krebs et al., 1997).
2.4 The requirements of a vaccine to be used in cattle are much more
stringent. It has been stated that such a vaccine must be capable of
protecting against establishment of persistent infection and that an outcome of
reduction in bacterial load in persistently infected animals, which may be a
good outcome for badger vaccination, would be unacceptable for cattle (Krebs
et al., 1997). Recent reviews from New Zealand (Buddle, 2001; Skinner et al.,
2001) have set out the detailed requirements for a cattle vaccine in developed
countries. As stated, the vaccine must establish a form of immunity which will
allow the animal to resist infection. The vaccine should also be safe, and be
acceptable to other countries which would be potential importers of vaccinated
cattle or cattle products. As part of that requirement, it will be necessary to be
able to differentiate vaccination from infection (Krebs et al., 1997). Skinner et
al. (2001) set the standard that the ideal cattle vaccine should allow the
animal to resist challenge without becoming positive to subsequent tuberculin
skin tests.
3. BCG.
3.1 Historical development of BCG.
3.1.1 The initial Bacillus Calmette Guérin was developed from a strain of M.
bovis, which had been isolated by Nocard from a case of tuberculous mastitis
by 230 passages through glycerinated bile potato medium between 1908 and
1919 (Oettinger et al., 1999). The initial strain was dispersed to many
countries in the 1920’s and continuing maintenance in differing conditions
83
resulted in the production of a considerable number of substrains (such as
Moreau, Tokyo, Gothenburg, Danish, Tice, Montreal, Connaught, Glaxo,
Merieux and Pasteur). Importantly, it has been shown that the substrains of
BCG do not have identical properties and differ, for example, in their antigenic
repertoire (Behr et al., 1999). Indeed, several important T-cell antigens of M.
bovis, such as MPB64, MPB70 and MPB83, are differentially expressed by
substrains of BCG (Li et al., 1993; Matsuo et al., 1995; Wiker et al., 1996).
These differences have the implication that the substrain of BCG that is
selected for vaccination will determine the antigenic profile of the resulting
immunological priming. To that end, it has been shown that different
substrains of BCG induce differing immune responses in mice (Lagranderie et
al., 1996). Therefore, it has been considered likely that the substrain
selected, and other factors such as dose and route of vaccination, may
influence the efficacy of BCG in cattle (Newell and Hewinson, 1995).
3.2 Use of BCG in human tuberculosis.
3.2.1 Around 3 billion doses of BCG have been used since 1921 as a safe,
inexpensive, single-shot vaccine to protect people from tuberculosis, but the
overall efficacy remains somewhat controversial (Colditz et al., 1994; Roche
et al., 1995; Wilson, 2000; Fine, 2001). Over the years, many studies have
investigated the benefits of BCG and protective efficacies ranging from 80% to
less that 0% have been reported (Fine, 1995; Roche et al., 1995). Metaanalysis of available published data indicated that BCG decreased the risk of
tuberculosis by 50% (Colditz et al., 1994). It is generally accepted that BCG
protects best against childhood and disseminated tuberculosis, but is less
effective against adult pulmonary tuberculosis, leading to a school of thought
that it protects better against internal, blood-borne spread than against initial
infection (Roche et al., 1995).
3.3 Potential of BCG for vaccinating cattle.
3.3.1 As an attenuated strain of M. bovis, the potential of BCG for vaccinating
cattle against disease caused by “wild-type” M. bovis was obvious to Calmette
and Guérin, who carried out early investigations in that species (Calmette and
Guérin, 1911). As in human tuberculosis, the additional benefits of being safe
and inexpensive mean that BCG has often been considered as an option to
control bovine tuberculosis over the last century (as reviewed by O’Reilly and
Daborn, 1995; Buddle, 2001 and Skinner et al., 2001). It is also clear that
BCG has been the prototype vaccine for tuberculosis in domestic livestock
and remains the standard against which novel candidate vaccines will be
compared (Griffin, 2000).
4. EXPERIMENTAL AND FIELD INVESTIGATIONS INTO THE POTENTIAL
OF BCG FOR CATTLE.
4.1 Early investigations.
4.1.1 Investigations have been made in several counties to determine
whether BCG offers potential in the control and eradication of bovine
84
tuberculosis. The studies have been based either on vaccination followed by
challenge with virulent M. bovis (vaccine-challenge experiments; Table 1) or
on monitoring the effects of vaccination on field situations where cattle were
exposed to M. bovis (field studies; Table 2). While it is not always obvious
how individual studies should be ascribed, an attempt has been made in
Tables 1 and 2 to rationalize the major published information in a
chronological and geographical manner.
4.1.2 The first experiments with BCG in cattle were performed by Calmette
and Guérin (1911; 1920 and 1924). Doses of BCG, up to 200 mg, were given
intravenously and subcutaneously prior to challenge with M. bovis. At post
mortem examination, tuberculous lesions were limited in number or absent,
although guinea pig isolations were reported to be positive in some of the nonlesioned cases. It was concluded that BCG conferred protection and
minimised lesion formation. The findings from subsequent French field trials
(Calmette and Guérin, 1920; Guérin et al., 1927) were also very encouraging,
with BCG vaccination reducing lesions or providing freedom from tuberculosis.
4.1.3 The results from the French investigations led to international interest in
the possibility of eradicating bovine tuberculosis by vaccinating cattle with
BCG. This was further stimulated by findings of an experiment in the Ukraine
(Tzeknovitzer, 1927) which concluded that BCG induced resistance to
tuberculosis in cattle.
4.1.4 Historically, the focus of investigations then moved to North America
where the outcomes do not seem to have been so positive. In Canada,
Watson et al. (1928) reported that investigations in an infected herd situation
showed that BCG did not provide any benefit in terms of resistance to
tuberculosis. A similar situation was reported in trials in USA, where live or
dead BCG showed some benefit in decreasing internal spread of tuberculosis
but did not prevent infection (Larson and Evans, 1929; Schroeder and
Crawford, 1929). A series of experimental investigations was carried out in
USA and is reported by Haring et al. (1930). BCG was given in large doses
(up to 100 mg or 109 cfu) and animals were challenged intravenously or orally.
It was found that live bacilli were preferable for the induction of protective
immunity, but that the level of protection was insufficient. A trial in an infected
herd also reported by Haring et al. (1930) found a degree of protection but
concluded that BCG induced skin test reactivity and was not appropriate for
tuberculosis eradication programmes.
4.1.5 An experimental study carried out in the 1930’s in UK used BCG doses
of 5 and 50 mg (Buxton and Glover, 1939). Variable protection (between 0
and 50%) was reported, with the higher dose providing better results. As
reviewed by Francis (1958), in the 1930’s there was also interest in the vole
bacillus (M. microti) as a potential vaccine strain. This was investigated in
calves and, after showing initial promise in inducing a relatively high degree of
immunity to M. bovis (Young and Paterson, 1949), it was ignored
subsequently due to concerns over virulence.
85
4.1.6 Zuckerman (1980) reviewed two trials which were carried out in UK in
the 1930’s and 1940’s, which were stated not to have been “widely published”.
The first trial was conduced in 4 herds infected with tuberculosis and lasted for
11 years. 47 animals were vaccinated at 6-month intervals. Ultimately, 25% of
these were found to have tuberculosis lesions, compared with 50% of their
contacts. The second trial involved more animals, but did not last as long due
to the advent of the national test-and-slaughter programme. In that case, 30%
of the vaccinated and 50% of the non-vaccinated animals were found to have
lesions.
4.1.7 Glover and Richie (1953) report on a UK trial carried out in 2 infected
areas. In that case, vaccination reduced the number of animals with lesions,
and there was an indication that vaccination was most successful if calves
were not subjected to early challenge. In another trial which was carried out
in an infected herd, it was found that considerable numbers of vaccinated
animals developed lesions, and it was concluded that test-and-slaughter was
a more realistic option (Doyle and Stuart, 1958). In other European trials,
however, more positive outcomes were reported. In two such programmes
carried out in Germany in the 1950’s, tuberculosis was successfully
eradicated from herds which were known to have been infected (Schellner
and Gaggermeier, 1955; Rolle and Wiethe, 1956).
4.1.8 Considering the variable outcomes which had been reported for the use
of BCG in cattle up until the 1950’s, an Expert Committee of the WHO/FAO
(1959) stated that: “generally speaking, vaccination has no place in the
eradication of tuberculosis in cattle.” This conclusion was based on a lack of
proven effect and the fact that BCG vaccination compromises the tuberculin
skin test.
4.1.9 In the situations which prevail in some countries, however, tuberculin
testing followed by slaughter of reacting animals may not be an option and, in
the face of a serious zoonotic problem, further work on BCG vaccination was
performed in some African countries (Mares, 1972).
Experimental
investigations reported from Malawi in 1972 showed that BCG produced
useful resistance to challenge with M. bovis, which was more apparent in
Zebu cattle than in Zebu-cross (Waddington and Ellwood, 1972; Ellwood and
Waddington, 1972). In Madagascar, Cheneau and Blancou (1975) compared
the potential of vaccination with live BCG, killed BCG and a trypsin extract of
the Koch bacillus and found the latter to provide greatest protection. Several
field trials were carried out in Malawi in the 1970s using 2.6 x 109 cfu of BCG.
Some reports from this phase (Ellwood, 1975; Moodie, 1977) concluded that
BCG was effective in controlling spread of tuberculosis in cattle. However,
other reports (Berggren, 1977; 1981) identified little benefit of BCG in
protecting cattle from infection. Contrary to these findings, trials carried out in
infected animals in USSR indicated that BCG had the potential to clear
infected herds within a period of years (Sibgatullin, 1982).
4.2 Recent investigations.
86
4.2.1 The reports considered above provide a range of conclusions on the
potential of BCG to be used effectively against bovine tuberculosis. Among
the possible reasons for this variation, it is apparent that the studies were
performed under a great range of conditions, using different types of cattle
with different infection backgrounds, different vaccination strategies, different
methods of assessment and different criteria for “success”. It has been
recognised that improved animal models were needed to allow advancement
of tuberculosis vaccine development (Griffin, 2000), and, in the 1990’s, Buddle
and co-workers modified the intra-tracheal method of experimentally infecting
cattle with M. bovis to allow a more controlled and appropriate assessment of
vaccines.
4.2.2 At that time in New Zealand, it was recognised that vaccination of cattle
was a possible option of addressing a tuberculosis problem confounded by
the presence of a reservoir of infection in possums. Furthermore, it had been
recognised that previous studies had vaccinated cattle with massive doses of
BCG, equivalent in many cases to in excess of 108 cfu (Skinner et al. 2001),
while it had been postulated that a “low dose” of BCG would provide more
effective protection by imprinting an appropriate pattern of immune response
(Bretscher, 1994; Griffin et al., 1999).
4.2.3 An experiment reported by Buddle et al. (1995a) compared vaccination
with 6 x 104 cfu BCG (low dose) with 6 x 106 cfu BCG (medium dose) in
groups of calves which were subsequently challenge intratracheally with M.
bovis. 10/16 of the non-vaccinated calves were found to have tuberculous
lesions, while only 6/30 vaccinates were lesioned. It was concluded that
either the low or medium dose of vaccine gave significant protection, but it is
of importance that an additional 3 calves from the vaccinated groups were
positive for M. bovis culture in the absence of lesions (i.e. overall 9/30
vaccinates were culture positive).
4.2.4 Further experiments were carried out in New Zealand to investigate the
effects of route of administration of BCG and compare BCG with an
alternative vaccine, killed M. vaccae (Buddle et al., 1995b). This study
confirmed the ability of BCG to reduce lesion formation in experimentallyinfected cattle, but detected no such effect for M. vaccae.
4.2.5 A subsequent experiment identified a potentially very important feature,
that cattle with pre-existing sensitisation to environmental mycobacteria may
not become effectively protected by BCG (Buddle et al., 1999). In that study,
cattle with pre-existing T-cell recognition of PPDA prior to immunisation with 5
x 105 cfu BCG had similar levels of lesion formation as the control group after
challenge with M. bovis.
4.2.6 It has been suggested that the problem of pre-sensitisation is caused by
inhibition of active metabolism of the viable vaccine strain and that a possible
strategy to overcome this is to develop subunit vaccines (Brandt et al., 2002).
An initial experiment to investigate such a vaccine in cattle has been reported
from New Zealand (Wedlock et al., 2000). In that experiment, although BCG
was found to give a significant level of protection from challenge with M. bovis,
87
the subunit vaccine (based on culture filtrate proteins of M. bovis and IL-2)
was seen to enhance extrathoracic spread of infection compared to nonvaccinates.
4.2.7 An alternative strategy to circumvent any adverse effect of
environmental pre-sensitisation may be to vaccinate animals while they are
very young. Recent data from experiments carried out in New Zealand
indicate that the approach of vaccinating neonatal calves with BCG holds
considerable promise in protection from challenge with M. bovis (Bryce
Buddle, personal communication).
5. CONCLUSIONS FROM FIELD STUDIES ON THE USE OF BCG IN
CATTLE.
5.1 It has been demonstrated that vaccination with BCG can provide a
considerable degree of protection from the development of tuberculous
lesions following experimental challenge with M. bovis. However, this outcome
has not always been reflected in field trials. Indeed, attempts to utilise BCG to
control natural tuberculosis have often given disappointing results (O’Reilly
and Daborn, 1995; Buddle, 2001; Skinner et al., 2001). The reasons for this
overall lack of success in field situations are not clearly understood. A
number of factors have been proposed relating to either the vaccine or the
target cattle, and include:
5.2 Factors relating to BCG.
5.2.1 Very large doses of BCG (up to 1010 cfu) were used in many field trials.
It is now considered that lower doses may induce more effective immunity
(Bretchner, 1994; Griffin et al., 1999).
5.2.2 Differing substrains of BCG were used in different trials. It has been
suggested that the lack of success in Malawi may relate to the use of BCG
Glaxo, which does not produce the dominant antigen MPB70 (C. Foster, 1992
– cited by O’Reilly and Daborn, 1995). Interestingly, individual strains of BCG
have had very different efficacies in different trials against human tuberculosis
(Fine, 1995).
5.2.3 The viability of the BCG vaccine is difficult to ascertain. In some cattle
experiments, it has been shown that the BCG must be viable to induce
effective immunity (Haring et al., 1930). In some trials, particularly in difficult
situations, the conditions may not have been optimal for storage and
presentation of the vaccine.
5.3 Factors relating to the cattle.
5.3.1 In human tuberculosis, it is considered that host genetics are relevant to
the development of effective immunity in response to BCG (Fine, 1998). This
may also be of fundamental importance in cattle, and it was noted by Ellwood
and Waddington (1972) that Zebu cattle developed more effective immunity to
BCG than cross breeds.
88
5.3.2 Factors such as stress may affect development of effective immunity.
Griffin et al. (1999) have shown that modelling of stressful conditions by
treatment with dexamethasone has a devastating effect on development of
anti-BCG responses in deer. Other intercurrent infections may also have an
adverse effect on immuno-competence.
5.3.3 In situations where bovine tuberculosis is endemic, cattle may be
exposed to M. bovis prior to vaccination. The WHO/FAO Expert Committee
(1959) considered that it was an essential condition that only animals free
from infection should be vaccinated.
5.3.4 In studies of BCG in human tuberculosis, it has become apparent that
geographical location, possibly relating to prevalence of environmental
mycobacteria, has an effect on vaccine efficacy (Palmer and Long, 1966;
Fine, 1995). It has been shown recently in mice that the effect of sensitisation
to environmental mycobacteria is due, at least in part, to the inhibition of BCG
activity (Brandt et al., 2002). In cattle experiments, it has been found that
animals with pre-vaccination T-cell reactivity to PPDA, presumably through
exposure to environmental organisms, do not develop effective immunity in
response to BCG (Buddle et al., 1999). Potentially, this type of scenario could
have had a profound effect on many of the vaccine trials which have been
performed to date.
6. VACCINE DEVELOPMENT.
6.1 A lack of clear success for BCG along with the difficulty of addressing
some of the factors listed above, have provided impetus towards the
development of novel vaccines for bovine tuberculosis. This work has been
developing in parallel with major initiatives to develop new vaccines for human
tuberculosis and enormous potential for cross-discipline research has been
recognised.
6.2 Recent scientific advances will facilitate greatly the development of new
vaccines for bovine tuberculosis. For example, characterisation of the M.
bovis genome will provide great advantage in rational production of novel
vaccines such as sub-unit proteins, DNA vaccines, vector vaccines, M. bovis
auxotrophs and recombinant strains of BCG. Also, progress in the field of
bovine immunology will lead to greater understanding of protective immune
responses and development of tests to differentiate between vaccinated cattle
and those infected with M. bovis.
6.3 With regard to understanding protective immunity, recent experiments in
New Zealand have shown that development of efficient protection is
associated with an early post-vaccine IFN-γ response (Skinner et al., 2001).
Also, in the same vein, it has been shown that post-challenge level of
pathology is related to the magnitude of the IFN-γ response directed towards
ESAT-6 (Vordermeier et al., 2002).
89
6.4 One major concern about vaccinating cattle with BCG has been that the
tuberculin skin test, which is often a pre-requisite for international trade, is
compromised (WHO/FAO, 1959). However, in the post-genomic era, it is
known that the process by which BCG evolved from M. bovis resulted in
deletion of defined stretches of DNA (Behr et al., 1999). This knowledge can
be utilised in the development of tests which can differentiate BCG-vaccinates
from cattle which have been exposed to M. bovis. Thus, only cattle which
have been exposed to the virulent organism will have responses to dominant
T-cell antigens such as ESAT-6 and CFP10, which are deleted from the
genome of all substrains of BCG (Pollock and Andersen, 1997; Buddle et al.,
1999; Vordermeier et al., 2002).
6.5 However, a possible category of animals, which have been effectively
protected by BCG vaccination and subsequently exposed to M. bovis, must
still be considered. Because of post-vaccine M. bovis exposure, these
animals may develop T-cell responses to antigens such as ESAT-6 and
CFP10 in the absence of disease or tuberculous pathology. It must be
recognised that further advances will be required to allow accurate
categorisation of such animals based on immunological parameters.
7. CONCLUSIONS.
7.1 As in human tuberculosis, BCG has many potential advantages for use
against tuberculosis in cattle. It is a safe, inexpensive vaccine for which there
is evidence of protective efficacy in experimental situations. However, a
number of factors, which are not fully understood, appear to compromise field
performance. Indeed, current expectations for BCG would probably fall well
short of the 90% efficacy which was indicated as necessary to provide
benefits in a mathematical model referred to by Krebs et al. (1997). It should
also be remembered that in experimental studies, the protective benefit
derived from BCG vaccination has often referred to limitation of lesions rather
than the prevention of infection. It is now generally stated that to have an
effective impact on bovine tuberculosis, a cattle vaccine must prevent
establishment and maintenance of infection. Indeed, the previous lack of
acceptable field performance for BCG may be a vindication of this current
standard.
7.2 From the literature reviewed, it is apparent that further developments in
vaccine application and possibly in vaccine selection are required to allow
effective use against bovine tuberculosis. Such advances will require greater
understanding of protective immunity and of several confounding factors such
as pre-sensitisation with environmental mycobacteria.
7.3 Importantly, in terms of future expectations, it should be noted from
human studies that even exposure to the complete tuberculosis organism may
not guarantee total protection from subsequent challenge in all individuals
(Fine, 1995) and, as suggested even from earliest times, it may be a reality
that cattle are not capable of developing an immune response which equates
to absolute protection against M. bovis (McFadyean, 1901 – cited by
Pritchard, 1988).
90
8. ACKNOWLEDGEMENT.
The input of Dr Jim McNair (VSD, Belfast) in the production of this Appendix is
gratefully acknowledged.
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95
TABLE 1. OVERVIEW OF VACCINE CHALLENGE EXPERIMENTS
Study
Country
Vaccine
M.bovis
Challenge
Assessment
Evidence for
protection
Calmette and Guérin
1911
France
Strain
BCG
Dose
200mg
Route
I/V1
I/V
PM4 / GP5
No lesions seen
1920
France
BCG
20mg
I/V
In-contact
PM / GP
Calmette and Guérin 1924
Tzeknovitzer
1927
France
Ukraine
BCG
BCG
50-100mg
S/C2
5mg I/V
0.005mg
Vallee
PM / GP
PM
Limited thoracic lesions.
GP -ve
No lesions seen. GP+ve
Visible lesions seen but
were fewer in number
compared to controls
Haring et al
USA
BCG
50-100mg
I/V-S/C
2mg I/V
PM
1 gm
I/V
2mg I/V
PM
USA
Killed,
virulent
BCG
S/C
Oral
PM / GP
USA
BCG
BCG
BCG
BCG
100mg
1gm
100mg
1.2-3.5 x
109 cfu8
I/V
Oral
I/D10
S/C
Oral
Oral
Oral
Oral
PM / GP
PM / GP
PM / GP
PM / GP
UK
BCG
5 and
50mg
S/C
5mg Oral
PM / GP
1930
USA
Buxton and Glover
1939
96
Moderate lesions in
lungs and thoracic LN.
GP +ve. Controls died of
miliary TB
Visible lesions in 3/4
calves, 4/4 control
calves had extensive
lesions
Visible lesions, GP-ve
Visible lesions, GP+ve
Visible lesions
3/4 calves lesion
positive
Visible lesions in most
vaccinated calves, GP
Authors' Conclusion
BCG prevents lesions but bacilli
still excreted via the intestines
BCG confers protection from incontact exposure
In general, BCG confers
resistance to experimental
infection compared to nonvaccinated controls
Live bacilli are necessary to
develop a protective response.
Dead bacilli provide little
protection
Insufficient protection using
BCG
Differences between control and
vaccinates groups insufficient to
identify protection
5mg BCG failed to protect,
50mg induced moderate
Waddington & Ellwood
Malawi
BCG Galaxo used according to
manufacturer's instructions
0.1-0.5mg
PM / B
Fewer lesions and
limited progression of
lesions in vaccine group
Madagascar
BCG
100mg
S/C
I/V
250mg
50mg
6 x 104
cfu
S/C
In contact
In contact
800 cfu I/T3
PM
PM
PM /H / B
6 x 106
cfu
2 x 105
cfu
53% developed lesions
15% developed lesions
20% vaccinated calves
lesion +ve, 30% culture
+ve; compared to 62.5%
controls
S/C
800 cfu I/T
S/C
2 x 103 cfu
I/T
PM / H / B
37% of vaccinated
calves were lesion and
culture positive
compared to 77% in the
M. vaccae group. 66%
of controls were
lesioned and culture
positive
USSR
Buddle et al
New
Zealand
New
Zealand
BCG
Pasteur
BCG
Pasteur
1995
BCG reduces the impact of
virulent challenge. Greater
protection in Zebu than Zebu
cross
Killed BCG and live BCG gave
slightly lower protection than
trypsin extract of Koch bacillus
(25.2%, 28.5% and 34.6%
respectively)
PM / H / B
Novak and Suyubaeva 1985
Buddle et al
protection with individual
0.1mg S/C
BCG, killed
Koch,
trypsin
extract
BCG
BK Karkov
BCG
Pasteur
1995
+ve. Protection 0-50%
BCG Galaxo used according to the
manufacturer's instructions
1972
Cheneau and Blancou 1975
7
Malawi
1972
Ellwood & Waddington
6
97
variation
BCG appears to produce a
useful degree of resistance to
progression of TB
BCG at 6 x 104 or 106 induced
significant protection against
virulent challenge
Killed M. vaccae induced no
protection against virulent
challenge but BCG did
2 x 103
cfu
2 x 105
cfu
2 x 109
cfu
5 x 105
S/C
1 x 103 cfu
I/T
PM / H / B
Lesions found in
vaccinated and control
calves
5 x 103 cfu
I/T
PM / H / B
50% of vaccinated
calves lesion +ve. All
calves were bacteriology
positive. 100% nonvaccinates were lesion
positive
75% of calves lesion
+ve. All calves were
bacteriology positive.
Fewer lesions were
found in the vaccinated
calves compared to
controls
Buddle et al
1999
New
Zealand
BCG
Pasteur
BCG
Pasteur
M. vaccae,
killed
BCG
Pasteur
Wedlock et al
2000
New
Zealand
BCG
Pasteur
1 x 106
S/C
CFP-IL29
200µg1mg
S/C
S/C
I/T
I/D
Superscripts:
1
Intra-venous
2
Sub-cutaneous
3
Intra-tracheal
4
Post Mortem
5
Guinea-Pig
6
Histopathology
7
Bacteriology
8
Colony forming unit
9
Culture filtrate protein-Interleukin-2
10
Intra-dermal
98
BCG induced little protection in
this study, possibly due to
previous exposure to
environmental mycobacteria
CFP-IL2 vaccination can reduce
the incidence of lesions but not
as much as BCG. High dose
CFP-IL2 can induce extra
thoracic spread
TABLE 2. OVERVIEW OF CONTROLED FIELD TRIALS BASED ON BCG VACCINATION
Study
Country
Vaccine
Dose
20mg
M.bovis
Challenge
Assessment
1920
France
Strain
BCG
Guérin et al
1927
France
BCG
Watson et al
1928
Canada
BCG
Larson and Evans
1929
USA
BCG
100mg
S/C2
0.5g
S/C
Schroeder & Crawford 1929
USA
Killed bacilli
No vaccine
BCG
Haring et al
1930
USA
BCG
50mg
S/C
Infected
herd
PM / GP4
Glover and Richie
1953
UK
BCG
50mg
I/V1
2 areas
with
infected
herd
PM / GP
Doyle and Stuart
1958
UK
BCG
100mg
S/C
Infected
PM / B5
Evidence for
protection
Authors' Conclusion
Route
In-contact
Infected
herd
Infected
herd
PM3
PM
All cattle showed TB
lesions
In-contact
PM
4/7 had TB
PM
PM
PM
2/8 had TB
2/6 had TB
Some degree of
resistance from
localisation and
generalisation of TB
No macroscopic lesions
seen but some LN were
bacilli positive
Infected
animals
99
8+27% of vaccinated
calves were lesioned.
Some LN were bacilli
positive. 52% of control
animals were affected
by TB
10 / 25 vaccinated cattle
BCG induced protection from
infection with reduced numbers
of lung lesions
Slaughtered cattle were free
from TB lesions
There was no evidence in favour
of the vaccinated animals nor
any indicators of greater
resistance
Calmette method of vaccination
had no value in protecting cattle
There was no immunity as
measured by the prevention of
infection
Some protection was conferred
but insufficient to use
vaccination as a means of
eradication. Skin reactivity to
vaccination renders cattle
unmarketable
Vaccination proved successful
when calves were not exposed
too early post-vaccination
Test and slaughter is a more
herd
Schellner & Gaggermeier
Germany
Strain P
1955
Rolle and Wiethe
1956
Bavaria
BCG
50mg
S/C
Ellwood
1975
Malawi
BCG
Galaxo
2.6 x 109
cfu6
S/C
Moodie
1977
Malawi
BCG
S/C
Berggren
1977
Malawi
BCG
Galaxo
2.6 x 109
cfu
2.6 x 109
cfu
Berggren
1981
Malawi
BCG
Galaxo
2.6 x 109
cfu
S/C
USSR
BCG
Sibgatullin
1982
S/C
were lesioned. 15 cattle
with no visible lesions
where culture negative
practical eradication policy than
vaccination
28 infected
herds
Complete success was met with
the Graub method (early
inoculation, segregation,
multiple vaccination)
Infected
herd
Infected
herd
Meat
inspection
TB was eradicated from a
severely infected herd over 7yrs
BCG vaccination is an effective
control measure for bovine TB in
Malawi
Infected
herd
Infected
herd
Meat
inspection
Meat
inspection
Infected
herd
PM / B
Infected
herd
Superscripts:
1. Intra-venous
2. Sub-cutaneous
3. Post Mortem
4. Guinea-Pig
5. Bacteriology
6. Colony forming unit
100
11.9% of vaccinated
calves were lesioned,
17.8% non-vaccinated
were lesion positive
Reduced numbers of
reactor cattle
With age matched
vaccine and control
groups there was no
difference in the levels
of protection
Similar levels of lesion
positive cattle were
found in vaccine and
non-vaccine groups
BCG confers protection against
spread of TB
BCG has no significant effect on
the control of bovine TB nor
does it reduce the incidence of
meat condemnations
BCG did not reduce the rate of
infection nor the progression of
lesions, gives little protection
against the Afro-Asian strain of
M.bovis
Over a five year period a herd
was declared free from TB
APPENDIX 13.
CHAIRMAN’S DISCUSSION PAPER ON FORMAT OF FINAL REPORT.
John Bourne
ISG, Location 105, 1A Page Street, London SW1P 4PQ
1. INTRODUCTION.
1.1 The use of vaccines in either cattle or wildlife remains a potential policy
option, although this option offers prospects only in the medium to longer
term. A vaccine development programme is already in place. This involves a
number of international collaborations which harness a global resource which
includes a significant effort to develop a vaccine against the human form of
TB.
1.2 For the future while success cannot be guaranteed, if a vaccine policy is
to be pursued for either cattle or wildlife, it must be recognised that a
demanding research programme would have to be put in place to provide
proof principle that a vaccine is likely to be effective. But more importantly its
value in the field must be validated before the Sub-Committee can
appropriately advise.
1.3 There are I believe a number of important questions that need further
discussion. The purpose of this Appendix is to revisit some of the major
questions.
2. WHAT IS AN EFFECTIVE CATTLE VACCINE?
2.1 Introduction.
2.1.1 We need to discuss under what circumstances could a cattle vaccine be
used and would BCG fit the bill?
2.1.2 The demands of an acceptable cattle vaccine are particularly severe
since it would be expected to both prevent the establishment of infection and
to eliminate transmission. Additionally it should not give a positive reading in
the tuberculin test (or any other immunological-based test) since this would
confuse the regular herd testing procedure and create serious regulatory
problems. However an additional concern about the use of cattle vaccination
in GB relates to the strong likelihood that a wildlife reservoir of TB infection
would persist in the countryside environment and exposure of cattle, protected
by a successful vaccine to this source of infection, would result in
immunological responses which might compromise the skin test.
2.1.3 Any diagnostic test based upon detecting an immune response would
need therefore to distinguish immune responses generated following infection
from those elicited following challenge of a protected vaccinated animal. This
would be difficult to achieve. In addition to being highly sensitive such a test
101
would have to have a high level of specificity for it to be acceptable, since
false positive reactions would trigger a herd breakdown control response.
2.2 Are these aims realistic or are these too restrictive? We must consider:
2.2.1 Accepting that it might not be feasible to prevent infection becoming
established in all cattle?
2.2.1.1 The apparent level of induced protection likely to depend on the level
of challenge.
2.2.1.2 That some individuals may not be capable of effective immunity.
2.2.2 And that there are also other impacting factors.
2.2.2.1
The possible effect of prevaccine exposure to environmental
mycobacteria.
2.2.2.2 There may be cattle with latent M. bovis.
2.3 Also, we need to explore whether the use of a vaccine to limit cattle to
cattle spread of infection has any potential?
2.3.1 Could vaccination be of value if there was a change of policy which
focussed on the protection of public health by “managing” zoonotic aspects of
the disease by for example banning the sale or consumption of nonpasteurised milk, strict abattoir monitoring etc, and limiting the disease in
cattle. It would be necessary to consider whether a vaccine capable of
decreasing shedding could be of benefit - the impact that it would be likely to
have on disease incidence, the limiting effect on pathology and visible lesions
at post mortem, the reduction in the number of cattle sacrificed to control the
disease and the possible limiting effect that cattle vaccination would have on
the disease in badgers by reducing cattle to badger transmission.
2.3.2 The only vaccine candidate that could be considered at the moment
would be BCG.
2.4 Does BCG have this potential?
2.4.1 Experimental use of BCG in cattle suggests a 50% to 75% efficacy and
an average of 75% reduction in disease severity. Although vaccinated
animals remain bacteriologically positive it might be expected that vaccination
would reduce the opportunity for disease transmission.
2.4.1.1 Immunological tests could be developed to differentiate vaccinated
from non vaccinated animals.
2.4.1.2 Naturally infected (from wildlife or cattle) but vaccinated and protected
animals could not be distinguished on the basis of immunological tests.
102
2.5 Research requirements.
2.5.1 In addition to what is already in place, there is a need to consider:
2.5.1.1 The design of a field trial; is it conventional?
2.5.1.2 The effect on cattle TB breakdowns; is it measurable?
2.5.1.3 The diagnostic test on live animal, is it available (with limitations
already identified)?
2.5.1.4 The size, time frame and cost to be considered?
3. WHAT IS AN EFFECTIVE BADGER VACCINE?
3.1 Introduction.
3.1.1 By contrast with cattle, vaccination of wildlife would require a less
demanding vaccine, since although widespread coverage of the population
would be the goal, the proportion of the population that would need to be
protected to influence the disease in cattle is not known and protection of
each individual badger would not be essential. The primary rôle of a wildlife
vaccine would be to reduce the severity of the disease in the target species
and the consequent rate of transmission to cattle. However a wildlife vaccine
would only be effective in controlling cattle TB if most infections derived from
wildlife.
3.2 Aims of vaccination programme.
3.2.1 To eradicate TB from the badger population, to reduce disease severity
and hence bacterial excretion.
3.2.1.1
This would be achieved by: immunising susceptible animals,
increasing the pool of immune animals and hence reducing transmission
below the level needed to sustain endemic infection.
3.2.1.2 This would require successful immunisation of a critical proportion of
susceptible animals.
3.2.1.3 What are the barriers?
3.2.1.3.1 The proportion of the population to be vaccinated is not known; it
might be high given the slow disease dynamics.
3.2.1.3.2 We would be likely to need a highly effective vaccine.
3.2.1.3.3 Vaccine delivery and uptake would need to highly effective.
3.2.1.3.4 Do we need to vaccinate cubs in the sett (vertical transmission)?
103
3.2.1.3.5 The influence of environmental Mycobacteria is unknown.
3.2.1.3.6 Coverage would need to be maintained for a long period to prevent
reinfection of the badger population by cattle.
3.2.1.3.7 Some influence groups would argue that badgers don’t need this.
3.2.2 To reduce exposure of cattle to TB by reducing bacterial shedding by
badgers.
3.2.2.1 This would be achieved by vaccination of an unknown population of
badgers.
3.2.2.2 What are the barriers?
3.2.2.2.1 The effect of vaccination on bacterial shedding is not known; what is
the rôle of super excretors?
3.2.2.2.2 The spatial relationship between infected badgers and cattle is not
known.
3.2.2.2.3 There would be a need for vaccination to be continued in perpetuity
since eradication would not be expected.
4. GENERAL ISSUES.
4.1 The proportion of cattle TB originating from badgers is not known.
4.2 Vaccination is likely to be less effective than culling, and thus detecting
any effect on cattle TB would require a field trial of an extent and duration
comparable with the culling trial but with a smaller expectation of success.
4.3 Coverage might have to be maintained in perpetuity if eradication is not
achieved (or extremely unlikely to be achieved).
4.4 Live vaccine in the environment may expose cattle and lead to spurious
breakdowns.
4.5 The effect of vaccine on already infected badgers is not known – it could
promote shedding or be lethal (but there is no evidence for this in other
species).
4.6 Interest groups could be uncooperative.
4.7 Vaccinating badgers is not a quick fix that can be implemented outside
trial areas with any expectation of effectiveness in the medium or short term.
4.8 With current policy for controlling cattle TB based on the tuberculin test
vaccinating badgers has the potential for “causing“ as many breakdowns as it
prevents.
104
4.9 The outcome of the culling trial will have a profound influence on the
expected success of any vaccination programme. Unless perturbation effects
are massive, vaccination is likely to be less effective than culling. The trial will
provide data that are essential if we are to provide informed scientific opinion.
5. NEXT STEPS.
5.1 Establishing the protective activity of candidate vaccines, including BCG.
An immune effect and some protection has been demonstrated following
intradermal vaccination of badgers with BCG, but the effects of bacterial
excretion and transmission have not been studied in detail and duration of
immunity has not been determined.
5.2 Protection studies are needed. Facilities in GB are not available; can we
rely solely on studies that will take place in RoI which will encompass:
5.2.1 Establishing an experimental colony of badgers.
5.2.2 Establishing an experimental challenge model.
5.2.3 Using this model to reach point of proof principle of vaccine candidate.
5.3 If we are satisfied about the relevance of the RoI studies to the GB
situation we could move on to consider field experimental trials and field
validation.
5.4 If our advice is that further experimental studies should be conducted in
GB, what additional information do we need?
5.4.1 Legal position.
5.4.2 Re-procurement and use of badgers as an experimental animal, given
that, it will be argued, this work will provide little if any benefits to the badger
population.
105
CHAPTER 14.
VACCINATION OF CATTLE AGAINST TB
Ivan Morrison
Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter
Bush, Roslin, Scotland EH25 9RG
1. INTRODUCTION.
1.1 Vaccination of cattle against TB would require either a vaccine that is
compatible with the diagnostic assay currently used for herd testing, or
changes in the way surveillance for TB is conducted to permit the use of
alternative vaccines. Any new control strategies incorporating vaccination
would not only need to be cost-effective, with respect to control of the disease
in cattle, but also would be required to maintain protection of human health.
2. PROSPECTS FOR VACCINATION IN THE SHORT TERM.
2.1 As discussed elsewhere, the only vaccine that is likely to be available for
use in the field over the next few years is BCG. Although vaccination of cattle
with BCG has been shown to reduce the severity of pathology following
challenge with virulent M. bovis, a significant proportion of the vaccinated
animals continue to harbour bacteria. Moreover, animals vaccinated with
BCG give a positive reaction in the tuberculin skin test, and hence cannot be
distinguished from infected animals. For these reasons, vaccination of cattle
with BCG is not a viable option at present.
3. POTENTIAL USE OF VACCINATION IN THE LONGER TERM.
3.1 For the last 50 years control of bovine TB in the UK and the rest of
Europe has relied on herd testing to identify and remove infected animals.
This strategy was originally adopted with the aim of eradicating the disease.
The only available vaccine, BCG, was not sufficiently effective for vaccination
to be considered as a primary strategy to achieve eradication, and BCG could
not be used in conjunction with herd testing because of interference with
interpretation of the skin test. Looking to the future, development of new
diagnostics and vaccines might allow alternative control strategies
incorporating vaccination to be considered:
3.2 Vaccination in conjunction with an alternative diagnostic test. Leaving
aside the issue of vaccination, there is a need to improve the sensitivity of the
diagnostic assay used in herd testing. Substantial research effort (funded by
DEFRA) is currently being devoted to development of TB-specific gamma
interferon assays incorporating defined M. bovis antigens. In the short term, it
is envisaged that such assays could be used in conjunction with the skin test
106
to improve the efficiency of herd testing. It is likely that a gamma interferon
assay with similar or superior sensitivity to that of the skin test will be
developed over the next few years. If sensitivity can be achieved along with a
high level of specificity, serious consideration should be given to replacing the
skin test with the gamma IFN assay as the primary diagnostic assay for herd
testing. Such a laboratory-based assay would allow improved standardisation
of TB testing and require only one farm visit per test (as compared to 2 at
present).
3.3 A diagnostic assay based on the use of defined antigens would also
potentially allow the use of vaccines that did not contain the antigens used in
the diagnostic assay. Since many of the candidate diagnostic antigens are
absent from BCG but present in wild-type M. bovis, either live attenuated or
sub-unit vaccines could be considered. However, as discussed elsewhere
(see Appendices 1 & 12), the diagnostic assay would not only need to
distinguish infected from vaccinated animals but also infected from vaccinated
immune animals that have been exposed to challenge with M. bovis. The
latter may be difficult to achieve but is amenable to experimental investigation.
3.4 Vaccination without herd testing. Current resources for control of TB are
focused on identification of animals once they have become infected with the
causative organism. If wildlife are confirmed as a major source of infection
and if measures to control infection in wildlife prove to be impractical,
unacceptable or ineffective, this control strategy will have a limited impact on
the problem and will continue to consume a large amount of resource. An
alternative radical approach would be to use vaccination of cattle as the
primary means of control in affected regions, dispense with routine herd
testing and focus resources on detection of infected carcasses in
slaughterhouses. Such a strategy would require a highly effective vaccine,
which reliably prevented systemic infection and substantially reduced
pathology and bacterial excretion. The principal aim would be to protect
human health, by ensuring that vaccination prevented organisms reaching the
mammary gland, reduced bacterial excretion to a level that posed negligible
risk to humans in contact with the live animal and limited pathology to, at
most, a few small lesions in tissues that are discarded following slaughter.
This approach would probably require a vaccine with protective activity
superior to that of BCG.
3.5 These strategies are dependent on advances in diagnostics and vaccine
development and would require rigorous experimental and field testing of the
candidate vaccines before they could be implemented. Legislative changes
would also be required to allow the new TB control policies to be adopted.
Nevertheless, in view of the uncertainty concerning the impact of other
approaches to improving control of bovine TB, we consider that the options for
vaccination of cattle need to be retained. In any event, much of the work on
testing vaccine candidates is relevant to both badgers and cattle and the
bovine experimental model allows studies of the properties of experimental
vaccines that are difficult to undertake in badgers.
107
APPENDIX 15
1.1 The Terms of Reference for the Sub-Committee were: “to assist the ISG
in advising Defra Ministers on the feasibility for pursuing a TB vaccination
strategy for either cattle or wildlife. This should also include consideration of
future research requirements in addition to those already in place”.
2.1 The Composition of the Sub-Committee was:
Meetings
attended: no /
max possible
Chairman:
Professor F J Bourne
Members:
Dr C L Cheeseman
Dr M J Colston
Professor C A Donnelly
Miss S M Eades
Professor P Fine
Dr B Grenfell
Dr R G Hewinson
Mr S Houghton
Professor W I Morrison
Dr J Pollock
Mr A G Simmons
ISG
7/7
Defra Central Science Laboratory,
Woodchester Park
National Institute of Medical Research,
London
ISG
Defra Animal Disease Control Division
London University, School of Hygiene &
Tropical Medicine
Cambridge University
Defra Veterinary Laboratories Agency,
Weybridge
Hoechst Roussel Ltd., Milton Keynes
ISG
Queens University, Belfast
Defra, Head, Veterinary Endemic Animal
Diseases & Zoonoses Division
ISG
London University, Imperial College
6/7
Dr R Woodroffe
Professor D B Young
Adviser:
Miss F A Stuart
Defra Science Directorate
Visiting Speakers:
Dr L Corner
Massey University, New Zealand
Dr E Gormley
University College, Dublin, Eire
Mr W Nash
Consultant
Secretariat:
Dr A L Patey
Mr J W Pitchford
Mr T K Matthewsa
Ms S Shahb
a = meetings 1 & 2; b = meetings 3-7
108
7/7
5/7
6/7
1/7
1/7
7/7
4/7
6/7
4/7
6/7
4/7
6/7
6/7
1/1
1/1
1/1
7/7
6/7
2/2
4/5
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high numbers of people infected with HIV.
●
In the United States, incidence of TB began to decline
around 1900, because of improved living conditions.
❍
●
●
●
TB cases have increased since 1985, most likely
due to the increase in HIV.
Tuberculosis continues to be a major health problem
worldwide. In 1997, the World Health Organization
(WHO) estimated that 32% of the global population
was infected with TB bacteria.
❍
7.9 million new cases of TB developed.
❍
1.87 million people died of this disease.
With the spread of AIDS, tuberculosis continues to lay
waste to large populations. The emergence of drugresistant organisms threatens to make this disease
once again incurable.
In 1993, the WHO declared tuberculosis a global
emergency.
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FAQ about BCG
Frequently Asked Questions about BCG
P D O Davies, Director, Tuberculosis Research Unit, Cardiothoracic
Centre, Liverpool. UK
Does it work?
Trials of the vaccine have been undertaken since it was first developed in the 1920s. The results have been
variable. About a third of the total trials have shown no protective effect. The remainders have shown
protection of up to 80%* at best lasting a maximum of 15 years. No trials on second or subsequent
vaccinations have shown any protective effect.
(*Protective efficacy is a measure of the proportion of people who would have got the disease had they not
had the vaccination. 80% protection means that 4 out of 5 individuals are protected. Efficacy for most
vaccines exceeds 95%. BCG is therefore a relatively weak protective vaccine.)
In summary
50% randomised control trials show it to be effective.70% Case-Control studies
show it to be effective.
Why is the effectiveness is variable?
The reasons for variability are not fully understood. There have been a number of
theories put forward, none of which seem to provide a total explanation
1.Methodological. All studies varied slightly in the way they were designed
2.Different vaccines. The development of BCG has meant that strains vary according to the time at which
each has been developed. Different vaccine strains were used in the trials and are in use across the world
today.
3.Tuberculin status of subjects. Within trials some individuals in both control or vaccinated group may
have been tuberculin positive and therefore had “natural “ protection. This may not have been accounted for
in some of the trials.
http://www.priory.com/cmol/bcg.htm (1 of 8) [04/01/06 23:21:44]
FAQ about BCG
4.Different strains of M.tuberculosis. New molecular techniques have demonstrated that there are a large
number of different strains of the bacterium. It is possible that different areas of the world have different
strains, which may vary in virulence.
5.Genetic differences in population. There is variation in individual susceptibility to tuberculosis. This could
have caused disparity in results.
6.Intensity of infecting dose. Infection and susceptibility to disease may be affected by the quantity of
bacteria inhaled.
7.Nutritional differences. It is known that different nutritional states can vary susceptibility to disease. The
poorly fed individual is more susceptible.
8.Protection of controls by environmental mycobacteria. These free living mycobacteria which resemble
M.tuberculosis sometimes cause disease. They may be responsible for infecting individuals therefore
providing partial immunity to M.tuberculosis.
How is BCG used in the UK?
Studies carried out by the British Medical Research Council in the 1950s showed that BCG, when given to
teenage school children gave about 75% protection for 15 years.(1). Since 1953 it has been national policy
to vaccinate all children aged 12-13. Thus in theory the entire population receives protection from early
teenage years through to about the age of 30. The reason for choosing that age range was because in the
1950s cases rates were highest in young adults. The limited length of time for which BCG appeared to be
protective would therefore be maximal at the age when most people suffered from the disease. Secondly the
form of tuberculosis which pre-teenage children suffer from (primary) is not usually infectious, whereas the
form suffered by adults is infectious. Providing protection during early adult life therefore reduced
transmission.
In addition to the national policy for all teenagers, BCG is given at birth to those at
high risk of disease; those with a family history of tuberculosis and those from
minority ethnic groups.(see below)
Is the policy of BCG vaccination the same throughout the world?
FAQ about BCG
No, mainly because of variation in trial results. Most countries give BCG at birth to
provide protection in the early years when infection can often lead to devastating
widespread disease such as miliary tuberculosis or tuberculous meningitis. This is
particularly important in high prevalence countries where the chance of being
infected in very early life is high. Some countries such as the USA have chosen not
to use it because most trials there have not shown any protective effect.
Why is there not international agreement on how to use BCG?
Again because of variation in trial results across the world.
In 1994 a “metanalysis” of all the trials was published. (2)This looked at a total of 1264 articles, 70 in depth,
14 prospective trials and 12 case-control studies. The authors found that seven trials show a protective effect
from death of 71%, five trials showed protection from meningitis of 64%, three, protection from disseminated
disease of 78% and three, protection from laboratory-confirmed disease of 83%.
The authors concluded that geographical site of study explained 66% of variability.
They also found that on average BCG reduces risk of infection leading to disease
by 50%.
This is probably an erroneous conclusion, as the efficacy of BCG cannot be averaged. Trials show it to be
80% protective in one place and 20% in another. Average efficacy should not be taken.
Is the efficacy of BCG waning?
Some workers believe that it is(3). This is because the BCG vaccine is continually being reproduced as part
of the manufacturing process and in common with other live organisms, which undergo this process, may be
becoming less virulent and therefore less able to provide immunity to those who are vaccinated.
In contrast sequential studies form the UK show that the 75% efficacy has been
FAQ about BCG
maintained (4,5)
Does giving BCG prevent the use of the tuberculin test in determining the
presence of infection with M. tuberculosis?
This is another area of controversy . BCG converts the tuberculin test from negative
to positive. Workers are split as to whether it is possible to tell the difference
between a positive test due to BCG alone and a positive test due to infection with
M.tuberculosis whether the individual has had previous BCG or not.
In the UK we believe it is possible to do this on the basis of the degree of
positivity.(6) The USA do not use BCG partly for the reason that they do not believe
it is possible to make the distinction.
The importance of this is the decision to give preventive therapy for Latent Tuberculosis Infection (LTBI).
The USA has relied on prevention by determining whether infection (without disease) is present on the basis
of regular tuberculin testing for those at risk of infection such as health workers. BCG is not given as it is
believed to interfere with the interpretation of the tuberculin test. Other countries, such as the UK, do
give BCG but in cases where infection has occurred in addition to BCG and where
the risk of disease is appreciable, such as in co-householders of Sputum Smear
positive patients, preventive therapy can be given if the tuberculin test is strongly
positive.(7)
Doea BCG protect against drug resistant tuberculosis
The probable answer to this is yes though evidence for this is necessarily sketchy. It
is probably more effective in preventing disease than providing preventive therapy to
those infected; a procedure for which there is no evidence of any efficacy at all. For
health care workers who may be exposed to drug resistant tuberculosis, even a low
protective efficacy of BCG would make vaccination worthwhile.
In a recent study of a mathematical model, BCG was preferred by small margin over
post-infection chemoprophylaxis. Threshold for protective efficacy was 26%.
BCG should be considered for health care workers with risk of MDRTB
exposure.(8,9)
FAQ about BCG
Should BCG still be used in low prevalence countries?
As rates of tuberculosis have declined the argument for continuing routine BCG to
the whole population becomes weaker. (10)For example if rates of disease are
5/100,00 and even if it is assumed that BCG gives 80% protection for 15 years then
vaccinating 100,000 people would prevent (0.8x5)x15=60 cases over 15 years.
A number of countries with very low rates of disease have stopped BCG vaccination, but due to the increase
of cases that has resulted at least one; the Check republic has restarted a routine BCG programme.
Conditions necessary to stop giving BCG include a good control programme, good
reporting especially of TB meningitis and the prevalence HIV and its possible impact
on TB increase must be evaluated.(11)
For example in 1975 mass vaccination in Sweden was replaced by selective
vaccination. As a result BCG coverage fell from95% to 1.8%. It then increased to
13.7% (12)
The result on TB cases is shown in the table below which shows rates of disease in
the Swedish and foreign born children at different percentage BCG cover.
BCG coverage
%
95
13
1.8
Incidence per 100,000 according to BCG Coverage:
Swedish
0.8
2.9
3.9
Foreign
2.6
13.2
39.4
FAQ about BCG
From these figures it can be calculated that the protective effect was 82%.
In the present climate of rapidly increasing cases of disease world wide and mass
travel, the decision is probably not whether to stop BCG but whether to increase its
use.(13)
“Arguments against use of BCG vaccine in a mass programme are not about efficacy but cost
effectiveness.” (14)
Can BCG be harmful?
Abscesses at the site of BCG injection are frequently reported. It is often assumed that this is due to bad
technique, as the injection should be given intra-cutaneaously and an accidental intramuscular injection may
result. Proximal lymph node swelling and abscess formation may rarely occur. If the injection is given at the
correct site, over insertion of Deltoid in the upper arm, the swelling will develop in the axillary lymph nodes.
Very rarely indeed, disseminated BCG disease may result in the
immunocompromised infant. This is usually fatal. For this reason BCG should not be
given to symptomatic HIV positive individuals.
In conclusion
I’m glad I had my BCG
PDODavies.
References
1.Hart PD. Efficacy and applicability of mass BCG vaccination in tuberculosis control
BMJ 19677;1:587-592.
2.Colditz GA et al.Efficacy of BCG Vaccine in the prevention of TuberculosisJAMA
702.Newborns and infants.Paediatrics 1995;96:29-35.
1994;271:698-
FAQ about BCG
3.Behr MA, Small PM Has BCG attenuated impotence?Nature 1997;389:133-134.
Casts doubt on continued efficacy
4.Sutherland I, Springett VH Effectiveness of BCG vaccination in England and
Wales in 1983.Tubercle 1987;68:81-92.5.Capewell S. et al.The current value of
tuberculin testing and BCG vaccination in school children Br. J. Dis. Chest
1986;80:254-264.
6.Joint Tuberculosis Committee of the British Thoracic SocietyControl
and prevention of
tuberculosis in the United Kingdom:Code of practice 2000 Thorax Thorax
2000;55:887-901.
7.Rathus EM. The Heaf multiple puncture test compared with the Mantoux test in
epidemiological surveys.Med J. Aust 1956;1:696-8.
8.Greenberg PD et al.Tuberculosis in House StaffA decision analysis comparing the
Tuberculin Screening Strategy with the BCG vaccination.Am Rev Respir Dis 1991;143:490495.
9.Stevens JP Daniel TMBCG immunization of health care workers exposed to MDRTB: a decision
analysisTubercle & Lung Dis. 1996;77:293-4.
10.Tala EO et al. Pros and Cons of BCG Vaccination in Countries with Low
Incidence of Tuberculosis.Infection Control and Hospital Epidemiology 1994;15:497499.
11.Trnka L Dankova D Svandova E.Six years experience with the discontinuation of
BCG vaccinationTubercle & Lung Disease 1993;74:167-72.
12.Romanus et al.The impact of changing BCG coverage on tuberculosis incidence
in Swedish-born childrenn between 1969 and 1989.Tubercle and Lung disease
1992;73:150-161.
13.Cobelens GJ, van Deutekom H, Draayer-Jansen WE et al: Risk of infection with M.tuberculosis in
travellers to areas of high tuberculosis endemicity. Lancet 2000;356:461-65.
14.Watson JM BCG - mass or selective vaccination?J. Hosp. Infect. 1995;30:508513.
Further reading.
FAQ about BCG
PGSmith and PEMFine BCG vaccination in Clinical Tuberculosis 2nd Editn Edit PDODavies, Chapman and
Hall, London 1998 pp417-434.
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[2005/07/01]
[2005/06/13]
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[2005/07/01]
[2005/06/13]
[2005/06/07]
[2005/04/18]
[2005/04/15]
[2005/04/11]
Links
Links
Other Mycobacteria Web Sites:
Johne's Information Center
National Milk Producers Federation (NMPF) Information
on Animal Health: Johne's Disease
United States Animal Health Association, 1999
Committee on Johne's Disease
University of Nebraska, Johne's Disease
http://www.mycosresearch.com/links.htm (1 of 3) [05/01/06 0:10:49]
Links
University of California Davis, Johne's Disease in Dairy
Cattle
and
UCD Vet Views California Cattleman, February 1997:
Johne's Disease, Part II
Case Western Reserve University, Tuberculosis Research
Unit
Colorado State University, TB Research Materials and
Vaccine Testing
WHO Tuberculosis Control Programme
Mycobacterium tuberculosis genome sequencing program
(Sanger)
CDC National Center for HIV, STD, and TB Prevention
NIAID: Focus on Tuberculosis
-TB research attains new heights in Colorado
-Closing in: The long road to a TB vaccine
Links
Copyright 1999, Mycos Research, LLC.
Web Site mycosresearch.com by Kenton Solutions
L.R.S. Institute of Tubercolisis & Respiratory Diseases
DNB Course
World TB Day
Director's Message
AIMS & Objectives
Visions
Conference
Vacancy
Interview
Departments
Tender
CT Scan
VCTC
DOTS Centers
Indian Journal of Tuberculosis
Patient Care Services
RNTCP DOTS Directory (Delhi)
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Teaching & Training
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Institute Publications
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Related Links
About the Site
Contact Us
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TB Unit Directory - India
L.R.S. Institute of Tubercolisis & Respiratory Diseases
Disclaimer : All rights reserved to Director, L.R.S. Institute of TB & Respiratory
Diseases
Designed,Developed & Maintained by :
Computer Section, L.R.S. Institute of TB & Respiratory Diseases.
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Updated on 13.10.2005
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NIAID Researchers Show How
Promising TB Drug Works
(12/26/2005, National Institute of
Allergy and Infectious Diseases)
From the National Institutes of
Health
Learn about Tuberculosis (National
Institute of Allergy and Infectious
Diseases) - Links to PDF
Also available in: Spanish
Learn about Tuberculosis Infection
(National Institute of Allergy and
Infectious Diseases) - Links to PDF
Tuberculosis Overview (National
Institute of Allergy and Infectious
Diseases)
Overviews
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Association)
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(American Lung Association)
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Department of Health
and Human Services
New Jersey Medical School National Tuberculosis Center
http://www.umdnj.edu/ntbcweb/tbsplash.html [05/01/06 1:51:23]
NJMS National TB Center - Links Page
Links to Related Resources
Tuberculosis Sites
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Action TB
Brown University's TB/HIV Lab
CDC's Division of TB Elimination
Charles P. Felton National Tuberculosis Center at Harlem Hospital
Ending Neglect: The Elimination of Tuberculosis in the United States - IOM Report
Francis J. Curry National Tuberculosis Center
Global Fund to Fight AIDS, TB, & Malaria
Global TB Drug Facility
Health Canada: Preventing the Transmission of Tuberculosis
International Union Against Tuberculosis and Lung Disease
Japan Anti-Tuberculosis Association
Multidrug-resistant Tuberculosis (MDR-TB) - Annotated Bibliography from the
University of Chicago
NHBLI TB Academic Award
National Center for Infectious Diseases, Division of AIDS, STD, and TB Laboratory
Research
National Jewish Center for Immunology and Respiratory Medicine
New Jersey Department of Health and Senior Services, TB Program
Northeast Regional RFLP Lab for DNA Typing
OSHA Directive CPL 2.106 Enforcement Procedures and Scheduling for Occupational
Exposure to TB
PHRI/Soros Russian Infectious Disease Program
RESULTS World Health/Diseases of Poverty Initiative
Sanger Sequencing Center Information about TB genetics
Sequella Incorporated - Moving Infectious Disease Technology from Promise to Product
Stanford University Center for Tuberculosis Research
STOP TB Initiative Website
TB Timebomb - The Global Epidemic of Multi-Drug Resistant Tuberculosis
TB in the Workplace - IOM Report
Tuberculosis and HIV Infection from the VA AIDS Information Newsletter
The Global Alliance for TB Drug Development
World Bank - Tuberculosis Control
http://www.umdnj.edu/ntbcweb/links_frm.html (1 of 2) [05/01/06 1:53:13]
NJMS National TB Center - Links Page
AIDS Related Sites
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Revised: Thursday, September 13, 2001
All contents copyright 1996 NJMS National Tuberculosis Center. All rights reserved.
http://www.umdnj.edu/ntbcweb/links_frm.html (2 of 2) [05/01/06 1:53:13]
http://www.paho.org/English/HCP/HCT/TUB/tuberculosis.htm
Surveillance
Prevention and Control
Other PAHO Materials
What's New
1998-2001
Featured Surveillance Items
PAHO Activities
General Info/Links
No. cases,
regional %...
Surveillance
Guidelines for HIV Surveillance among
Tuberculosis Patients (2nd ed.)
The main objective of these guidelines is to provide a framework for the
methods to be used for measuring HIV prevalence among tuberculosis
patients and to encourage implementation of HIV surveillance. The guidelines
are aimed at managers of national tuberculosis programs (NTPs) and
Workshop
national AIDS programs (NAPs), those responsible for HIV surveillance, and
on
public-health decision-makers at national and subnational level. They form part of the
TB/HIV series on "Second-Generation Surveillance" (SGS). This page offers a summary,
lists the recommendations, and links to the e-book on the WHO website.
tb-hiv-surv-who.htm
Planning
Communication
for
Tuberculosis
Control in the
Americas:
Summary
Report :
Informe
resumido
(Cochabamba,
Bolivia, 6–7
October 2005;
prepared by
Silvio
Waisbord,
Academy for
Educational
Development /
AED)
This expert meeting in
communication provided
a venue not only for
bringing together
specialized consultants
but also for forming a
regional working group to
continuously advise PAHO
on the use of
communication for
tuberculosis control.
Objectives were to form a
group of consultants to
provide technical
assistance in planning
communication for the
National Tuberculosis
Programs (NTPs), reach
agreements on the terms
and principles of mass
communication, and
define criteria and work
operations.
tb-taller-cochabamba-oct05.htm tb-tallercochabamba-oct-05.pdf
Regional Meeting of the Tuberculosis
Laboratory Network (Mexico City, 6–8
September 2004)
The PAHO TB Program has just published (in Spanish) the final report
for this meeting, the objectives of which were (1) to analyze and
discuss aspects related to the areas of quality control, National Tuberculosis Programs
(NTPs) using current and new techniques, and TB Laboratory Networks managing
information; (2) become acquainted with the experiences of selected countries that have
successfully dealt with these areas; (3) get to know the work of the laboratories currently
carrying out reference functions in the Region; (4) distribute and discuss regional
proposals; and (5) promote collaboration and communication networks among those in
charge of TB Laboratories and the Heads of National TB Programs.
tb-labs-2004.htm
Epidemiological Status of TB (Region of
the Americas, 2004)
This presentation of 19 slides—including tables, figures, and
maps—illustrates and summarizes the epidemiological situation of
tuberculosis in the Region up to 2004. It includes data on multidrugresistant TB (MDR-TB), TB/HIV, the extension of the DOTS/TAES
strategy up to now as well as its achievements and challenges.
PowerPoint
... more Surveillance Features.
Situation Reports
Epidemiological Status of TB (Region of the Americas, 2004)
Incidence/Mortality/Case Fatality
SIEPI Epidemiological Information System
Public Health Agency of Canada's Tuberculosis Prevention and Control Site
Statistical Tables, TB in the Americas: Incidence, National Programs, DOTS Coverage
Guidelines and Manuals
Tuberculosis: A Manual for Medical Students
Epidemiological Surveillance Systems (ESS)
Second Meeting of a Surveillance Network for Emerging Infectious Diseases (EID) in the
Southern Cone Region (Brasilia, Brazil, 11-13 May 1999)
Country Profiles
Tuberculosis: Number of Cases and AFB (+), Reduction Rate (Region of the Americas, by
country and year, 2001–2002)
Statistical Databases
SIEPI Epidemiological Information System
http://www.paho.org/English/HCP/HCT/TUB/tuberculosis.htm (1 of 2) [05/01/06 1:55:18]
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... more items.
Regional Core Health Data System - Table Generator 2004
Product Types and/or Keywords:
Product Types (register under only one): Situation Reports, Country
Profiles, Forms, Guidelines and Manuals, Health Profiles and Data, Statistical
Databases, Other Databases
Keywords (no limit, or key in Product type/s in keyword field for crossreferencing): Surveillance features TUBERCULOSIS, Annual status reports,
Incidence/Mortality/Fatality, Incidence and disease registries, Resistance
surveillance, Epidemiological surveillance systems, Geographic information
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Back
Top
http://www.paho.org/English/HCP/HCT/TUB/tuberculosis.htm (2 of 2) [05/01/06 1:55:18]
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Philippine Tuberculosis Society Inc. Website
PTSI is a non-profit charitable organization founded on
July 29, 1910, to combat the spread of tuberculosis and
kindred diseases in the Philippines. It has been in the
forefront in the fight against TB ever since.
Quezon Institute
Hospital
Field Operation
Division
Burden of Illness
PTSI Critical Role and
Continuing Needs
News Archive:
Pulmonary Medicine Specialty Training
World TB Day
Controlling TB The Manila Manifesto
How to Help Fight the
Lung Diseases
National Research &
Training Center
Central Laboratory
Click here for your
donation
We want to hear
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http://www.ptsi.org.ph/ [05/01/06 1:57:46]
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yugoslavia zambia zealand zimbabwe .
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http://www.rapidbloodtests.com/index.html (2 of 2) [05/01/06 2:06:20]
Registre de Tuberculosi
CONJUNT MÍNIM DE DADES PER A LA VIGILÀNCIA DE LA TUBERCULOSI A
EUROPA.
Recomanacions del grup de treball de l'Organització Mundial de la Salut (OMS) i de la Regió
Europea de la Unió Internacional contra la Tuberculosi i les Malalties Pulmonars (IUATLD) per a
la uniformització de la recollida de dades dels casos de tuberculosi.
Guia per al compliment del full de
declaració de cas de tuberculosi,
Programa de prevenció i control de la
tuberculosi a Andorra (PPCT)
(15 de març del 2000)
Fer click per
veure el full
Definició del cas
●
Cas "definit" de tuberculosi
1. cas amb malaltia confirmada per cultiu provocada pel complex M. tuberculosis.
2. cas amb frotis positiu per bacils acidoresistents (AFP) si no es disposa de
laboratoris de nivell II (que puguin processar mostres per al cultiu) o quan no es
pot esperar el cultiu rutinari d'espècies extretes de tots els casos.
●
També s'han de notificar els casos "no definits", els quals han de complir les dues
condicions següents:
1. quan un clínic cregui que els signes i/o els símptomes clínics i/o radiològics del
pacient són compatibles amb la tuberculosi, i
2. quan un clínic decideixi tractar el pacient amb una teràpia completa contra la
tuberculosi.
Els casos "definits" (i, quan sigui aplicable, els "no definits") de tuberculosi pulmonar
s'han de dividir en funció del resultat del frotis provocat o espontani en:
❍
❍
❍
casos de frotis positiu
casos de frotis negatiu
casos "demostrats" o "no demostrats" : només els casos que donen positiu en el
microscopi de material de rentada broncoalveolar o gàstrica no haurien de
considerar-se frotis positiu d'esput. Aquests casos es poden qualificar de
"demostrats" o "no demostrats" tenint en compte els resultats del cultiu i altres
criteris.
http://www.col-legidemetges.ad/docs/fulltb.html (1 of 5) [05/01/06 2:08:03]
Variables essencials
Les variables essencials són: informació que descrigui el cas, incloent-hi el temps, el lloc i la
persona, com també els detalls de la localització de la malaltia, l'estat bacteriològic i el fet si el
pacient ha estat tractat anteriorment.
1. Persona afectada
Edat i sexe: La data de naixement, que permet calcular l'edat en el moment en què es va iniciar
el tractament, i el sexe són variables que s'han de saber de cada pacient.
País de naixement. A les societats de cultura heterogènia, la incidència de la tuberculosi pot
variar d'una manera important en diferents grups ètnics. En vista de la importància creixent de la
tuberculosi als països europeus entre els immigrants i altres estrangers, el Grup de Treball sobre
el Control de la Tuberculosi i Migració Internacional va identificar el país de naixement com una
variable addicional que s'hauria de recollir rutinàriament [5]. En alguns països, l'origen ètnic, la
ciutadania o la ciutadania dels pares pot ser més important que el país de naixement a l'hora de
descriure la demografia dels pacients de tuberculosi.
El lloc de residència. El lloc de residència d'un pacient de tuberculosi és essencial per a l'acció
de la salut pública. El lloc de residència ha de ser el lloc on el pacient estava vivint en el moment
en què es va iniciar el tractament. En el cas de persones sense llar, migrants, detinguts.., es pot
donar el lloc de residència dins del país durant els 3 mesos anteriors, o es pot buscar qualsevol
altra solució que els països individualment considerin apropiada.
Localització de la malaltia.
2. Localització principal
3. Localització menor
La localització de la malaltia s'ha de recollir en tots els pacients. Atès que els pacients poden
tenir diverses localitzacions de malaltia, es recomana que es recullin com a mínim dues
localitzacions, una de principal i una de secundària (o menor), quan sigui aplicable. Ja que la
classificació de la localització de la malaltia pot variar a diferents països, es recomana que es
facin servir les localitzacions següents, perquè permetran fer les agregacions que siguin
necessàries en un país concret:
Tuberculosi pulmonar: tuberculosi del parènquima del pulmó i de l'arbre
tràqueobronquial. La tuberculosi pulmonar, si hi és present, sempre s'ha d'inscriure com
a localització principal, sigui quin sigui l'altre lloc que pugui estar afectat.
Tuberculosi extrapulmonar: Tuberculosi que afecta qualsevol altre lloc diferent dels que
afecta la pulmonar.
- Tuberculosi pleural. Tuberculosi extrapulmonar que només és una pleuresia
tuberculosa, amb efusió o sense.
- Tuberculosi limfàtica. És la que afecta el sistema limfàtic. A causa de les
manifestacions intratoràciques de la tuberculosi en els infants i pacients infectats
amb el virus de la immunodeficiència humana (VIH), la tuberculosi limfàtica es
divideix en:
1. Intratoràcica - tuberculosi limfàtica intratoràcica
2. Extratoràcica - tuberculosi limfàtica que no sigui la tuberculosi limfàtica
intratoràcica.
Quan la tuberculosi en infants afecta tant el parènquima del pulmó com un
component limfàtic, s'ha de classificar com a localització principal, la pulmonar, i
com a localització secundària, la tuberculosi limfàtica intratoràcica.
- Tuberculosi osteoarticular. Tuberculosi que afecta els ossos i/o les articulacions;
es subdivideix en:
1. tuberculosi espinal i
2. altres tuberculosis osteoarticulars que no siguin l'espinal.
- Tuberculosi del sistema nerviós central (CNS). La tuberculosi del sistema
nerviós central se subdivideix en:
1. meningitis tuberculosa i
2. una altra tuberculosi del sistema nerviós central que no sigui la meningitis.
- Tuberculosi genitourinària. La tuberculosi del sistema gènitourinari, inclou la
tuberculosi renal, ureteral, de la bufeta i del tracte genital masculí i femení.
- Tuberculosi del tracte peritoneal/digestiu. Aquesta tuberculosi inclou la
tuberculosi del peritoneu, amb ascitis o sense, i la tuberculosi del tracte digestiu.
- Altres. Altres localitzacions extrapulmonars, incloent-hi la tuberculosi laríngia, i
per a l'anàlisi de països concrets es poden anomenar específicament.
- Tuberculosi disseminada. La tuberculosi disseminada inclou tuberculosis en
més de dos òrgans o la tuberculosi miliar. Si un d'aquests llocs afectat és el
parènquima del pulmó, el cas s'hauria de classificar com a tuberculosi pulmonar o
com a tuberculosi disseminada. Per tant, la tuberculosi miliar, per exemple, es pot
classificar com a pulmonar i com a disseminada. Quan el complex M. tuberculosis
ha estat aïllat de la sang, la localització de la malaltia s'ha de designar com a
"disseminada".
4. Estat bacteriològic
La informació sobre l'estat bacteriològic s'ha d'incloure sempre. El metge ha d'enregistrar:
- La mostra i data de recollida de la localització principal o, si és negativa o sense
resposta, la de la localització secundària que hagi donat un resultat positiu (ex.: frotis
d'esput positiu, tuberculosi pulmonar confirmada per cultiu o frotis de biòpsia negatiu,
tuberculosi limfàtica confirmada per cultiu).
- el resultat i la data:
- de l'examen microscòpic directe (negatiu o positiu respecte dels bacils
acidoresistents, o examen no realitzat).
- del cultiu (negatiu o positiu respecte del complex M. tuberculosis, o examen no
realitzat).
- l'espècia identificada: M. Tuberculosis (MT), Mycobacterium bovis (MB), o
Mycobacterium africanum (MA),.
- L'examen histològic amb evidència de bacils acidoresistents hauria de
considerar-se com un examen microscòpic positiu i, per tant, s'hauria de registrar
també així.
5. Cas recurrent o nou cas
Abans de començar el tractament per a la tuberculosi, és important establir el següent: 1) que el
pacient té tuberculosi activa; 2) si el pacient ha patit de tuberculosi anteriorment; i, si és així, 3)
quin tractament se li va donar anteriorment. Les dues primeres preguntes són de caràcter tant
epidemiològic com clínic, i la tercera té una importància clínica ja que la resposta determinarà el
tractament més apropiat per a l'episodi de tuberculosi en qüestió.
Per als efectes de la salut pública és essencial informar sobre tots els casos de tuberculosi que
hagin estat diagnosticats per metges. Per a l'epidemiologia, on les tendències en la incidència
són d'especial interès, és molt important conèixer si un cas notificat ha tingut o no tuberculosi
prèviament. S'ha d'anar amb compte a l'hora d'assegurar-se que no es repeteixen els informes
dels casos crònics i dels pacients que van i vénen de forma intermitent. La resposta a les
preguntes d'aquest apartat hauria d'aclarir aquestes qüestions:
- la primera pregunta demana si al pacient se li havia diagnosticat tuberculosi
anteriorment. Si la resposta és afirmativa, la segona pregunta respon l'any de l'episodi
anterior i, si pot ser, el mes. La tercera pregunta estableix si al pacient se li va fer un
tractament amb quimioteràpia i, si la resposta és afirmativa, si es va considerar
satisfactori o no. Això permetrà classificar aquests casos en recaiguda i recurrència amb
quimioteràpia prèvia o sense i, per tant, millorar la definició dels casos.
6. El temps
La data d'inici del tractament:
L'ideal, per obtenir estimacions acurades de la incidència de la malaltia, seria conèixer la data
del seu començament, però això no acostuma a ser factible; també la data del diagnòstic pot ser
difícil de fixar en el temps, per això es recomana que la "data d'inici del tractament" ,
considerada una dada proxy se registri en tots els casos.
La data d'inici del tractament es defineix com la data en la qual el metge està prou
segur de la seva diagnosi i inicia el tractament adequat per a la tuberculosi. Per a la
tuberculosi pulmonar, aquesta acostuma a ser quan s'obté del laboratori un resultat de
frotis d'esput positiu o, en els casos de frotis d'esput negatiu, quan el metge ha reunit
proves clíniques i/o radiològiques suficients per a la diagnosi que justifiquen l'inici del
tractament. Quan no es pot disposar de la data d'inici del tractament, aquesta es pot
substituir per la data de notificació del cas. I per als casos que no han rebut mai cap
tractament, com ara la diagnosi postmortem, aquesta ha de substituir la data del
diagnòstic.
Darrera modificació 26/1/01
RIT/JATA Home Page in English
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Stanford Center for Tuberculosis Research Guestbook
Stanford Center for Tuberculosis
Research Guestbook
Thank you for visiting our pages. We invite those with research interests to Add to this email address list
we are keeping! We request that you include your email address and only a few lines for contact
information and keywords or phrases characterizing your research interests.
This page is provided for those interested in identifying research-related contacts. Please note multiple
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from our home page; there are many sources for general information on tuberculosis disease. Don't
neglect to talk to your health care provider!
Indentification and Cure of side effects of Isoniazide & Rifamipicin
Sundip <[email protected]>
New Delhi, Delhi India - Wed Jan 10 09:04:24 2001
send me information regarding my thesis topic that is: immunodiagnosis of intrathoracic tb in
children by elisa for igg antibodies.
dr ps varma <[email protected]>
gulbarga, karnataka india - Mon Jan 1 16:00:39 2001
Dear Sir, I am an experienced researcher on Applied Environmental Microbiology and Microbial
Technology. Is it possible to apply for a postdoc position in your group to do the genetic research of
environmental microbiology? In last year, I just got a Ph.D. in Microbiology in Shandong
University. During recent two years, I am mainly looking for special microbes for organic
desulfurization and denitrification. I have got about more than 20 bacteria desulfurizing DBT,
benzothiophene, nonbenzo-thiophene, alkylated benzothiophene and methyl-benzothiophene and
methyl-DBT with 4S pathways or other pathways. One of the bacteria is thermophilic (under 45-60
centridegrees)to desulfurizing petroleum very well. I am also screening the solvent tolerant strain. I
am trying to study on the genomic genes and oxido-reductases of the interesting bacteria. I would
also join in your group on Environmental Research to contribute my experience on the enviroment.
John P. XU, Ph.D. The State Key Lab of Microbial Technolgy Shandong Universtiy Jinan 250100,
PR China Email: [email protected], 2000/12/31
John Ping XU <[email protected]>
Jinan, Shandong PR China - Sun Dec 31 11:58:46 2000
My research interests are human tuberculosis, bovine tuberculosis, siderophores of mycobacteria
http://www.stanford.edu/group/molepi/guestbook.html (1 of 58) [05/01/06 2:27:09]
and pcr diagnosis of mycobacteria
Mallikarjuna reddy.M <[email protected]>
Hyderabad, Andhrapradesh India - Thu Dec 21 15:46:45 2000
Hi! I am yasir. I am intersted to do some thing for T.B patients, thats why I am keenly interested to
my Doc in this research. I have done Mphil(biotechnology).I have experienced all the molecular
biology techniques,PCR diagnostics, sequencing,Southern, Northern and westren analysis.Gel
documentation and cloning.
yasir-ul-Musawar <[email protected]>
faisalabad, punjab Pakistan - Tue Dec 19 16:52:52 2000
Sarcoidosis mycobacterial DNA Gen Probe
Ahmet <[email protected]>
Izmir, Turkey - Sun Dec 10 21:42:49 2000
working as general manager in a bulk drug manufacturing company. products being manufactured
are RIFAMPICIN, ETHAMBUTOL,PYRACINAMIDE,ISONIACIN HYDRAZIDE,. would be
interested in new molucules based on anti TB drugs. qualified as M.Sc (research) PhD (by
research).looking for assistanceship in development of new molucules.25 years of industrial
experience in product identification, development in lab , scaling up to pilot plant and finally to the
production stage. waiting for early reply.
DR RAJNIKANT VYAS <[email protected]>
mumbai, maharashtrs india - Fri Dec 8 16:13:09 2000
working as a professional librarian in an engineering college. looking for some projects in field of
library and information science.qualified masters degree in library and information science.would
like to takeup some research projects with academic structures. waiting for the early reply.
LEENA R VYAS <[email protected]>
MUMBAI, MAHARASHTRA india - Thu Dec 7 15:43:43 2000
working as a professional librarian in an engineering college. looking for some projects in field of
library and information science.qualified masters degree in library and information science.would
like to takeup some research projects with academic structures. waiting for the early reply.
LEENA R VYAS <[email protected]>
MUMBAI, MAHARASHTRA india - Thu Dec 7 15:42:38 2000
I am Head of Laboratory of Molecular Biology, St.Petersburg Pasteur Institute. I will be happy to
be on you mail list. We are providing research in molecular epidemiology of TB by fingerprinting
(IS6110-RFLP, spoligotyping and RLBH for searching for the nutations to drug resistance etc.).
We have a computer data bank derived by GelCompar including more than 70 RFLPs and many
spoligotypes of Russian strains. I am interested to make contacts in the same field with any
interested researcher. Olga Narvskaya
Olga Narvskaya <[email protected]>
St.Petersburg, Russia - Mon Dec 4 10:09:27 2000
I am trying to locate the final records of my grandmother who suppose -dly died of Tuberculosis in
1940, somewhere in Northern Illinois. Probably in Adams County, Illinois. I don't know where to
look for her records. Her name was Jennie Sue Cookson, nee Bushman, born in 1883.
Joseph A. Braun <[email protected]>
Farmington, Missouri USA - Sun Dec 3 22:53:56 2000
TUBERCULOSIS DIAGNOSIS, tuberculosis serology, epidemiology
URSZULA DEMKOW <[email protected]>
WARSAW, POLAND - Fri Dec 1 15:08:10 2000
i have just submitted my thesis. i am interested in the field of tuberculosis immunology especially in
the CMI response induce by proteins of M.tuberculosis. and how the macrophages of the contacts
of tb patients process antigens differently. i would like information of labs working on this aspect. i
amm also interested in proteomic analysis of such proteins which elicited a protective immune
rseponse in contacts as compared to the pateints
shobhita johari <[email protected]>
delhi, delhi India - Thu Nov 30 07:36:52 2000
Available schollarships for foreign students in Germany, France, Spain, Portugal, England, Irland,
Scotland, and all Southern America.
Ekaterina Belotsvetova <[email protected]>
Moscow, Russia - Tue Nov 21 21:09:29 2000
Schollarships for foreign students in Germany, France, Spain, Portugal, England, Irland, Scotland,
and all Southern America.
Ekaterina Belotsvetova <[email protected]>
Moscow, Russia - Tue Nov 21 21:07:53 2000
Curriculum Vitae Dear Sir/Madam, In reference to the position, I would like to be considered for
this position and have provided a CV and a brief list of the techniques I have used during the
course of my research. 1- Personal details, TITLE Holding PhD degree in Molecular Microbiology
From U.K NAME JAMSHID SURNAME RAHEB DATE OF BIRTH 17 / 3 /1962 PERMANENT
ADDRESS 19, Saviz, Ghiasvand, Dampezeshki, (Contact address) Tehran 13416, IRAN WORKE
ADDRESS National Research Center for Genetic Engineering and Biotechnology, P. O. Box: 141556343 Tehran, IRAN TEL (HOME) (0098) 21 6039344 (Dr Jamshid Raheb) TEL (WORKE) (0098)
21 6413626 (Dr Jamshid Raheb) FAX (0098) 21 6419834 E-MAIL [email protected] HEALTH
no disability ENGLISH LANGUAGE Speaking fluently Listening fluently Reading fluently
Writing fluently NATIVE LANGUAGE Azeri & Persian 2- Higher education, Subject Degree
From To University Country Molecular PhD 1994 1998 The University U.K. ENGLAND
Microbiology of Warwick Bacteriology Ms.C 1987 1991 Tarbiat Modarres IRAN University
Microbiology Bs.C 1983 1987 Tehran University IRAN 3-Ph.D thesis For many years physiological,
morphological and particularly molecular studies on gliding bacteria were impossible due to the
lack of a suitable technique for the genetic manipulation of this group of bacteria including
Flexibacter chinensis. Our study has focused on the physiological and morphological changes in
molecular level in this organism during the transition from the exponential to stationary phase of
growth, and during long -term stress condition. Our data demonstrate that there is a dramatic
change in respiration activity and enzymes during the stationary phase which can not be seen in the
exponential phase. Parallel to this bacterial morphology changes with a particularly noticeable size
reduction in this usually filamentous bacterium. With the collaboration of Wisconsin University in
USA we have developed a method for the molecular study of this group of bacteria. We have
constructed two mutants for the genes which produce two novel sigma factors, KatF(sS) and
RpoH(s32), and have investigated the effect of these mutants with respect to cell size changes
during the transition from growth to starvation conditions and under heat stress. The mutants
were unable to change from the filamentous to coccoidal form and consequently were unable to
survive stress as effectively as the parental strain which could undergo morphological changes. Our
data have demonstrated the importance of cell division in Flexibacter chinensis for the survival of
this bacterium under stress conditions. 4- Research work. The Microbial sulfur-specific
transformation which selectively desulfurize organic sulfur compounds in fossil fuels, has been
identified. We have cloned a 4kb gene locus from Rhodococcus erytheropolis IGTS8 (4S pathway)
on a broad host range plasmid with integration ability in chromosome of gram negative bacteria.
This organized as one operon with three genes (dszA, dszB and dszC)under the control of single
promoter. The dsz gene has been cloned under control of tac promoter in different pseudomonas
solvent tolerant species. We have applied an industrial microorganism , with the ability in
biological desulfurization. In this way, using molecular and microbiological techniques we
successfully constructed a manipulated bacterium with two relevant industrial application, that is
biosurfactant production and desulfurization of fossil fuel. Further researches is in progress to find
out the influence of the biosurfactants on DBT desulfurization. This is the new alternatives to
commercialize the biodesulfurization of crude oil processes. 5- Work experiences I have at least
four years experiences in laboratory work in microbiology and molecular microbiology in full time
basis. I have learnt many techniques in this time including molecular cloning, DNA sequencing,
southern hybridisation, northern hybridisation, two dimentional gel electrophoresis, DNA
separation techniques, DNA cloning methods using different vectors including several suicide and
other vectors, general microbiology and relevant computer skills. 6- Skills I have had more than
four years laboratory experience and have used various techniques involved in the detection,
isolation and manipulation of nucleic acids and feel that I could make a significant contribution to
your program. I have made contributions to the field of molecular biology of bacteria, due to
working with a particularly difficult bacterial strain, Flexibacter, to manipulate using conventional
molecular biology techniques. I have learned many techniques in Warwick University in United
Kingdom and National Research Center for Genetic Engineering and Biotechnology, including
molecular cloning, polymerase chain reaction, DNA sequencing, southern hybridization, northern
hybridization, western blots, DNA separation techniques, two-dimensional gel electrophoresis,
general microbiology, DNA library, Over-expression of proteins, and computer skills. 7-Resarch
interests. Molecular Biology and Microbiology Research. 8- Publication and record Currently three
works for publication on the molecular biology and physiology of Flexibacter are being prepared
for publication. 9- Referees 1- Dr S Mahmoud A Najafi ( Ph.D, Assistant Professor). National
Research Centre for Genetics Engineering and Biotechnology, P.O. Box 14155-6343 Tehran-IRAN.
Tel 00 98-21-4316643. Fax 00 98- 21-6419834 Email [email protected] 2- Dr Seyed A Ghorashi (
Ph.D, Assistant Professor). National Research Centre for Genetics Engineering and Biotechnology,
P.O. Box 14155-6343 Tehran-IRAN. Tel 00 98-21-7891692. Fax 00 98- 21-7891692 Email
[email protected] 3- Dr Alireza Zomorodipoor ( Ph.D, Assistant Professor). National Research
Centre for Genetics Engineering and Biotechnology, P.O. Box 14155-6343 Tehran-IRAN. Tel 00 9821-4429018. Fax 00 98- 21-6419834 Email [email protected] 4- Dr Bagher Yakhchali ( Ph.D,
Assistant Professor). National Research Centre for Genetics Engineering and Biotechnology, P.O.
Box 14155-6343 Tehran-IRAN. Tel 00 98-21-3347512. Fax 00 98- 21-6419834 Email
[email protected] 10- Hobbies Sports, music, cinema, and arts.
Dr Jamshid Raheb <[email protected]>
Tehran, Tehran IRAN - Fri Nov 10 13:00:05 2000
SOS FROM CHINA! My mother was burned by pulmonary tuberculosis, which was controlled
goodly for some time. Unfortunetely, the illness rebaddened recently, the tuberculosis ball has
formed, said by the doctor, but there is not effective medicine in China that can enter into the
tuberculosis ball to kill the bacteria. The only choice it operation, but it may bring some danger to
the patient. I am here to ask for a favor that whether there are some effective medicine in US. Your
assistance and advice is appreciated.
Yong Luo <[email protected]>
Chongqing, China - Wed Nov 8 23:11:50 2000
I would appreciate any information about collaboration in the field of BCG phylogeny and
comparative genomic studies of BCG Vaccines. Thank you in advance!
Tzvetelina Stefanova <[email protected]>
Sofia, Bulgaria - Tue Oct 31 07:57:34 2000
I'm a market analyst. My interest is to keep informed of the latest medical research on TB.
Ms. Homa Christensen <[email protected]>
Valencia, CA U.S.A. - Mon Oct 30 22:36:39 2000
THIS SITE ROTTS! I DON'T LIKE IT MAN!!!!! BUILD A NEW ONE YOU FESTY POO!!!
Sorry, It's actually quite good!!!!@@@@ Man!
Nar CHo <[email protected]>
With only 2 people, This One Jamaica - Mon Oct 16 23:12:52 2000
Information on Mycobacteria Fortuitum
Nancy Wagoner
Watsonville, CA US - Sun Oct 15 19:57:47 2000
i am a fresh post-graduate , done my M.Sc.(microbiology). i am interested in doing research in my
field & especially medical or applied microbiology.so please , do contact me at my e-mail if you
have any information. At present i'm working with a reputed pharmaceutical co. in my own city as
a sr. microbiologist.my future plans are to go for research.
PINKAL DIWAN <[email protected]>
ahmedabad, gujarat india - Sun Oct 15 13:47:20 2000
information on Muti-drug resistant Tuberculosis.(Especially India,and to be more specific
Karnataka,India)
vidya <[email protected]>
- Sun Oct 15 01:45:15 2000
I am interested in speaking with anyone who has information about the former Mt. Kipp
sanitorium located in Glen Gardner, New Jersey. I am writing a research paper on the institution
and how its role has changed.
Karin Gruss <[email protected]>
- Sat Oct 14 21:37:43 2000
Film research: writer needs accounts of patients, doctors, nurses, admin. workers associated with
tb sanitoriums in 1940s-50s. Also those involved with tb screening of US public schools. Many
thanks, [email protected]
patricia roberts <[email protected]>
toronto, ontario canada - Wed Oct 11 15:45:55 2000
Interested in it 2 much !
savita chauhan <[email protected]>
Indore, MP INDIA - Tue Oct 10 17:42:14 2000
My department is advising the Swiss government on various international health issues. A recent
topic of concern and interest is the tuberculosis in penitentiary centers in countries of the former
Eastern Block and possibilities to control it. Nicolaus Lorenz MD, MSc Head of Department Swiss
Tropical Institute Swiss Centre for International Health Socinstrasse 57 P.O. Box CH-4002
Basel/Switzerland Tel. +41 61 284 8 125 Fax + 41 61 271 86 54
http://www.sti.unibas.ch/scih/scih.htm
Dr. Nicolaus Lorenz <[email protected]>
Basel, Switzerland - Wed Oct 4 12:23:00 2000
My theory is proven correct. One of my relatives complained of back pain. We thought maybe it
was muscle strain. We went to the doctor for a check up. After the check up she was given a
medicine which is for TB. Aha! So I asked my relative. Have you been lacking sleep. She said yes.
She said she was working a lot. Could not get much sleep because of a lot of worries. She does get
enough rest and sleep she says. But there is a difference between a genuine rest and sleep and just
closing your eyes and pretending to be asleep. When you worry don't do it while you are resting.
Start worrying once you wake up. When you rest, just free your mind of worries. And just
concentrate on sleeping. They said she was coughing and her back really hurts.She even skipped
one day of work because of it. So I told her that her lungs are strained. And that she should let it
expand. I told her about the "Ulcer Theory". And the next day she was working already. Had I not
told her about the "Ulcer Theory" she would be in a hospital coughing blood already. And now
she's fine.
Norman Greg <[email protected]>
CA U.S.A. - Wed Sep 27 23:20:04 2000
Hello everybody, I shall highly appreciate if you send me detailed information on PCR based
diagnosis of TB and MDR-TB.I shall be happy to receive the details about the PCR protocols,
primer designs and information regarding detection kits and their reference. Thank you
Dr Nilanjan Das <[email protected]>
Calcutta, West Bengal India - Wed Sep 27 18:47:45 2000
I have been working in the medical research center in Russia (Novosibirsk State medical
University).We are developing the project about dependence with hypertermia (temperature
increase) and pulmonary tuberculosis. I would highly appreciate if somebody could provide me the
information about it.(do you have an experience to treat a people with this type of treatment, what
kind of results were achieved) Or may be you know where can i find this information. I hope that
there is the possibility of fruitful cooperation. [email protected]
Elena <[email protected]>
Novosibirsk, RU Russia - Sat Sep 16 13:44:28 2000
I am presently researching on the history and statistics of tuberculosis. Hope you'll help me to
accomlish this research through giving addresss that are relevant to my research. Thanks
bernard <[email protected]>
manila, philippines - Wed Sep 13 02:18:44 2000
Mycobacterium bovis ADN isolation in milk. PCR
Cristian Leiva <[email protected]>
Santa Fe, Santa Fe Argentina - Fri Sep 8 21:07:03 2000
Tuberculosis-Diagnosis-serology
Tsigeweini Asgedom <[email protected]>
Bergen, Bergen Norway - Fri Sep 8 13:46:20 2000
Seeking for Co-operation and Support -----a specific remedy for tuberculosis Now, a specific
tuberculosis remedy, which belongs to Traditional Chinese Medicine has been discovered. It's
named " Jiupin Baoling Pellet". According to the results of observation from more than 1,000
cases, this remedy has outstanding result in treating pulmonary tuberculosis, tuberculosis of lymph
nodes and bone tuberculosis. The curative rate may reach over 85%. This completely natural
remedy is adapted to pharmacopeia compatibility clo9sely. The intranasal usage enables the
effectiveconstituents exchange with qi and blood in lungs. According to Traditional Chinese
Medicine theory, tuberculosis is caused by infection of " certain worm ". People are attacked by
this worm at the state of deficiency of vital- qi and blood. Pulmonary tuberculosis occurred when
the worm existed in lungs. If the worm reached bone marrow from the blood circulation, bone
tuberculosis and tuberculosis of lymph node would form. Among the constituents of this pellet,
secretio bufonis has the functions of detoxification, analgesis, inducing insuscitationa and treating
the toxifying disease with poisonous agents: Unbelliferae can promote blood circulation to stop pain
and tonify the blood. If the course lasted too long, this chronic disease may demage qi and blood,
even cause stagnancy of qi and blood stasis. Deficiency of qi may prevent the folw of blood, and
deficiency of blood may do harm to channedl and collaterals. The symptoms of blood stasis and
stagnation of qi can be relieved by the use of umbelliferae in the remedy. Another component --horner nest can be used for eliminating wind and toxic material, stopping pain and even killing the
worm. Because of the cause of disease mentioned above, the use of hornet nest can achieve expected
results. With the rich clinical practice and hard research, the use of the components is efficient, and
the results are satisfied. According to outside body experience, the tuberculomyces which have
drug resistance to anti- tuberculosis drugs are sensitive to the remedy. In clinical use obvilus results
of treatment have been achieved especially for the patients with long lasting tuberculosis. All right
reserved by ZhaoDong. Any co-operations in research, development, investment and sale are
welcome.
ZhaoDong <[email protected]>
- Fri Sep 8 13:08:53 2000
i'm reserching for the case of ashtma it's a disease that can kill and no one has found a cure for it
yet i have ben reserchen about it for over 18 years and still have not found the closes to it i have the
disease my self and believe me i have allmost died of it alot of times i would like to find something
that is close to it so i my self can have a good life to just like other people too. so if any one out there
can give me some pointers i would sped it where everyone will know that you have gave me infor.
and you will be in that book that i write about this killer disease and god will thatnk you too. i
know i would; thank you again; ms. june;;
june lopez <[email protected]>
houston, tex. 77020 usa - Fri Sep 1 17:26:32 2000
Dine in or take out?
Shang-hai Chef <[email protected]>
- Tue Aug 29 08:11:09 2000
lady doctors are invited to have sex with andhra doctor
suresh <[email protected]>
- Thu Aug 17 19:23:09 2000
Hi there!. I would like to know about tuberculosis diagnosis and antigen immunogenicity
evaluation, collaboration programs between institutions and MSc and PhD schollarships.
Jorge Luis Gonzalez Quintana <[email protected]>
Havana, Cuba - Thu Aug 17 18:45:44 2000
Deteriorating liver.
Tom Crowley <[email protected]>
Shelby Twerp, MI USA - Wed Aug 16 04:56:44 2000
i am originally from bangladesh.i,Dr.md.nazmul haque, doing ph.d in microbiology from dhaka
university.i have strong interest in doing reseach in microbiology.for that iwantjoin in ph.d
programme in usa.are there any scholorship or assistanceship for me.pleasesend me the response as
soon as possible.
dr.md nazmul haque <[email protected]>
dhaka, bangladesh bangladesh - Sun Aug 13 06:45:50 2000
I am interested in the application of bioinformatics on studying the virulence genes of M.
tuberculosis. My mailing address: School of Graduate Studies Mapua Institute of Technology
Intramuros, Manila 1002 Philippines
Bonifacio T. Doma,Jr. <[email protected]>
- Sat Aug 12 16:20:14 2000
cool!
Jango <[email protected]>
- Fri Aug 11 10:49:52 2000
am a respiratory therapist..i have a case study report this tuesday about pleural effusion and
pulmonary edema and am having a hard time finding patient data,history etc.. please HELP! JAE
RRT
jae <[email protected]>
manila, manila phillipnes - Sat Aug 5 06:27:36 2000
I have a sister who is a doctor, in her practice with patients with Tuberculosis she got the Pott´s
disease; I want to known a Medical Center in the Conus of U.S. which can help us to treat her as
aid for foreign patient with this disease; any help is welcome.
Enrique A. Posada <[email protected]>
N.Cuscatlan, La Libertad El Salavdor - Tue Aug 1 04:32:09 2000
I am doing research in production and quatitative techniques in india and Looking for any
additional scholarships/sponserships by organisations to carry out studies.If U know any of the
organisations pls inform me.Thanks
jha T.K <[email protected]>
Ahmedabad, Gujrat india - Mon Jul 31 18:41:34 2000
I am doing research in production and quatitative techniques in india and Looking for any
additional scholarships/sponserships by organisations to carry out studies.If U know any of the
organisations pls inform me.Thanks
jha T.K <tarun_kumar_jha>
ahmedabad, gujrat india - Mon Jul 31 18:36:07 2000
genome project is my intrest,reply if any contacts.thank you!
gokul <[email protected]>
mysore, karnataka india - Thu Jul 27 16:00:56 2000
Great Site!
PageCrafters.net <[email protected]>
- Wed Jul 26 22:15:19 2000
AFLP/cDNA AFLP, mycobacterial functional genomics
Dr Niyaz Ahmed <[email protected]>
Hyderabad, AP India - Tue Jul 25 12:25:11 2000
Dear Sir, I am director of PPD providing in IRAN.I would be very pleased if I be in your mailling
list and have an opportunity to take higher education. Bye. With Best Wishes. Dr. Nader Mosavari
Nader Mosavari <[email protected]>
Karaj, Tehran Iran - Tue Jul 25 06:41:07 2000
I am a medical graduate,presently working as a medical officer in a Govt. hospital in Pakistan.I
have also done post graduate training in Tuberculosis.Iwant to do post graduate diploma/ degree in
EPIDIMIOLOGY from Australia.Iwill be thankful if any body can guide me about this.I am also
interested in any information regarding financial assistance/scholarships offered by the Australian
universities/institutions.I have IMMIGRATION VISA for Australia.
Dr.Shazia Shaukat <[email protected]>
Karachi, Sindh Pakistan - Mon Jul 24 13:31:51 2000
analyzing, designing, installment and teaching of the analog circuit and the digital circuit; Digital
imaging processing£¬pattern recognition for developing the software in C, assemble language
Bao Susu <[email protected]>
Guangzhou, Guangdong P.R.China - Mon Jul 24 13:24:09 2000
Healthy nutrition is important also.
Ryan Mills
- Mon Jul 17 07:16:44 2000
As I have read in one web page as a result of my web search. I can only wonder why it would need
a person to spend eight hours a day for six months or 24 hours a day for 2 months before he or she
gets infected with TB. I call it duplicating habits. It's when u acquire a persons habits. "TB is an
ulcer". An ulcer of the lungs. If u think u have TB, get plenty of rest and sleep. And relax ur body.
The less movement the better. Until you recover. "Getting enough rest and sleep expands the
lungs". Preventing it from shrinking or tightening up due to fatigue or lack of sleep. Shrinking or
tightening up of the lungs could cause one to spew blood. It's like twisting a wet towelette. Let ur
lungs expand. Don't stress ur lungs out.
Mark Polido <[email protected]>
Manila, Philippines - Wed Jul 12 08:38:47 2000
I'm looking for a current phylogenetic tree of Mycobacteria, as complete as possible, as well as a bit
of information on each species- whether or not it is free-living, and whether or not it has any
horizontal gene transfer. Any leads would be most appreciated. Thanks.
Hunter Fraser <[email protected]>
- Tue Jul 11 17:56:22 2000
Please check also my message on the message board. And don't forget to e-mail me. Thanks.
Ryan Mills <[email protected]>
Los Angeles, CA USA - Sun Jul 9 08:14:17 2000
Good air ventilation, a quiet surrounding and plenty of rest and sleep could cure TB. Pressures of
day to day life, not getting enough sleep and getting up early in the morning combined with an over
fatigued and tired body could lead to TB. Our lungs like our muscles could get over worked. To the
point that it's grinding itself. That it wants to spew blood. Children who lack sleep because of the
pressures of school could get TB. That is why the virue can't be cured by madicine. Because it is not
a virus and you don't need medicine to cure it. Maybe a drug or medicine to make the patient calm
and relaxed to have plenty of rest and sleep might help. E-mail me and let me know if I have a
point or not. The name I use is not my real name. Thanks
Ryan Mills <[email protected]>
Los Angeles, CA USA - Sun Jul 9 08:00:17 2000
Fixed dose combinations of antitubercular drugs, Bioequivalence of FDCs
Pavankumar M. Sancheti <[email protected]>
Chandigarh, Punjab India - Fri Jul 7 13:45:21 2000
In my research, I try to indentify the Mycobacterium Tuberculosis species by using phagemediated antibody library technology. At this moment, I got trouble to coat M.TB( fixed by
Formalin) to the ployabsorb ELISA plates. When I got M.TB. samples from my patron, the cells
clamped together very tightly and the sonication was useless to the clamps. Expert said that the
glass surface was better that plastics. Can I get some information about people do ELISA with
M.TB.? Thank you!
Kezhi Dai <[email protected]>
Hull, East Yorkshire U.K. - Wed Jul 5 11:00:08 2000
I am looking for accounts/stories from people who spent time in tb sanitariums during the 1940 and
early 1950's. Any ideas on where to look? [email protected]
Julie Greer <[email protected]>
- Thu Jun 29 02:12:51 2000
What is the % composition of mycobacteria in the environment? Is it essential to obtain LICENCE
for working in TB BACILLI ? Working in ecology of MYCOBACTERIUM in aquaculture ponds.
chandrika senior scientist,CMFRI, COCHIN INDIA
DR .V. Chandrika <[email protected]>
Cochin ,682014, Kerala INDIA - Tue Jun 20 18:53:54 2000
I need information about History of Tuberculosisi in India . Web addresses will be helpful.
Dr. Irene Churruca <[email protected]>
Barcelona , Barcelona Spain - Tue Jun 20 14:17:13 2000
hi! i am reshma. i am studing in mithibai collage. i am in 2nd year of microbiology. i want to do
genetic. actually, i don't know that it is possible after TYBsc or after postgraduation. please tell me
university in maharastra, other requirements for genetics. please help me .
reshma <[email protected]>
bombay, maharastra india - Thu Jun 15 15:48:47 2000
I'm doing a paper on Tuberculosis, the history and how it began the "1health century" at the
beginning of the 21st century. If you have any information regarding any of these please send it to
me.
Rebecca <[email protected]>
New Hampshire United States - Wed Jun 14 17:39:54 2000
I'm doing a paper on Tuberculosis being the beginning of the health century, any information I can
get would be very helpful.
Rebecca <[email protected]>
Wilton, New Hampshire United States - Wed Jun 14 17:31:57 2000
i am doing a paper on Tuberculosis especially in the bones and articulations. Any information
would be helpful
alex s. <[email protected]>
Cali, Valle del Cauca Colombia - Tue Jun 6 22:27:00 2000
i am doing a paper on Tuberculosis especially in the bones and articulations. Any information
would be helpful
alex s.
Cali, Valle del Cauca Colombia - Tue Jun 6 22:26:35 2000
I am a student at UCLA and I was infected with TB about a year ago. I am now trying to do a
reseach paper on TB and I would really appreciate it if you could send me some information about
how TB started, what it is , and how to prevent and cure it.
Meital Amir <OOgigi>
santa monica , California - Sat May 20 17:47:52 2000
Mycobacteria culture and sensitivity
DR. SATADAL DAS <[email protected]>
- Sat May 20 14:08:48 2000
DNA microarrays in TB research, Proteomics in TB research, Malaria Research.
Susmith Mukund <[email protected]>
New Delhi, New Delhi India - Fri May 19 17:37:22 2000
As an internist I am interested in the incidence of atypical mycobacterium as the causal agent of
multiorgan extrapulmonary manifestation such peripheral lymphadenitis or pleural effusion,
which is difficult to differentiate from mycobacterium tuberculosis complex. I hope some of you
could share your experience on using current method to diagnose it such as molecular analysis
(PCR and sequensing) or immunologic method. Thank you.
Zul Dahlan <[email protected]>
Bandung, Indonesia - Wed May 17 03:42:19 2000
As an internist I am interested in the report of atypical mycobacterium as the causal agent for
extrapulmonary manifestation such as peripheral lymphadenitis or pleural effusion, which is
difficult to differentiate from mycobacterium tuberculosis complex. I hope some of you can share
your experience on how to diagnose in by current method such as molecular analysis or
immunologic method. Thanks.
Zuldahlan <[email protected]>
Bandung, Indonesia - Wed May 17 03:29:34 2000
Hey can you please send some names of some hospitals that help only in the healing of TB, I need a
list of hospitals for my Health class. Thank you very much, if you can email me back by April 27th.
luv to all.
Holly <[email protected]>
Evansville, Indiana USA - Thu Apr 27 04:04:50 2000
Just passing through...very interesting site - I'll be back. Best wishes, Sheila
Digital-Price - Furniture
Boston, MA United States - Tue Apr 25 18:45:59 2000
This is a very nice place !
Protector 1uno <[email protected]>
Gospic, Li Croatia - Thu Apr 20 07:35:12 2000
I would like to be on your mailing list. I am head of TB Research,BLUE PETER RESEARCH
CENTER,Cherlapally,Hyd,501 301,A.P.,INDIA. My areas of research are Drug Resistance in
M.tuberculosis,By culture and molecular techniques.
Dr.Suhail Naser. <[email protected]>
HYDERABAD, A.P. INDIA. - Sat Apr 15 07:06:15 2000
I have just got into my internship(S.N.Medical College,agra).please send me information regarding
miliary tuberculosis.
Nupur Pruthi <[email protected]>
agra, U.P INDIA - Fri Apr 14 09:21:15 2000
I am originally from Turkey and very much interested to do any kind of research related with tbc.
I am an M.D. and prefer clinical or epidemiological researches.
Sukran Timbil <[email protected]>
Athens, GA USA - Mon Apr 10 22:20:33 2000
diagnosis multidrug resistence fingerprintings
Maria Noel Cortinas <[email protected]>
Montevideo, Uruguay - Mon Apr 10 21:12:18 2000
Pseudomonas aeruginosa , Imipenem and Ceftazidime(solvent,diluent,storage,...), MIC(minimum
inhibitory concentration) ,
M. A. Rezai <[email protected]>
Tehran, Tehran Iran - Mon Apr 10 09:02:03 2000
A recent breakout, this week, of TB has just happened in our community Jr. High. With a possible
infection of 200 - 250 kids I want to know in laymen's terms what TB is about, how it starts, it's
infectious rate, symptoms and incubation periods. This is a prime concern in our community right
now. Has a lot of parents scared, their children are being tested by school. Is this typically a good
thing to test so many students in such a short amount of time? Are the tests effective and what
treatments are available in the US? Thank you.
Mrs.Melanie Davis <[email protected]>
Hillsboro , OR USA - Tue Mar 28 08:34:17 2000
I have been looking for information on my paper due this Tuesday... This webpage was a great
place to look for info. I am a 6th grade student and Science is a great intrest of mine. Thanks alot
this webpage helped so much
Clay Dallas <[email protected]>
Dallas, Texas USA - Thu Mar 23 02:10:18 2000
I'm looking for a sanitorium in Franklin County or somewhere around there called "Savilisville
Sanitorium" in the 1940's. Of course, it has been closed down for years. I'm loking for ANY
information what so ever. Thanks, Vicki G.
Vicki Gladfelter <[email protected]>
- Tue Mar 21 14:37:40 2000
send me addresses of women's/girls of South Delhi(India) based who are interested having sex at
any time. Thanks, Jassi
Arvind Jassi <[email protected]>
New Delhi(South), Delhi India - Wed Mar 15 08:30:48 2000
send me addresses of women's/girls who are interested having sex at any time. Thanks, Jassi
Arvind Jassi <[email protected]>
New Delhi(South), Delhi India - Wed Mar 15 08:29:16 2000
I am highly interested on the research been done on M. bovis. Molecular biology, gene expression
adn diagnosis.
ana maria zarraga <[email protected]>
valdivia, chile - Tue Mar 14 01:11:26 2000
Please send me info on tb asap, thanks.
scotty mcdonald <[email protected]>
lincoln, NE USA - Tue Mar 14 00:17:29 2000
please place me on the mailing list, thanks.
Todd Weisse <[email protected]>
New York, NY USA - Thu Mar 9 18:49:13 2000
Mycabacteria-macrophage interaction Signal Transduction Dormancy in mycobacteria
Sadhana Majumdar <[email protected]>
Houston, Texas USA - Mon Mar 6 19:39:27 2000
Can some one please tell me of a good web site where i can find out about Teberculosis. I am from
Scotland and a family member of my boy friend here has it. PLease suggest a web site for me!
Thank you
Clara <[email protected]>
Amsterdam, Netherlands Holland - Wed Feb 23 12:35:35 2000
Yeah! Tuberculosis is fucking cool! Yeah! Yeah!
Elan Gerzon <[email protected]>
california, usa globe - Mon Feb 14 18:32:09 2000
I'm a high school student doing some reasearch on antibiotic resistance for my senior Bio class.
Any suggestions?
Andi G <[email protected]>
- Fri Feb 11 22:26:51 2000
Hi, biological research has always been of great interest to me. I am especially interested in how
bilogical pathogens effect cultural patterns. I have a B.A. from Binghamton University (S.U.N.Y) in
theAnthropological Sciences... I am currently pursuing a second B.A. in Biology...Please contact me
if you have any research availability in the New York City area. Thank You, Ian C. Lord
Ian C Lord <[email protected]>
Queens, NY US - Sun Feb 6 01:11:25 2000
clinical aspects
sandeep saluja <[email protected]>
new delhi, DELHI india - Sat Feb 5 23:46:10 2000
I'm a graduate of B.S. Medical Technology of Far Eastern Unversity-NRMF, working at De La
Salle Medical Center HSC-A. King Research Center-TB Reseach Laboratory Level II. I'm a
Tubercologist, my work is purely concentrated on TB identification, culture and sensitivity, and we
are working out procedures in preventing the spread of it.PTB is not a JOKE!.
Eric Matthew S. J. Dela Cruz, B.S.MT, RMT <[email protected]>
Imus, Cavite Philippines - Fri Feb 4 10:31:47 2000
A research about serum A.D.Alevel in pulmonary T.B.If you have iny interest or idea please
contact.
Dr.HAKIM <[email protected]>
TEHRAN, IRAN - Wed Feb 2 22:06:17 2000
vaccines against tuberculosis, improved Mycobacterium bovis BCG, Salmonella spp. as
recombinant antigen delivery device
Juergen Hess <[email protected]>
Berlin, Germany - Tue Feb 1 13:09:39 2000
I am a highschool student interested in holistic medical research and development for a future
profession and I am looking for any suggestions to any colleges dealing with this field,
Suggestions??
Lindsey Nero <[email protected]>
Mt.Holly, NJ USA - Fri Jan 28 21:27:35 2000
I'm a graduate student and would like to obtain new full text articles on Mycobacteriophage.
Wendell O. Junia <[email protected]>
Manila, Philippines - Fri Jan 28 11:08:47 2000
Email me with info about Tuberculosis.
Shauna <[email protected]>
Texas USA - Tue Jan 25 22:31:58 2000
I'm a Medical Resident and I'm making a paper on the Incidence of Lung Ca in patients presenting
as PTB. I've seen a # of patients who have been treated as PTB but on biopsy or pleural fluid
studies showed CA.
Joseph E. Poblacion, MD <[email protected]>
Cebu City, Philippines - Sun Jan 9 06:18:54 2000
We are interested in molecular characterization and drug sensitivity of Mtb strains. Also,
serodiagnosis of infection by Mtb is of our interest.
Angel Gustavo GUEVARA PhD <[email protected]>
Quito, Pichincha Ecuador - Wed Dec 22 16:05:23 1999
TB.Microbiology $ Epidemiology
Mir.Mohammad Ziaei <[email protected]>
Tabriz, East Azerbaijan Iran - Mon Dec 13 19:54:18 1999
HIV-TB, cytokines in TB, controlled clinical trials in tuberculosis
Soumya Swaminathan <[email protected]>
Chennai, Tamilnadu India - Sun Dec 12 16:30:30 1999
effects on body, treatments, symptoms
Rachel Wilford <[email protected]>
Millsboro, DE USA - Tue Dec 7 22:59:35 1999
effects on body, treatments, symptoms
effects on body treatments symptoms
Too big of words. I don't understand it. Please use smaller words, or maybe hyperlinks to the
definations of big words. Thank you. tammi
Tammy <[email protected]>
Bremerton, WA USA - Sat Nov 27 21:44:55 1999
I am a student completely fascinated with molecular biology and genetics. I have performed
research on transgenic mice in embryonic develpoment at the EIB/NCI/NIH, the most incredible
experience I have gained yet. My interests mainly include the following: the human genome
research project, cancer research, and anything affiliated with genetics.
Leana Movsessian <[email protected]>
Germantown, Maryland USA - Mon Nov 22 20:26:03 1999
I am a student completely fascinated with molecular biology and genetics. I have performed
research on transgenic mice to decode all genes coding for embryonic develpoment and the
EIB/NCI/NIH. My interests mainly include the following: the human genome research project,
cancer research, and anything affiliated with genetics.
Germantown, Maryland USA - Mon Nov 22 20:25:06 1999
Genetics, Molecular biology, research in cancer cells, human genome project, etc
Germantown, Marylan USA - Mon Nov 22 20:22:18 1999
I'm italian. I'm going to finish my PhD at the end of 1999. The subject of my thesis is: Tuberculosis
in human fetal brain: microglia infection with M. tuberculosis and different strains of M. avium. I
studied mycobacterial effects on microglia cell cultures (cytokines expression and production,
chemokines expression) I'm looking for a post-doc in California to study tuberculosis. I have a
strong background in immunocytochemistry, human fetal neurons cell cultures. If you have any
ongoing projects in this area please contact me.
Monica Curto <[email protected]>
- Mon Nov 1 08:14:14 1999
I am a Masters student (history) at San Diego State researching the social effects of Tuberculosis in
Mexico and the border region. Any help is appreciated.
Christine Moore <[email protected]>
Oceanside, Ca USA - Thu Oct 28 16:08:46 1999
i am carrying my research studies at masters level in computer assisted molecular modelling.my
main topic is tuberculosis and isoniazed..i will be thankful to any of my friend who give
information to me.
khawaja sohail qamar <[email protected]>
penang, penang malaysia - Tue Oct 26 01:36:56 1999
i am carrying my research studies at masters level in computer assisted molecular modelling.my
main topic is tuberculosis and isoniazed..
khawaja sohail qamar <[email protected]>
penang, penang malaysia - Tue Oct 26 01:25:17 1999
Elisa in diagnosis of primary tuberculosis in children Sero Diagnosis of primary tuberculosis in
Children using 38KDA and 16 KDA Pathozyme TB complex in diagnosis of tuberculosis in
children
Fred Castro <[email protected]>
Makati, Philippines - Sun Oct 24 14:02:20 1999
Databases Statistics Data Mining Meta Data Epidemiology Geography
Don Van Dyke <[email protected]>
Raleigh, NC USA - Wed Oct 20 18:08:50 1999
Another TB positive person. Have been told never, repeat never, to get another TB test again. As
far as I know, I have no symptoms. Have been positive for 30+ years. Just sharing this with you.
Agnes Truske <[email protected]>
Albuquerque , NM USA - Wed Oct 13 19:54:00 1999
I am doing a cell projest on Tuberculosis
Rebecca Galloway <[email protected]>
Sanford, North Carolina Lee - Mon Oct 11 21:55:21 1999
secreted proteins from M.tb for vaccination
mao huaxong <[email protected]>
Guangzhou, Guangdong china - Sun Oct 10 08:05:13 1999
I am a Medical doctor with a Master's degree in Biostatistics. I'm interested in current research on
multidrug resistance and current evaluation of the DOTS programme.
Dr Alexander Quarshie <[email protected]>
- Thu Oct 7 22:39:44 1999
I am a Medica doctor with a Master's degree in Biostatistics. I'm interested in current research on
multidrug resistance and current evaluation of the DOTS programme.
Dr Alexander Quarshie <[email protected]>
- Thu Oct 7 22:38:43 1999
I am doing this for a science extra credit project.
Connie Gillaspie <[email protected]>
Midland, SD USA - Wed Oct 6 13:35:13 1999
I am a student conducting research on the controlling of TB. Although I have only begun my
research, I will be conducting and submitting information regarding the testing of a particular
drug and its derivatives. Any information about TB research is greatly appreciated as I am just
getting started.
Amber Garcia <[email protected]>
Bethany, WV USA - Tue Oct 5 00:32:22 1999
I hold Ph.D. degree in Vet.Public Hlth from U.K. I am an assiss.Prof. at dep. Microbiol., Col. Vet.
Med. Baghdad previousely, now am looking for a job in Jordan. I used to supervise many M.Sc.
and Ph.D. research projects and I worked on many types of Bacteria, mainly Campylobacter,
Salmonella, Moraxella, S.aureus, Streptococci ( esp. Enterococci), Pasteurella, E.coli, Klebsiella
and I was always interested to work on T.B. because it is widely distributed in our country and in
many other countries, and more important, my wife was suffering from bone T.B. and is being
treated since February 1999, until and her condition improved quite well on an intensive course of
INH-Ethambutol-Rifampicin. I used to work in a private human clinical lab. and I was extremely
efficient in preparing acid-fast smears and I did some improvements on the routine methods under
use by most laboratories. I shall be very glad to keep in continuous touch with you. Thank you.
Dr. Amir S. Rahim Al-Obaidi <[email protected]>
Amman none, none Jordan - Sun Oct 3 17:29:59 1999
I am a pulmonary physician working in the Centre for Tuberculosis &Chest Diseases since 1990.I
hold two diplomas in Tubercular &Chest Diseases from Pakistan.My spheres of interest are
MULTIDRUG RESISTANCE IN TB,SERODIAGNOSIS OF TB AND REVIEWING THE
EFFICACY OF BCG VACCINE.Iam particularly distressed at the re emergence of this great killer
disease and needs a global effort to combat this trend.Iwould be indebted if I am in anyway able to
contribute towards the research in TB.Iwelcome anyone with similiar concern to get in touch with
me.
DR. SYED FASIHUDDIN <[email protected]>
MAKKAH, SAUDI ARABIA - Sun Oct 3 10:24:22 1999
I am a pulmonary physician working in the Centre for Tuberculosis &Chest Diseases since 1990.I
hold two diplomas in Tubercular &Chest Diseases from Pakistan.My spheres of interest are
MULTIDRUG RESISTANCE IN TB,SERODIAGNOSIS OF TB AND REVIEWING THE
EFFICACY OF BCG VACCINE.Iam particularly distressed at the re emergence of this great killer
disease and needs a global effort to combat this trend.Iwould be indebted if I am in anyway able to
contribute towards the research in TB.Iwelcome anyone with similiar cocern to get in touch with
me.
DR. SYED FASIHUDDIN <[email protected]>
MAKKAH, SAUDI ARABIA - Sun Oct 3 10:19:04 1999
What is tuberculosis.
Lori Palmer <[email protected]>
Doswell, VA USA - Fri Oct 1 13:20:42 1999
Epidemiology
Jill Mengel <[email protected]>
Lancaster, PA Lancaster - Thu Sep 30 01:24:08 1999
know someone with tb
Melissa <[email protected]>
Pa 17011 - Wed Sep 29 22:44:39 1999
Sanatoria in Davos, Switzerland, c. 1930-1945; the work of Dr Gustav Maurer
William Lee <[email protected]>
Vancouver, Washington USA - Wed Sep 22 06:28:49 1999
I would like if I can receive some posters I can use for Health education.
Boubker Naouri <[email protected]>
Kissimmee, Fl USA - Fri Sep 17 19:15:57 1999
mycobacteria, membrane proteins, detergent soluble and water soluble ones, molecular biology
Anjana Gupta <[email protected]>
New Delhi India - Fri Sep 17 04:17:48 1999
Mycobacteria, BCG , membrane proteins, detergent soluble ones, molecular biology
Anjana Gupta <[email protected]>
new delhi india - Thu Sep 16 04:25:41 1999
iam doing my MS in Computer Science.and iam very much interested in Medicine.
naveenkota <[email protected]>
MORGANTOWN, WV USA - Thu Sep 9 13:38:40 1999
test
test
- Mon Aug 30 19:11:37 1999
Dear sir, Here I attached a personal resume to apply for a post doctor research in new drug
research and development.I hope you will read it carefully and reply me. your sincerely, Jie Yang
JIe Yang <[email protected]>
kunming, yunnan P. R. China - Mon Jul 26 02:38:13 PDT 1999
I am a graduate student working on " Synthesis of cell wall fragments of Mycobacterium
tuberculosis" at National Chemical Laboratory, PUNE. I would appreciate any information
regarding the synthesis of cell wall fragments or developement of new drugs based on the inhibition
of arabinan biosynthesis. My contact addresss: Srinivas Hotha, Senior Research Fellow, Organic
Chemistry:Technology, Pune - 411 008, India; e-mail:[email protected]
Srinivas <[email protected]>
PUNE, Maharashtra INDIA - Fri Jul 23 08:13:13 PDT 1999
Drugs Resistance.
Guillermo A. Paredes <[email protected]>
Martinez, CA USA - Tue Jul 20 21:30:12 PDT 1999
Interest: Social History of Tuberculosis in Australia; specifics re people who came to colonial
Australia 'for their health', i,.e. the cure for 'consumption'.
Lois Baglin <[email protected]>
East Brighton, Victoria Australia - Mon Jul 19 22:08:36 PDT 1999
Extrapulmonary tuberculosis
Anna Marie G. Pato <[email protected]>
Cebu, Cebu Philippines - Fri Jul 16 06:19:17 PDT 1999
I'm a surgical resident and is interested in the management of extrapulmonary tuberculosis, since
we still have a high incidence of tb in our country we still see and treat patients with
extrapulmonary tb.
Jose Roy Z. Gregorio, M.D. <[email protected]>
Quezon City, Philippines - Sat Jul 3 01:00:28 PDT 1999
I have a bachelor's degree (honors) in Molecular, Cellular, and Developmental Biology and will be
studying infectious diseases as a graduate student. I would like to volunteer either in clinical or
laboratory environments - I have experience in both areas. Please contact me if you would like
assistance and are located in the SF area.
Kiersten Israel-Ballard <[email protected]>
Santa Cruz, CA USA - Tue Jun 29 21:28:37 PDT 1999
I want to volunteer in your research project. I am a medical doctor and already had one year
clinical experience (internship in Internal medicine at New York Hospital ).Want to volunteer
while waiting for residency.I hope to hear from you soon.
Roeliza Ebbah-Pascua <[email protected]>
San Jose, California - Tue Jun 29 09:58:07 PDT 1999
Tuberculosis and Patient's Compliance/Treatment Partners (DOTS)
DR. DOMILYN VILLARREIZ <[email protected]>
Davao, Philippines - Tue Jun 15 03:32:34 PDT 1999
Spatial epidemiology of TB
Phil Atkinson <[email protected]>
London, UK - Tue Jun 8 09:10:42 PDT 1999
Bovine TB, molecular epidemiology, RFLP, spoligotyping, PFGE, VNTR, AFLP, virulence,
transmissibility, stability, genomics, direct detection, PCR
Robin Skuce <[email protected]>
Belfast, Northern Ireland - Tue Jun 8 06:42:57 PDT 1999
tuberculosis diagnosis, prevention, treatment We will be interested to know whether a case where
M.tb. has been isolated twice on two different days by Bactec and confirmed by use of TMA of
Gene Probe should be treated or not. General consesus is not people who are infected as the above
case should not be treated. Why. Are they not in danger to themselved in future ? How does one get
extrapulmonary tuberculosis such as renal, bone or meningitis, or lymphadenitis. Are these
infected people also dangerous to other. Would appreciate to form and be part of discussion group
on this type of matter. I am new web learner and would appreciate reply by e-mail.
Dr.Suresh Amin <[email protected]>
Baroda, Gujarat India - Sun Jun 6 19:02:22 PDT 1999
RFC and ELISA in Paratuberculosis
Dr. Valeriu Crangus <[email protected]>
Bucharest, Romania - Thu Jun 3 07:01:57 PDT 1999
I am interested to conduct an evaluation study on the TB Program of our local government. Are
there available research literature in this area?
Dr. Jocelyn C. Kintanar, <[email protected]>
Cebu, Cebu Philippines - Mon May 31 05:56:10 PDT 1999
I am researching the effects and damage caused by bacterial infections following surgical
procedures within major hospitals. I am interested in hearing from anyone who following infection
has tested positive for Tuberculosis, Mycomplasma, Toxomplasma, Luekemia, Cytomegolivirus.
My research interest is in particular to women who have had caesarian section.
Liani Simpson <[email protected]>
Brisbane, Queensland Australia - Thu May 20 21:07:49 PDT 1999
I'm a graphic designer and i've been assigned a project to create a stamp collection related to
Tuberculosis and its history. I need all the visual information i can get about subjects, people linked
to this disease and pictures of the bacteria itself. Websites with good pictures related with TB will
help very much. This work will help ANTDR (Associacao Nacional de Tuberculose e Doencas
Respiratorias) in its fight against this plague. Any help i could get would be very important.
Thanks in advance.
Antonio Manuel Silva <[email protected]>
Lisbon, Portugal - Thu May 20 13:31:50 PDT 1999
DNA based methods for diagnosis of tubersulosis and molecular epidemiology. Interested in
collaborations.
Dr Madhu Goyal <[email protected]>
Hatfield, U.K - Mon May 17 06:13:41 PDT 1999
I'm doing a science report on tuberculosis and I really, Really,REALLY need pictures of the
tuberculosis microbe. Katrina
Katrina Howe <[email protected]>
Fairbanks, AK USA - Fri Apr 30 13:22:55 PDT 1999
I am currently conducting some research on the increasing occurance of antibiotic immunity of TB
and would appreciate any info. that could be given. Thank you.
Matt Nelson <[email protected]>
Tacoma, WA USA - Tue Apr 20 23:28:50 PDT 1999
interested in vaccine development for tuberculosis. by using molecular techniques and
bacteriophage.
M.S.Ranjith mehendarkar <[email protected]>
chennai, tamil nadu india - Fri Apr 9 10:46:26 PDT 1999
i am a post graduate student doing my thesis work on mycodot LAM test efficacy in diagnosing TB
cases,please send me any information regading this
s satish madhav <[email protected]>
visakhapatnam, andhrapradesh india - Fri Apr 9 00:13:07 PDT 1999
Gene expression regulation in stationary-phase of bacterial growth cycle. Molecular mechanism
underlying to adaptive mutation process in stationary-phase. Molecular mechanism of antibiotic
resistance.
José María Gómez Gómez <[email protected]>
Madrid, Madrid Spain - Mon Mar 29 10:49:06 PST 1999
Vibrio cholerae, Population Genetics, Molecular Evolutionary Genetics, Pulsed Field Gel
Electrophoresis, Bacterial Diversity.
Diego Riaño <[email protected]>
Santafé de Bogotá D. C., Cundinamarca Colombia - Sun Mar 28 18:58:55 PST 1999
TB and STDs in Migrant Farmworkers.
David Much, Ph.D. <[email protected]>
- Tue Mar 23 14:30:24 PST 1999
I am a Ph.D in applied Biology with specialisation in Immunodiagnosis of tuberculosis. I am at
present looking for a postdoc position in any of the following fields-- Mol.Biology/ Immunology.
Dr Mythili Kameswaran <[email protected]>
Mumbai, Maharastra INDIA - Tue Mar 23 00:44:38 PST 1999
Multidrug resistant tuberculosis Tuberculosis in AIDS patients Effect of Tb prophylaxis in drugresistant isolates
José Luis Fuentes Allen <[email protected]>
Mexico, D.F. MEXICO - Sun Mar 21 17:21:24 PST 1999
I would like to know more about the diagnostic aspect of tb. especiallly the modern methods. Is
there any association for tuberculosis?
Elizabeth Anne Scicluna <[email protected]>
Malta - Sat Mar 20 12:38:44 PST 1999
Hi, We would like to inform you that our Singapore Anti-Tuberculosis Association (SATA) website
has changed its homepage address from Http://rs.nic.net.sg/virtuoucity/sata to
Http://home2.pacific.net.sg/~satakat/index.html but our Email address remains the same as
[email protected]. Please update or help to link our new webpage address to your site. Thank
you. Regards SATA
Henry <[email protected]>
- Fri Mar 12 19:50:17 PST 1999
Susceptibility of man to bovine tuberculosis - Koch stated, most medical men believed the intestins
would suffer first. "I myself," he wrote, "have seen primary tuberculosis of the intestines only
twice. ...at Charity Hospital in Berline, only ten cases in five years. Primary TB of intestine w/o
lungs and bronchia never occured, in 933 cases. Biedart found only 16 cases in 3104 postmortems
on tubercuar children. So how then can we accunt for the inter-transmissibility of human and
bovine tuberculosis?" (Koch) The solution? The very tiny dark particles within each of the diseased
cells are actually plasmids. They are far too small to be clearly identified with an ordinary
microscope. Note also, plasmids are the microorganisms that transfer genes between various stains
of bacteria. it is not only tuberculosis that produces plasmids. The same microorganism(s) also
transfer genes, DNA, or drug resistant modlues between drug resistant bacteria. Hence, the very
dark, tiny particles within each cancer cell, turn out to be the same thing - plasmids. The plasmid
transfers into a weakened cell, and it resets the genes. Some plasmid are self-transferable. All are
self replicating. Hence, this well-hidden genetic altering mechanism is what produces tuberculosis,
as well as all kinds of cancers and tumors. Onces the new gene(s) are transplanted, the newly
completed genetic material functions completely FROM INSIDE THE IMMUNE
SURVEILLANCE SYSTEM OF THE HOST. Hence, this explains the subtle inheritance patterns
found in many disease, such as TB, MS, MD, Diabetes, Leprosy - and any of these, as well as
cancers and tumors are only PSEUDO-GENETIC in the orgin. Would you agree with these
statements, or not? Please let me know.
Bruce D McKay, Bio Epistemologist <[email protected]>
Tampa, FL USA - Fri Mar 5 00:23:09 PST 1999
Studying Mycobacterium paratuberculosis. Interested in tuberculosis virulence factors, antibiotic
resistance mechanisms, cell wall components, identification/location of these genes(plasmid?).
Jason Azat <[email protected]>
Santa Barbara, CA USA - Sat Feb 27 22:52:39 PST 1999
I am conducting a study on the toxic elements in hair analysis of both patients diagnosed with TB
and family members that don't have the disease. I need information or research done on the effects
or lack of of nutrients and toxic elements in TB. I work in Hospital Santa Clara, the most
important hospital for TB in South America and we are in great need for help and support.
John E. Bastidas M.D. <[email protected]>
Bogotá, Colombia - Fri Feb 12 04:16:37 PST 1999
I am a PhD student and my research involves in vitro screening of antimycobacterial (both
sensitive and MDR strains) activity by South African medicinal plants. Any relevant information in
this respect will be greatly appreciated.
Namrita Lall <mailto:[email protected]>
Pretoria, Gauteng South Africa - Thu Feb 11 00:09:20 PST 1999
I have an interesting case on tuberculosis of gall bladder. I need some references regarding the
tuberculosis of Gall Bladder
Dr. O. P. Sudrania <[email protected]>
Siliguri, West Bengal India - Wed Feb 10 03:28:40 PST 1999
I'm doing and investigation about tuberculosis, Immunology, Genetics, diagnostic in LCR I would
like to have some information about this, if you please by able to send me these information
victor Minera <[email protected]>
Guatemala, Guatemala Guatemala - Tue Feb 9 10:16:03 PST 1999
radiology tuberculosis diagnostic
Olga Malyscheva <[email protected]>
Moscow, mo Russia - Sun Feb 7 23:59:28 PST 1999
tuberculosis
Olga Malyscheva <[email protected]>
moscow, mo RF - Sun Feb 7 07:33:12 PST 1999
I am the student of medicine faculty of Cerrahpaþa and 1 year left to be a doctor.I just want to
learn more about every patience and especially about tuberculosis because of the fact that
tuberculosis is a very important patience in my country.
Ozan Karatað <[email protected]>
Ýstanbul, Türkiye - Sat Feb 6 08:00:34 PST 1999
Me: TB epidemiologist at the World Health Organization (but applying to medical school, hoping
to be able to go back to California!). In the meantime, my research interests include TB and
gender, particularly gender-based differences in the delivery of TB care (a common problem in the
developing world), among other things...
Suzanne K. Scheele <[email protected]>
Geneva, Switzerland - Tue Feb 2 07:00:02 PST 1999
Ihave a 5 month old patient with tuberculous meningitis&cavitary lesions.How frequent we see
cavitary tuberculosis in children?
Soner Sarmasýk <[email protected]>
Istanbul, Turkiye - Wed Jan 27 11:51:43 PST 1999
Doing some research work related to tuberculosis, Immunology, Genetics
MengZhang <[email protected]>
Beijing, PRChina - Tue Jan 26 03:14:00 PST 1999
Looking for more info about the guidelines on testing positive on the Manatoux test when the BCG
was given over 22 years ago.
Shelagh Taylor <[email protected]>
Great Lakes, IL USA - Fri Jan 22 07:28:41 PST 1999
I am a doctor specializing in the spheres of immunology, allergies, infectious diseases, pediatrics,
gastro-intestinology, endocrinology and also cancer diseases in the recent past. In 1985 I started to
develop this method of diagnosis for different diseases, the foundation being in immunological
reactions, registered with the help of the immuno-bio-chemo-luminescence naturally present in the
body, and stimulated in the acidic agent hydrogen peroxide. With the use of standard methods of
testing as a control I compared them for many years with this method of analysis and it has proved
extremely accurate.
Yakuba Nataliya <[email protected]>
Toronto, Ontario Canada - Thu Jan 21 02:43:01 PST 1999
Any research findings on TB in immigrants to developing countries. Are they responsible for
transmission to the indeginous peoples or is the reverse true?
Kenneth <[email protected]>
Montreal, Quebec Canada - Mon Jan 18 15:07:02 PST 1999
Any research findings on TB in immigrants in developing countries. Are they responsible for
transmission to the indeginous peoples or is the reverse true?
Kenneth <[email protected]>
Montreal, Quebec Canada - Mon Jan 18 15:05:23 PST 1999
I want to know about multiresistant tuberculosis, any information or link will be useful. Thank
Katherine Hernandez <[email protected]>
Lima, Lima Perú - Mon Jan 18 14:51:49 PST 1999
Research on Active TB in adults who have had no sympotoms, negative skin tests and negative
chest Xrays negative smears, but does have positive culture of liquid from a washing of the lungs
due to a broncochope as result of a chronic non-productive cough for years..
Kay <[email protected]>
Dalton, GA USA - Sun Jan 10 22:54:04 PST 1999
Genetics, MHC, T cell receptors, thymic education.
PITCHAPPAN <[email protected]>
MADURAI, Tamil Nadu INDIA - Thu Jan 7 07:54:56 PST 1999
Tuberculosis in children and adolescent, profilaxis, epidemiology, treatment.
Datchev <[email protected]>
Rousse, Bulgaria - Wed Jan 6 14:12:51 PST 1999
Portable TB Isolation Systems For Healthcare and other needs eliminates most respirator use
Ted Arts <[email protected]>
Buffalo, NY USA - Wed Jan 6 06:48:34 PST 1999
We want to express several recombinant proteins from M.tuberculosis. Where can we get the
corrseponding DNA or cDNA?
Werner Schmitz <[email protected]>
Wuerzburg, Germany - Tue Dec 15 01:36:05 PST 1998
I am a school nurse, our District TB policy was to conduct mass PPD skin testing on the 7th grade
students. I have found a 30% conversion rate with a 2nd PPD test, in those students that had only
redness (no induration) with the 1st PPD test. I would be interested in any research or information
regarding the signifecance of redness only reaction to a PPD skin test and its correlation to TB
infection in this or any age group. please contact me at [email protected] thank you L. Lee
RN,BSN
Lynn Lee <[email protected]>
Brownsville, Texas USA - Thu Nov 26 19:02:35 PST 1998
I am a 3 rd year Bsc student and my final year project is a kit review of Gen Probe MTB kit. I am
intrested to hear from any one else who has used this kit so that we can share useful information or
anyone who can provide useful links. THANKS
Latham Yates <[email protected]>
Weymouth , Dorset England - Wed Nov 25 10:28:05 PST 1998
I am in my final year (BSc hons applied biological sciences), my final project involves Heminested
inverse PCR for rapid identification of M.tb strains. I would be grateful for any information or
links to information you can provide. Thanks
Elaine Connor <[email protected]>
Manchester, England - Wed Nov 25 07:10:19 PST 1998
I am a medical Doctor.Iwas a researcher in my country(Epidemiology of TB and execution of
DOT's).I got to canada recently and I'd like to continue epidemiological study of TB here too.
Would you please introduce me organizations or research centers of TB anywhere in
Canada.Thank you.
Nooshin Ahmadi pour <[email protected]>
Montreal, Quebec Canada - Thu Nov 19 20:21:00 PST 1998
MDR TB
MARCIA SEISCENTO <600@apm,.org.br>
são paulo, são paulo brazil - Tue Nov 17 12:41:31 PST 1998
Tuberculosis,Fibreoptic Bronchoscopy,treatment of TB
DR BHARAT GOPAL;MD <[email protected]>
delhi, delhi india - Sat Nov 7 01:06:06 PST 1998
Was there any Clinincal trials done in using morhine or heroin in treating Tuberculous or any lung
diseases?
Helena Bonner <[email protected]>
coleraine, N.Ireland - Thu Nov 5 04:39:52 PST 1998
I am interested in all aspects related to molecular drug resistant mechanisms employed by TB.
Eric T. Y. Leung <[email protected]>
- Wed Nov 4 21:58:54 PST 1998
I am interested in any reported case dealing with Mycobacterium tuberculosis infection leading to
Interstitial lung disease or pulmonary fibrosis or any new treatment modalities for tuberculosis
infection or disease.
Emilina Montero-Luz <[email protected]>
Manila , Philippines - Mon Nov 2 21:47:43 PST 1998
I need information about resistance to Tuberculosis in Perú
HENRI PEREA <henriperea@hotmail>
AREQUIPA, AREQUIPA PERU - Sun Nov 1 21:00:11 PST 1998
I am interested in research about susceptibility genetic and TB or others topics about Molecular
Genetic in this disease
Paula Andrea Granda Carvajal <[email protected]>
Medellín, Antioquia Colombia - Wed Oct 14 14:42:59 PDT 1998
I'd really apreciate if anyone could send me any file rellated with tuberculosis treatment. Chemical
aspects of the drugs, farmacology, etc. Any kind of information would be usefull. Thanks!
Julian Catalan <[email protected]>
Blumenau, SC Brasil - Tue Oct 13 15:52:29 PDT 1998
Please include infor regarding epidimiology of TB within the Asian population in America.
Christine Nguyen <christine112.hotmail.com>
san jose, california U.S.A - Tue Oct 13 12:54:44 PDT 1998
I'm a biologist working at the hygiene institut in Morocco I'm unteresting in huomoral response to
mycobateium tuberculosis,SDS PAGE.
LARBI BAASSI <[email protected]>
Rabat, Morocco - Fri Oct 9 08:57:21 PDT 1998
Please forward all information/latest research papers on TUBERCULOSIS regarding D.O.T.
[direct observation treatment].
Khalid <[email protected]>
Karachi, Karachi Pakistan - Tue Oct 6 07:54:09 PDT 1998
Interest in PCR of gene probe. The local distributer claims that we can do sensitivity by PCR. Is it
true ?
Dr Suresh Amin <[email protected]>
Baroda, Gujarat india - Sun Oct 4 17:09:13 PDT 1998
slide culture of M.tuberculosis
Dr.N.Selvakumar <[email protected]>
Chennai 600 031, TamilNadu India - Fri Oct 2 19:19:32 PDT 1998
Diagnosis of tuberculosis, Culture methods Bactec, PCR , Nontubercular mycobacteria , their
pathogenicity, treatment if any. Envirommental mycobacteria, Rifampin resistant gene band in
MTb.
Dr Suresh Amin <[email protected]>
Baroda, Gujarat India - Wed Sep 23 08:21:07 PDT 1998
Adenocarcinoma Plueral effusion in females Treatment available in India
Monali Jain <[email protected]>
Mumbai, Maharashtra India - Mon Sep 21 05:46:32 PDT 1998
So nice a site. I would like to continue studying on TB. I am looking for some hard workers to do
research. The world is my country. It does not matter to me where to work. Waiting for you!
Babak Shokouhi <[email protected]>
Tehran, Iran - Sat Sep 19 14:24:56 PDT 1998
I'm a medicine student from Brasil and I need some information in order to apply in my research
:epidemiology of pleural tuberculosis and diagnosis statistics of ADA and citological analysis of
pleural effusion.
Juliana Ferreira de Oliva <[email protected]>
Santos, São Paulo Brasil - Wed Sep 16 10:54:20 PDT 1998
New Diagnostic techniques for Tuberculosis
Anjul Shrivastava <[email protected]>
Bangalore, Karnataka India - Wed Aug 19 09:31:34 PDT 1998
I am a 5th year medicine student in Colombia. The incidence of TBC is very high down here since
this is a third world nation. I am planning on doing my thesis about the efficiency of the ADA
(Adenosine Deaminase) test in patients with pleural effusion due to TBC. I would be interested in
any information or previous studies that have been done about this theme. My mailing address is:
Federico Castellanos Arango Calle 80 No. 55-22 Apto. 7A Barranquilla, COLOMBIA I am very
thankful for all the information you can provide me.
Federico castellanos Arango <[email protected]>
Barranquilla, Atlantico Colombia - Thu Aug 13 20:24:52 PDT 1998
Dear colleagues I am very interesting to develop relations with researchers and organisations
involved in study of immunology and genetics of tuberculosis. I am representing the group of
azerbaijanian scientists from the Institute of Lung Diseases and TB. We are also very interesting in
investigation of efficacy of BCG vaccination and new forms of prevention of tuberculosis. We'll
appreciate any interest and suggestions to us. Looking forward to hearing from you.
Professor Alexandr UMNYASHKIN <[email protected]>
Baku, Azerbaijan - Wed Aug 12 01:23:57 PDT 1998
epidemiology of tuberculosis in Volgograd Russia multiple drug resistance in Volgograd Russia
sexually transmitted infections in Volgograd Russia public health or population programs for
tuberculosis control in Russia therapy for tuberculosis in Russia
Jim Wohlleb <[email protected]>
Little Rock, AR USA - Thu Aug 6 03:45:15 PDT 1998
In February of this year, my 6-year-old son was diagnosed with TB meningitis. This in turn caused
hydrocephalus, which caused several strokes to his mid- brain. We were told he had 1 week--1
month to live. If by some chance he did live he would be a vegetable. Right now he is at Methodist
Hospital in Indianapolis and is learning how to talk and walk all over again. What I'm looking for
is statistics on the survival of children who have been diagnosed with this disease and the possibility
of more strokes (what are the odds of him having more). I would also like to know if there is a
chance for him to recover completely. Please e-mail to me any information on TB Meningitis so I
can know what would be reasonable expectations for me to have. Thank you for your time and
efforts.
Holly M. Gimenez <[email protected]>
Muncie, IN USA - Fri Jul 31 12:35:56 PDT 1998
I am interested in information on the spread of TB in Russia since the fall of the Soviet Union.
Thank you. genise ghee
Genise O. Ghee <[email protected]>
- Wed Jul 29 06:10:11 PDT 1998
Iam a professor of Biochemistry of the school of medicine, our proyect is is RFLP of multiresistant
strain of Mycobacterium Tuberculosis here in the valley of Mexicali the incidence of tb is around
49 per 100,000 we have around 650 new cases of tb per year reported by the Helth department the
number or multiresistant strains (2 or more antifimic drugs) is almost 30%. Multidrug resistant
strain,RFLP,IS6110,Inmunological response anti-tb DNA probes
Acosta-Valle Hector <[email protected]>
Mexicali, Baja California Mexico - Mon Jul 27 13:53:09 PDT 1998
kindly send me updates on pott's disease (journals, etc..) thru e-mail. i will highly appreciate it if
you could send it by tuesday next week because i have a case presentation re: pott's disease on
friday, thanks in advance. more power! dr. abner m. hornedo department of pediatrics de los
santos medical center quezon city, philippines
abner m. hornedo, m.d. <[email protected]>
quezon city, philippines - Fri Jul 24 21:37:32 PDT 1998
What kind of fish are in the picture of Peter Small? Did he really catch them?? How many are
there?? What did they weigh??
Lizzie
- Sun Jul 19 07:15:16 PDT 1998
I would appreciate any information about all forms of TB throughout history in New York state
especially sanitoriums>Thank-you
Rebecca Guthrie <[email protected]>
- Wed Jul 1 20:56:10 PDT 1998
Clinical Tuberculosis, Chapman and Hall London, 1998. Why is the AIDS conference in Geneva
not telling the world that the commonest cause of death in AIDS patients is tuberculosis?
Peter Davies <[email protected]>
Liverpool, UK - Mon Jun 29 04:01:49 PDT 1998
I am in need of information about TB to be used as a teaching tool for children and parents in a
pediatric hospital in Boston
Ed Gilbert <[email protected]>
Evertt , MA. U.S.A. - Wed Jun 24 16:34:26 PDT 1998
Rapid mycobacterial identification by PCR-Restriction Enzme Analysis (hsp65 gene) How to make
it more practical for use in heavy burden clinical laboratories?
O. Kaya Koksalan <[email protected]>
Istanbul, Turkey - Mon Jun 22 11:35:22 PDT 1998
MDR tuberculosis,molecular methods of rapid identification of drug resistance,molecular
mechanisms drug resistance
Edward Generozov <[email protected]>
Moscow, Moscow Russian Federation - Fri Jun 19 04:47:14 PDT 1998
Medical Air Technology Corporation provides leading edge Air Purification systems for hospital,
correctional and long term care facilities. We work closely with infection control personnel,facility
management,safety officers, engineers and architects to provide individually designed rooms that
are GUARANTEED and CERTIFIED in writing to meet or exceed all present CDC guidelines and
OSHA regulations. For more information on TUBERCULOSIS / AIRBORNE INFECTION
CONTROL for the 21st century visit our website www.medair.com Thank you
Jeff Olarte <[email protected]>
mission viejo, ca usa - Thu May 28 09:32:11 PDT 1998
Medical Air Technology Corporation provides leading edge Air Purification systems for hospital,
correctional and long term care facilities. We work closely with infection control personnel,facility
management,safety officers, engineers and architects to provide individually designed rooms that
are GUARANTEED and CERTIFIED in writing to meet or exceed all present CDC guidelines and
OSHA regulations. For more information on TUBERCULOSIS / AIRBORNE INFECTION
CONTROL for the 21st century visit our website www.medair.com Thank you
Jeff Olarte <[email protected]>
mission viejo, ca usa - Thu May 28 09:26:03 PDT 1998
I am a student of medice at the UIA in Costa Rica, I am working about multidrug resistant
tuberculosis and management. I would appreciate any input in this matter.
Andres Obando Valverde <[email protected]>
Cartago, Costa Rica - Mon May 25 23:03:46 PDT 1998
I am working at mycobacterial laboratory which is a top national referral center for the country.
We examined about 100 samples per day, almost one third of them got MDR. I would like to share
the data and learn more from TB experts in Stanford as well as other institute in USA
Dr. Tjandra Yoga Aditama SpP(K) DTM&H DTCE <[email protected]>
Jakarta, Jakarta Indonesia - Wed May 20 07:11:27 PDT 1998
Differentiate between MOTT and M.TB in extra pulmonary specimens. regards, Bela Oza
Bela Oza <[email protected]>
Vadadora, Gujarat India - Tue May 19 19:49:25 PDT 1998
diagnostic mycobacteriology; molecular typing of MTB; drug resistance surveillance programmes;
epidemiology of atypical mycobacterioses; Mycobacterium haemophilum
David Dawson <[email protected]>
Brisbane, Queensland Australia - Tue May 19 15:25:27 PDT 1998
Multidrug resistant tuberculosis,surveillance and management
Tulay Torun <[email protected]>
Istanbul, Turkey - Tue May 19 14:32:37 PDT 1998
Mycobacterium Avian Intracellular Complex, Pan Sinisitus, Pneumonia > 3 + Fx. Ribs < coughing
since 10/97 -- 4/15/98. Associated with Herpes Simplex I and systemic yeast--infections recently
diagnosed--Possible Occupational Exposure ?? HIV possible. Pet dog uthanized & checked for
above. Mother & friend also spent time w/ me checked for TB. What experience or info do you
have on this subject ? Thank You, [email protected]
J. Stutts <[email protected]>
White Plains, NY USA - Sun May 10 14:34:43 PDT 1998
I am working at Mycobacterial Laboratory which is also a WHO Collaborating Center in Jakarta Indonesia and a national top referral laboratory for our 200 million people country. We examined
about 100 TB samples every day, mostly using conventional method. I would like to share our
result and learn more about TB from the expert in UK and other European countries.
Dr Tjandra Y Aditama SpP(K) DTM&H DTCE <[email protected]>
Jakarta, Jakarta Indonesia - Fri May 8 23:15:05 PDT 1998
I am a graduate student working on " Novel immunodominant antigens of BCG-Tuberculosis
complex " interested molecular mechanisms granuloma formation, mycobacterial virulence and
impaired macrophage function. other interest include Rheumatoid arthriris, Stroke and cancer. Dr
Vinayak D Kanade, Dept of Microbiology and Cell Biology, Indian Institute of Science, Bangalore
560012, Karnataka State, INDIA.
Dr Vinayak D Kanade <[email protected]>
Bangalore , Karnataka INDIA - Sun May 3 09:57:15 PDT 1998
tb anything
Jeff Bauer <[email protected]>
New york, New york U.S.A - Fri May 1 18:18:36 PDT 1998
I am doing a term paper for Anatomy. I am a junior in high school. I am very interested in the
study of this disease. if applicable, please send me any info. Thanks.
H. Khan <[email protected]>
- Tue Apr 28 19:15:15 PDT 1998
Isoniazid, Serodiagnosis, Newer drugs, Culture methods, Slow release preparations of antiTB
drugs
Dr.Rajesh M.Ballal <[email protected]>
Nagpur, Maharashtra India - Tue Apr 28 04:01:16 PDT 1998
This is a really helpful web page.
Jasmine Lopez
Bellevue, IA U.S.A - Fri Apr 24 12:40:35 PDT 1998
(M. bovis)Tuberculin production, quality assurance, potency assay Animal (domestic and
exotic)tuberculosis diagnosis
Dr. Elizabeth Rohonczy <[email protected]>
Nepean, Ontario Canada - Fri Apr 24 09:53:44 PDT 1998
Found the web-site very useful in researching a project on TB Trends in Dudley, UK. Keep up the
good work everybody.
Simon Round
Wolverhampton, UK - Wed Apr 22 01:25:05 PDT 1998
Simon Round
Simon Round
Rapidly Growing Mycobacteria, SDS-PAGE of whole cell proteins of nontuberculous
mycobacteria, GLC for identification of mycobacteria, other molecular methods for identification
of mycobacteria.
Jaime Esteban <[email protected]>
Madrid, Madrid Spain - Tue Apr 21 05:53:50 PDT 1998
I'm a senior at Richard Stockton College of New Jersey. I'm working on a research paper for my
Molecular Genetics class I found MDR-TB to be a very interesting topic. I would appreciate any
input in this matter. Anything to do with Molecular Bio will be an asset.
Sunil Daniel <[email protected]>
Absecon, NJ USA - Sun Apr 19 19:40:09 PDT 1998
userdata 128.249.49.110
mo <[email protected]>
- Thu Apr 16 21:38:08 PDT 1998
Mycobacteria, multi-drug resistance, NAD biosynthesis, isoniazid catalase
Riccardi Giovanna <[email protected]>
Pavia, Italy - Thu Apr 16 07:21:31 PDT 1998
Occupational Medicine/Industrial Hygiene/Environmental Health especially related to health care
workers
Nicola Magnavita <[email protected]>
Rome, Italy - Sun Apr 12 08:05:48 PDT 1998
miliary: diagnosis, treatment Is imipenem ussefull in tb?
Jakob, Ernest <[email protected]>
Córdoba, Córdoba Argentina - Thu Apr 9 13:06:35 PDT 1998
Occupational Medicine / Industrial Hygiene / Environmental health - especially related to remote,
industrial construction locations.
Dennis J. Allen, CIH <[email protected]>
Birmingham, AL USA - Mon Apr 6 06:06:02 PDT 1998
Bacteria Viruses Infectous Disease
Adam Peteson <[email protected]>
CA USA - Sun Apr 5 11:41:41 PDT 1998
I am a doctor working at the National Research Hematological center. We are interested whether
you had got clinical cases of association of tuberculosis with pure red cell aplasia. We have just had
a patient who had been suffering for a long time of chronic lymphocytic leukemia ( T-cell origin).
She died of disseminated tuberculosis which was diagnosed only at autopsy.
Romanova Larisa <[email protected]>
Moscow, Russia - Fri Apr 3 01:01:10 PST 1998
I am a student at Monash University, Australia, keenly interested in the tuberculosis epidemic
which has re-emerged even in a drug resistant strain. I would be interested to maintain contact
with Stanford's development in TB research, as your commitment is well known.
Daniel Jontof-Hutter <[email protected]>
Melbourne, Victoria Australia - Thu Apr 2 20:02:21 PST 1998
research on: 1. new drugs 2. new vaccines (for primary disease and adult disease) 3. treatment
failures
Dr. Gina S. Itchon <[email protected]>
Cagayan de Oro, Philippines - Thu Apr 2 17:56:25 PST 1998
I want to have information about IgA determination by ELISA test ,usefull for diagnosis in
children tuberculosis.Also I can provide some results of research in Extrapulmonary tuberculosis,
and trends of bacteriological resistance in pacients from all the cities in Bolivia.
mirtha camacho <[email protected]>
La Paz, La Paz. Bolivia - Thu Apr 2 15:18:09 PST 1998
Hi... I'm writing a paper on paleopathology (New World) concerning tuberculosis from a zoonotic
perspective. Do you have any information concerning mammoth/elephant, bison, etc (pleistocene)
tb-man transmission? Thank you...Tammy
Tammy Grady <[email protected]>
Calgary, Alberta Canada - Wed Mar 25 12:06:24 PST 1998
tuberculosis; Surveillance; quintessential public health service; public health informatics;
Epidemiology
Sunitha V. Narayanan <[email protected]>
Moscow, Russia Russia - Tue Mar 24 08:57:19 PST 1998
I am a high school student I'd like some information about TB i can use in my research paper can
you help me?please?
Carrie Childers but its my dad's comp name <[email protected]>
gray, tn usa - Mon Mar 23 18:55:25 PST 1998
lawsuits regarding contracting t.b. @ employment. contracting @ correctional facilities. statute of
limitations. any other related topics or ideas.
roland gray <[email protected]>
Yigo, GU (guam) - Mon Mar 23 03:46:47 PST 1998
Need information on engineering and environmental controls for airborne infection isolation rooms
in health care facilities looking for research regarding anterooms
scott carroll <[email protected]>
little rock, ar usa - Thu Mar 19 14:48:09 PST 1998
nefrotoxicity of antituberculos drugs
Munteanu Mircea <[email protected]>
timisoara, timis Romania - Fri Mar 13 14:51:23 PST 1998
Serology culture resistant strains
Srinivasan P Dr <[email protected]>
Chennai, Tamilnadu India - Fri Mar 13 03:05:57 PST 1998
incidence and statistics on tb cases in the US and the world mdr tb statistics
jonel p. saludes <[email protected]>
manila, philippines - Thu Mar 12 02:46:10 PST 1998
I'm doing a research paper on Native American Health Services, I understand American Indians
have a history with the disease 'Tuberculosis'. Please write to me if there is any further
information. Sincerely, Lucynda Gorman
Lucynda Gorman <[email protected]>
Tempe, AZ US - Tue Mar 10 05:24:00 PST 1998
information on extrapulmonary tuberculosis especially the female reproductive system bone joints
Eroica Chmura <mailto:[email protected]>
- Mon Mar 9 10:28:49 PST 1998
i am a 8th grade student doing a report on tb and i would be glad if you would help me out and
send me info whenever it is possible. thank you very much billy
Billy Stewart <[email protected]>
dearborn hts., michigan united states - Sun Mar 8 20:02:26 PST 1998
I'm giving a speech on Tuberculosis on 3-11-98 and would like any information you might have on
case studies or any statistics regarding TB.
JoKasta McMillen <[email protected]>
Bridgman, MI USA - Fri Mar 6 11:23:56 PST 1998
I am doing a GNVQ and need research on TB and the people it effects.ASAP please.
Hannah Aylward <[email protected]>
London, England - Thu Mar 5 04:50:41 PST 1998
Public Health Lab Border Health MDR TB Mexicali, Mexico
Bob Freeman <[email protected]>
El Centro, CA USA - Tue Feb 24 08:23:44 PST 1998
Molecular interactions between MTB and human macrophage. MTB gene expression pattern
Francesca Mariani <[email protected]>
Rome, Italy - Thu Feb 19 01:58:30 PST 1998
I went to the gulf in 90/91. In March of 1997, I found out I was TB Positive after a positive skin test.
I completed the regimen of six months isoniazid. If you need someone for post treatment study, I'd
like to volunteer, and I'm in the area. Jonathan L. Hopwood
Jonathan L. Hopwood <[email protected]>
Menlo Park, CA US - Sat Feb 14 14:54:14 PST 1998
TUBERCULOSIS CUTANEAS
PRESEDO JULIO <[email protected]>
BUENOS AIRES, ARGENTINA - Sun Feb 8 20:50:28 PST 1998
I am a graduate student at the University of Georgia. I am currently working on an intervention
proposal for a Strategies of Health Promotion course. My interest is in examining TB in the South
African children population.
Preston Clark <[email protected]>
Athens , GA United States - Thu Feb 5 18:17:06 PST 1998
I am a graduate student at the University of Georgia. I am working on an intervention proposal for
a Strategies of Health Promotion course. My interest in examining TB in the South African
children population.
Preston Clark <[email protected]>
Athens , GA United States - Thu Feb 5 18:14:25 PST 1998
Tratamiento de Tuberculosis drogoresistente. Drugresistant Tuberculosis Treatment
Felix Canal <[email protected]>
Lima, Peru - Wed Feb 4 13:52:39 PST 1998
Data concerning incidence of suspect/confirmed infectious Tb in the long-term health care setting
(e.g. skilled nursing and assited living facilities).
Chris Davis <[email protected]>
Gaithersburg, MD - Wed Feb 4 08:53:19 PST 1998
TB clinic Follow-up of patients on anti-TB medication Treatment of MRTB
Dr. Gilles Blanchette <[email protected]>
Montreal, Quebec Canada - Tue Feb 3 18:48:53 PST 1998
I'm in the 8th grade and doing a Science Fair Prject on TB. Please provide me with any
information possible by the end of the week.
William Kipp <[email protected]>
Springfield, Illinois USA - Mon Feb 2 19:54:42 PST 1998
I am undertaking a Masters Degree in Health Economics and have chosen Tuberculosis as my
subject in order to cost new drugs against predicted benefits to the health service.
David H Higgins <[email protected]>
London, England - Mon Jan 26 06:27:23 PST 1998
FL Department of Corrections Office of Health Services, Environmetal Health 2601 Blair Stone RD
Tallahassee, FL 32399-2500
Gregory S. Redmon <[email protected]>
Tallahassee, FL US - Fri Jan 23 06:43:38 PST 1998
molecular typing methods, rapid identification of drug resistance
Beate Heym <[email protected]>
Paris, France - Thu Jan 22 02:34:48 PST 1998
Immunopathology of TB Efficicy of Anti-TB Vaccine
Feng Pei Zhong <[email protected]>
Beijing, China - Wed Jan 21 19:16:15 PST 1998
Recurrence How would TB be identified if it were to recure? Ten years post can TB re-appear, the
patient followed the TB drug program and no further problems related to TB. Currently there
appears to be a small spot on the lung. Not able to preform biopsy. Could it be TB?
Eliot Bernstein <[email protected]>
CDM, CA usa - Wed Jan 21 08:24:15 PST 1998
TB infection control public health issues worker exposures conversion rates in general population
Teresa A. Caruthers <[email protected]>
Washington, DC US - Wed Jan 21 08:05:36 PST 1998
Diagnostic Tests for Tuberculosis
Gavin Horrigan, CSL Biosciences <[email protected]>
Melbourne, Victoria Australia - Mon Jan 19 05:02:15 PST 1998
Diagnostic Tests for Tuberculosis
Gavin Horrigan, CSL Biosciences <[email protected]>
Melbourne, Victoria Australia - Mon Jan 19 05:01:07 PST 1998
I'm innterested in "Tuberculosis" and I would like to have more inforamtion on it. If it's possible
plese send a couple of pages I don't mind Martin Ronnig
Martin Ronning <[email protected]>
Brussels, Belgium - Mon Jan 19 01:57:36 PST 1998
Patient education, college health issues, promotion of skin testing, skin testing results and
medications used.
Jo Buczko <[email protected]>
Pasadena, CA USA - Sun Jan 18 11:34:40 PST 1998
Patient education, college health issues, promotion of skin testing, skin testing results and
medications used.
Jo Buczko <[email protected]>
Pasadena, CA USA - Sun Jan 18 11:34:22 PST 1998
Epidemiology of tuberculosis
Prikazsky Vladimir, M.D. <[email protected]>
Prague 10, Czech Republic - Sun Jan 18 08:40:58 PST 1998
Tuberculosis of the fpine Tuberculosis of the potts
Jess dela Merced <[email protected]>
Pasig, Philippines - Thu Jan 15 21:23:08 PST 1998
Interested in finding a position as a research assistant for Summer 98 in San Francisco area. I am
currently attending Bryn Mawr College' s postbaccalaureate pre-medical program and have some
additional reasearch/lab experience. I graduated from Princeton University in 1996, and I am
entering Jefferson Medical College in the fall. Would love suggestions from those already immersed
in research as to how they found their wonderful positions. Thanks.
Laurie Gustafson <[email protected]>
- Mon Jan 12 12:36:37 PST 1998
international opportunities- I am a 2nd year veterinary student who would like to help with
research abroad (preferably epidemics in impoverished countries) during the summer months of
1998
Lena Gutberlet <[email protected]>
Blacksburg, VA usa - Mon Jan 12 09:18:16 PST 1998
international opportunities- I am a 2nd year veterinary student who would like to help with
research abroad (preferably epidemics in impoverished countries) during the summer months of
1998
international opportunities- I would like to help with research abroad during the summer months
of 1998
I would be grateful for any information relating to the instance of TB in Ireland, past and present,
general information on TB would be likewise valuable. Thanking you, in anticipation....
Edel <[email protected]>
Co.Kildare, Ireland - Mon Jan 12 05:31:13 PST 1998
Hey, cool page here. Yah, well THAT'S ALL hahahahahahaha yelling's DUMB!!!
Ben Jones <[email protected]>
Pitwomen, New Jersey USA - Sun Jan 11 14:55:46 PST 1998
social impact of tuberculosis in urban areas
Amy Harrington <[email protected]>
- Sat Jan 10 22:56:34 PST 1998
MDR Tuberculosis
Dr. S. Martínez-Selmo <martí[email protected]>
Santo Domingo, Distrito Nacional Dominican Republic - Sat Jan 10 18:47:49 PST 1998
Interests: Tuberculosis in Colorado throughout history We need some information, please!!!!
jessica Perino <[email protected]>
Durango, Co USA - Sat Jan 10 15:02:46 PST 1998
Antimocrobial Susceptibility Testing
Ron Dudek <[email protected]>
Hercules, CA USA - Thu Jan 8 18:56:13 PST 1998
TB in other organs than lungs.
Loriane Frewing <[email protected]>
Langley, B.C. Canada - Thu Jan 8 13:30:29 PST 1998
Dear Sirs: Be very pleased of directing me you with motive of requesting informacion on the
disease called granuloma tuberculosis or tumor endumedular, the request is due to that I have to a
relative with that disease and wanted to know of the fact that is tried and which isyour cure. From
already I thank your time, and I wait prompt response.
Ariel Pola <[email protected]>
Godoy Cruz, Mendoza argentina - Thu Jan 8 05:14:58 PST 1998
I don't have a comment at this point, but ask me later.
MMMMM....I Forgot <[email protected]>
Crazyville, Calafornia (DUH!!!) - Mon Jan 5 20:18:58 PST 1998
Please inform me if my newborn is at risk of contracting TB. My uncle has TB that recently
became active again after being dormant for a number of years. If my baby comes in contact with
him, is it likely, or possible, that it will infect my son? Please reply as I am very concerned and will
keep my son away from my uncle if I have to. Thank-you.
Traci Lizotte <[email protected]>
Chilliwack, BC Canada - Mon Jan 5 20:11:41 PST 1998
Environmental Health & Safety
Joe Rizkallah <[email protected]>
Long Beach, California USA - Mon Jan 5 17:53:53 PST 1998
Drug resistance tuberculosis serveilance and management
Dr.Md.Rabiul Hossain <[email protected]>
Dhaka, Bangladesh - Fri Jan 2 17:09:46 PST 1998
I would like to know about tuberculosis on the skin, because two years ago I had that problem. I
need to know if I'm going to have more problems when I´ll decide to become mother.I finish my
treatment, but sometimes I have some little samples of Tb.
Lucia Diaz <[email protected]>
Mexico, D.F Mexico - Fri Jan 2 14:00:57 PST 1998
Alternative approaches to TB control (esp. MDR)
Sudeep Rao, M.D. <[email protected]>
Baltimore, MD U.S.A - Fri Jan 2 13:16:07 PST 1998
tuberculosis of urogenital tract the evolution prognosis and treatment i am doing research on these
topics and would be thankful if you can guide me to obtain some information thank you and a
happy new year
bafiq nizar <[email protected]>
constanta, constanta romania - Fri Jan 2 04:51:04 PST 1998
Drug resistant strainsof TB currently in proliferation, research, discoveries, etc...
James McMurray <[email protected]>
Venice, CA. U.S.A. - Wed Dec 31 19:58:18 PST 1997
I need informations about the transmission of TB.Ihad some cases in my family and i would like to
know how to stop the transmission thanks.
francis <[email protected]>
yaounde, cameroun - Wed Dec 31 08:38:20 PST 1997
i like your web page it was very helping to me in my TB reort thanks a lot . keep trying to find a
cure and update this site asap . thank you so much , dominkue
dominikue
whitehaven , pa usa - Mon Dec 29 15:58:36 PST 1997
tuberculosis, cyclopropyl mycolic acids, treatment, mode of action, dormant bacilli,
d taylor <[email protected]>
adelaide, south australia australia - Mon Dec 29 15:42:32 PST 1997
Diagnosis; Diagnosis by Polimerase Chain Reaction
Claudia Morais <[email protected]>
Coimbra, Portugal - Fri Dec 26 11:52:31 PST 1997
tuberculosis mdr and dr tuberculosis
JACINTA GRACE-PARKER <[email protected]>
london, United kingdom - Tue Dec 23 09:03:52 PST 1997
I'm interested in contacts study of tbc patients. Do you have any protocol? QP of contacts in tbc
resistant cases (INH,...)
Neus Camps Cura <[email protected]>
Girona, catalonia spain - Mon Dec 22 11:51:43 PST 1997
I'm very interesting in coinfection HIV-M.tuberculosis in penitentiary population. I'm working in
temporal trend of coinfection HIV-M.tuberculosis in penitentiary pooulation of Spain.
Vicente Martin Sanchez <[email protected]>
24005 LEON, SPAIN - Mon Dec 22 09:31:54 PST 1997
I am very intersted in the system regerding the care of TB patients especially highly infectious Pts.
in USA. Do most of hospitals have isolation wards or how to isolate these pts from other
immunocompromised pts?
Shuji kurane, M.D. <[email protected]>
Tokyo, JAPAN - Sun Dec 21 10:01:21 PST 1997
Tuberculosis, mycobacteria, BCG vaccination
Victoria Romanus <[email protected]>
Stockholm, Sweden - Thu Dec 18 05:58:21 PST 1997
I need info.
Andrew Rosenthal <[email protected]>
Wilmette, Illinois USA - Tue Dec 16 17:31:51 PST 1997
Necesito información sobre tuberculosis y brucella en bovinos para titulación de medicos
Veterinarios
mvz. mercedes guillermina nuñez gutierrez <[email protected]>
guzmán, jalisco mexico - Tue Dec 16 13:25:32 PST 1997
Am interested in TB pathology and prevention particularly pertaining to prisons in developing
countries.
Adrienne Acomb <[email protected]>
Washington, DC USA - Thu Dec 11 12:35:10 PST 1997
TB and homelessness
Theresa Butler <[email protected]>
- Wed Dec 10 12:24:51 PST 1997
Diagnostics
Maria Scully <[email protected]>
Buffalo, NY USA - Wed Dec 10 05:44:15 PST 1997
I would appreciate any information on TB possible. Especially pictures dealing with the bacteria
and patients
Abigail Nickel <[email protected]>
College Station, Texas USA - Wed Dec 10 02:08:43 PST 1997
State Tuberculosis Program Manager - All areas
Kim Field <[email protected]>
Olympia, Washington USA - Tue Dec 9 14:43:42 PST 1997
Encapsulated TB
Melody Becker <[email protected]>
Whitehouse, TN USA - Mon Dec 8 12:08:26 PST 1997
I am pregnant and I saw that having lupus could affect my pregnancy. I don't know of having
lupus and I don't know much about it. I was trying to find out how you get tested for it.
Brandi Donley <[email protected]>
Grand Rapids, Michigan U.S.A. - Mon Dec 8 09:39:00 PST 1997
Any expert information pertaining to the residual effects of pneumo-throax treatments on the heart
muscle. Please respond. This information would be very important to me and my family.
Forrest Stephanian <[email protected]>
- Sun Dec 7 19:07:01 PST 1997
I am a ninth grader conducting a research project pertaining to drug-resistand TB. I am in need of
primary research and secondary research. If you can help, thank you.
James Waters <[email protected]>
New York, New York USA - Sun Dec 7 15:38:55 PST 1997
Molecular Genetics of Tuberculosis
Manu Deeudom <[email protected]>
Fort Collins, Colorado USA - Thu Dec 4 14:06:35 PST 1997
I like your homepage! Good design! If you have time, come to our german homepage. Hallo,
herzlichen Glückwunsch zur gelungenen Homepage. Ausgesprochen gutes Design. Auf jeden Fall
eine Bereicherung fürs Netz. Hoffentlich kommen noch viele Besucher vorbei. Mit einem
freundlichen Gruß aus Deutschland!
Erich
Berlin, DDR - Wed Dec 3 17:46:39 PST 1997
Hi I am a child from I.E Weldon I am doing a project on Tuberculosis My Grandma has the
disease I was wondering if any of you could e-mail me with some websites or information on the
disease at [email protected] Thank you
Brad Frost <[email protected]>
Norwood, Ontario Canada - Mon Dec 1 10:25:41 PST 1997
I am doing a report on tuberculosis and would like to find some more information. especially
primary sources, like people that had the disease or that live with it today.
Lmeister <[email protected]>
Minneapolis, Minnesota USA - Thu Nov 27 11:51:44 PST 1997
tuberculosis in general atypical mycobacteria and treatment
H.P.J. Daemen <[email protected]>
Eindhoven, The Netherlands - Tue Nov 25 05:44:00 PST 1997
-We are interested in pharmacokinnetics of tuberculostatic drugs in AIDS patients. -Also, we are
researching in DOT prophylaxis in drug users with isoniazid twice weekly.
j. portilla <[email protected]>
alicante, spain - Mon Nov 24 16:52:18 PST 1997
TB fascinates me!!!! I am a second year medical student at Mayo Medical School. I am currently
seeking a position with a team researching TB in an endemic area. I am a hard worker and very
committed. Please contact me if you are aware of any potential projects. Thank you!!! Sue
Susan Kearney <[email protected]>
- Sun Nov 23 14:32:00 PST 1997
We've reported three of the first short course tratment reports of TB/HIV in Peru, case control
study. We need more information about local experiencies with 6 months/four drugs/short course
TB treatment
Oswaldo Jave Castillo <[email protected]>
Lima, Lima Peru - Tue Nov 18 13:33:25 PST 1997
HIV/TB Multidrug-resistant TB Short course treatment Molecular epidemiology Third World
TB/HIV research
Oswaldo Jave Castillo <[email protected]>
Lima, Lima Peru - Tue Nov 18 12:35:57 PST 1997
Looking for info about how M.Tuberculosis escapes the immune system and develops into TB
disease
Margarida Monteiro <[email protected]>
Almada, Portugal - Sat Nov 15 11:09:02 PST 1997
I don't have any comments at this time.
Corey Zadlo <[email protected]>
Chicago, IL USA - Fri Nov 14 12:38:05 PST 1997
Personal experience of having TB
Diane Morris <[email protected]>
Mt. Vernon, Tx USA - Wed Nov 12 08:14:55 PST 1997
tuberculosis, drug resistance, transmission, and treatment.
Scott Richardson <[email protected]>
sorrento, la usa - Sat Nov 8 09:33:13 PST 1997
I am interested in any materials on tuberculosis.
Jill Sanders <[email protected]>
Stevens Point, WI USA - Tue Nov 4 12:10:36 PST 1997
INFORMATION REGARDING TUBERCULOSIS RESEARCH
Dr.V.VISHWANATH <[email protected]>
FERRARA, ITALY - Tue Nov 4 07:01:12 PST 1997
I'm doing my BSc Genetics and biochemistry at the university of Wales, Aberystwyth. I am
interested in the treatment to TB and in its future research into new treatments for MDR-TB.
Karen Barker <[email protected]>
Ceredigion, Wales UK - Fri Oct 31 08:42:37 PST 1997
I have an uncle who is diabetic and was diagnosed lately to have potts disease. Is potts disease
curable in this case? Or is it more likely to spread through the rest of the body? Thanks in advance.
Mostafa Afifi <[email protected]>
Helioplis, Cairo Egypt - Fri Oct 31 01:59:12 PST 1997
I'm spanish from Barcelona. I'm working in Tuberculosis recombinant vaccine. I'm very interested
to work in New york city the next year 1998, due to my wife's work. I 've got a grant, then the
economic source is already solved for next year 1998. Please contact with me if you are interested in
my collaboration. Thank you very much. All together will fight against tuberculosis.
Dr. Juan Joseph Munne MD PhD in Medicine <[email protected]>
Barcelona, Catalunya Spain - Thu Oct 30 16:03:23 PST 1997
I'm spanish from Barcelona. I'm working in Tuberculosis recombinant vaccine. I'm very interested
to work in New york city the next year 1998, due to my wife's work. I 've got a grant, then the
economic source is already solved for next year 1998. Please contact with me if you are interest in
my collaboration. Thank you very much. All together will fight against tuberculosis.
Dr. Juan Joseph Munne MD PhD in Medicine <[email protected]>
Barcelona, Catalunya Spain - Thu Oct 30 15:57:02 PST 1997
I've recently started my Ph.D. at McGill University in genetic susceptibility of tuberculosis in
humans. I'm interested in becoming a part of the TB network of researchers.
Suneil (Neil) Malik <[email protected]>
- Sat Oct 25 11:42:15 PDT 1997
M. avium complex drug therapy...My aunt has developed complications from miliary TB and
M.avium complex, and cannot tolerate the current drug therapy...please send any information on
any and all options for treating this terrible disease.
Connie Koch <[email protected]>
Arden, NC USA - Wed Oct 22 07:29:21 PDT 1997
M. avium complex drug therapy
Connie Koch <[email protected]>
Arden, NC USA - Wed Oct 22 07:24:58 PDT 1997
Looking for Global statistics on TB in 1997
Dr. Shagufta Iram <[email protected]>
Lahore, Pakistan - Sun Oct 19 01:43:28 PDT 1997
Latent infections, interaction with HIV
Gale W. Newman, Ph.D. <[email protected]>
Atlanta, GA US - Fri Oct 17 11:43:03 PDT 1997
I am in need of information about diagnostics for hydatidosis and statistics about hydatidosis in
Peru. And some epidemiology, please. Thank you.
Alfonso Barnechea <[email protected]>
Lima, Lima Peru - Wed Oct 15 15:47:34 PDT 1997
On the queries, the replys are not there....
Joanna McGinn <[email protected]>
- Fri Oct 10 12:54:48 PDT 1997
DNA fingerprinting (by RAPD) of Mycobacterium tuberculosis strains to determine if MTB strains
corelate with epidemiological groups in patients which would assist in successfully seeking TB
contacts.
Cynthia B Fisher <Fisher.Cynthia@bay_pines.va.gov>
Bay Pines, FLorida USA - Fri Oct 10 09:28:56 PDT 1997
RFLP, virulence, resistance. Molecular Mecanisms of Mtb resistance. Methods for detection
Jose C. Palomares <[email protected]>
Seville, Spain - Sat Oct 4 14:01:03 PDT 1997
ANY INFORMATION ABOUT SOLVENT OR VOLATILE ORGANIC COMPUND AND
PULMONARY TUBERCULOSIS, WORK EXPOSURE
DR. JOSE LUIS ROBLES L. <[email protected]>
matamoros, tamaulipas mexico - Mon Sep 29 20:14:50 PDT 1997
immunology of TB secreted proteins vaccines
Dr.S.Vijaya <[email protected]>
Bangalore, Karnataka INDIA - Fri Sep 26 08:51:19 PDT 1997
Molecular mechanisms of intracellular survival Molecular mechanisms of resistance to ethambutol
Vincent Escuyer <[email protected]>
Paris, France - Wed Sep 24 01:33:03 PDT 1997
Thanx for helping me with my informative speech on TB!
Kari Nygaard <[email protected]>
Sioux Falls, South Dakota USA - Tue Sep 23 11:37:05 PDT 1997
Veterinarian with canine patient with avian tuberulosis. Interested in any information on canine
tuberculosis.
Kirsten Leach <[email protected]>
Taupo, New Zealand - Sat Sep 20 16:12:11 PDT 1997
I am a nursing student who is concerned with 2 fellow class mates that have tested positive on a
PPD test several years ago, one was tested twice and had a severe reaction. They were told various
things form they cannot take meds, to the meds will make their hair fall out, to they are healthy
enough they should be okay. Each is in mid 20s early 30s. Any information would be helpful.
Sarah Lieberenz <[email protected]>
Midland, Texas USA - Thu Sep 11 22:20:38 PDT 1997
Tuberculosis in Native Americans
Miles Rudd, MD <[email protected]>
Warm Springs, OR USA - Wed Sep 10 23:18:06 PDT 1997
VIRULENCE/PATHOGENECITY, ELICIT PROTECTIVE IMMUNE RESPONSE,
ZHUQING LI <[email protected]>
TOLEDO, OHIO, 43699 U.S.A. - Tue Sep 9 08:48:47 PDT 1997
Doctoral research Research Hypothesis: A culturally-sensitive health education intervention will
have an effect upon knowledge of tuberculosis and behaviors related to the incidence of
tuberculosis among the Bemba of sub-Saharan Africa. Date to begin research: January 1999.
Estimated length: Six months. Funding needed: $20,000 (inclusive of round-trip transportation and
cost of living in Zambia). Does anyone know of a funding source? Thank You.
Marie G. Heithmar <[email protected]>
Valrico (near Tampa), Florida U.S.A. - Tue Sep 9 08:41:20 PDT 1997
We are interested to start a pilot study concerning the treatment of tuberculosis in the county of
Iasi (Romania). We have already obtained the support of the WHO. Dr Traian Mihaescu Clinic of
Pulmonary Diseases 30 Dr I Cihac St Iasi 6600 Romania tel:+40.32.214406 fax:+40.32.213532
Traian Mihaescu <[email protected]>
Iasi, Romania - Sun Sep 7 03:58:45 PDT 1997
tuberculoma
flora samwel <[email protected]>
dar es salaam, tanzania - Sun Aug 31 05:48:23 PDT 1997
HIV Methadone maintenance programs Heroin on prescription AIDS Society of Kamloops
/Methadone Advocacy & Advisory Group
John Anderson <[email protected]>
Kamloops, British Columbia Canada - Tue Aug 26 15:45:27 PDT 1997
pathophysiology of tb. how to diagnose(symptoms)
Tseliso Nkuebe <[email protected]>
Durban, South Africa - Sat Aug 23 09:52:31 PDT 1997
-all aspects of TB, currrently invloved in Community Health program at the Ubniversity of Natal
as a medical Student
Naeem Sader <[email protected]>
Durban, KwaZulu/Natal South Africa - Sat Aug 23 09:48:19 PDT 1997
I am interested in communicating with anyone who has treated TB-meningitis or has suffered from
it. Please contact me at [email protected] or 714-824-4971
Julia Gelfand <[email protected]>
Irvine, CALIF USA - Mon Aug 11 10:48:36 PDT 1997
I am involved in a project which deals with the effect of UV light on the nosocomial transmission of
MTB and would like information related to the topic.
Tracey <[email protected]>
Durban, Natal South Africa - Mon Aug 11 06:18:09 PDT 1997
I work in the area of image processing/rcognition and I am very interested in acquiring a large
dataset of slides or digitised images from slides of both ZN-stained and auramine-stained TB bacilli
in sputum.
Colin Campbell <[email protected]>
Bristol, Avon England - Mon Aug 11 02:43:26 PDT 1997
Interested in collaborating on TB research projects. Diagnosis, novel therapies
Dr. Alexander D. Simidchiev <[email protected]>
Sofia, Bulgaria - Fri Aug 1 14:51:41 PDT 1997
I might have TB and need to knnow more info about the disease.
Debbie Taillon <[email protected]>
Stittsville, Ontario Canada - Fri Aug 1 09:17:59 PDT 1997
I need information about : molecular biology mycobacterium thuberculosis
VIVIANA DADOR M.D. <[email protected]>
lima, peru - Mon Jul 28 10:46:22 PDT 1997
I am looking for a suitable post-doc position. Have extensive experience in the field of tuberculosis
for the past 10 years. Have experience in Immmunology, Microbiology, Mol. Biology &
Biochemistry. Have developed Immunodiagnostic tests for tuberculosis.
Dr. Mythili Kameswaran <[email protected]>
Bombay, Maharastra India - Mon Jul 28 00:16:08 PDT 1997
I major in clinical pathology, especially microbiology. In korea, patients with active tuberculosis
are about 1% of all population. So, I have a great interest in tuberculosis. I have studied the
usefulness of TB PCR for the diagnosis of tuberculous meningitis. I would like to exchange opinions
on molecular diagnosis and epidemiologic studies.
Jae-Seok Kim, M.D. <[email protected]>
Seoul, Korea - Sun Jul 27 05:26:34 PDT 1997
Diagnosis, prevention and treatment of tuberculosis. Identification of species and strain specific
DNA sequences. Methods for isolation of mycobacteria from clinical samples.
Lakshmi Kantham <[email protected]>
Hawthorn East, Vic 3123 Australia - Thu Jul 24 22:39:15 PDT 1997
tuberculosis vaccines and cytokine responses
Robert G. Townley M.D. <[email protected]>
Omaha, NE USA - Tue Jul 22 16:26:37 PDT 1997
I am currently doing research on therapy for MDR-TB resistant to the usual triple Anti-Koch's.
Any form of help is highly appreciated. Thanks!
Dr. Leonard Lao <[email protected]>
Caloocan, Philippines - Tue Jul 22 05:44:51 PDT 1997
This is a Very Nice Site!...Come visit us at World Association of Persons with Disabilities [WAPD]The Sleeping Giant is waking up! HELP you give TODAY is HELP you get Tomorrow..... BE A
PARTNER!
George Kerford, President/CEO [WAPD] <[email protected]>
San Antonio, Texas USA - Sat Jul 19 13:59:00 PDT 1997
I am from Pakistan and working with tuberculosis for last four years. Ihave worked both with
immunology and molecular pathology of mycobacteria. I have optimized the diagnosis of
extrapulmonary tuberculosis from blood and have successfully applied the techniqu to the
diagnosis of 120 clinical isolates (paper in preparation) Besides this I have also done molecular
epidemiology of tuberculosis using both Is6110 and Is 1081 for the differentiation of organism
within tuberculosis compelex and for the differentiation between M.bovis and Mtuberculosis.
Currently Iam working with the Mtp40 gene. Iam intrested in doing my Phd and persuing my
work in the same field. I am intrested in looking at the intracellular signalling followed by
phagocytosis of tubercel bacillie. If you have any ongoing projects in the related areas please
contact me.
Shaper Mirza <[email protected]>
birmingham, Alabama united States - Fri Jul 18 14:39:07 PDT 1997
Mechanism of phagocytosis of Mycobacteria by macrophages Gallium as Treatment
Aniva Orava <[email protected]>
- Tue Jul 15 19:38:37 PDT 1997
I am working in the field of paleopathology at the department of anatomy (University of
Göttingen). I am interested in bone alterations of the internal surface of the skull caused by
tuberculosis. At the moment I am investigating a medieval skeletal population from Germany.
Many skulls show signs of meningeal tuberculosis. I would like to have more information about
recent cases of meningitis caused by tuberculosis, because we would like to compare our
histological specimens with specimens from recent cases.
Thorsten Schlomm <[email protected]>
Göttingen, Niedersachsen Germany - Mon Jul 14 13:43:27 PDT 1997
especially multiresistant tuberculosis strains in Balkans I'm from the European part of Turkey
Metin Otkun <[email protected]>
Edirne, Turkey - Mon Jul 14 10:33:14 PDT 1997
I am working in epidemiology of tuberculosis in Cajamarca Peru, with PPD inmunoreaccion
research in all this area also with Hystoplasmin an Paracoccidioidin, .My research also involve
Intestinal Parasites and anothers as Cysticercosis, Fasciolasis, Hydatidosis etc.I need information of
the last foundings in this subjects in Peru.
Zoila Villavicencio de Muck <[email protected]>
Cajamarca, Cajamarca Peru - Sat Jul 12 17:31:14 PDT 1997
I would like to receive information on BCG revaccination and protection against tuberculosis BCG
revaccination tuberculosis immunity tuberculosis and vaccines
Reinaldo de Menezes Martins <[email protected]>
Rio de Janeiro, RJ Brazil - Tue Jul 8 19:18:36 PDT 1997
Actually I am researching in multiresistent patients with TB treatment. I would like to receive any
information about this.
Carlos Manuel Young <[email protected]>
Guatemala, Guatemala Guatemala - Tue Jul 8 14:35:39 PDT 1997
Estoy interesado en la epidmioogía de la tuberculosis. Saludos
Santiago Rubio <[email protected]>
Zaragoza, Spain - Mon Jul 7 10:21:24 PDT 1997
I am interested on TB molecular diagnosis
Dr.Khalid M. Bindayna <[email protected]>
Bahrain - Wed Jul 2 08:17:13 PDT 1997
I´m a student of medicine, I have to make a paper of TBC, epidemiolgy, drug resistance, and terapy
of TBC (PAHO protocol )
Juan Gallegos Flores <[email protected]>
Arequipa, Perú - Sat Jun 28 11:25:16 PDT 1997
I am a physician at the childrens infectious hospital in St. Petersburg, Russia. I specialize in TB &
minengitis. I would like to discuss surgery applications for the treatment of TB. I am in San
Francisco, CA from July 7-16th and from July 30 to Aug 9, 1997. I would like to discuss surgical
treatment of TB with you. I have had several succesful cases and I would like to discuss & share
this information with you. In CA my telephone number is 415-592-1397. I would like very much to
visit Stanford and view your facility. Best regards Lioudmila Klotchkova
Lioudmila klotchkova <[email protected]>
Belmont, CA USA - Fri Jun 27 15:19:24 PDT 1997
Diagnostic mycobacteriology. Microcolonies detection on Middlebrook 7H11 agar. Rapidly
growing mycobacteria
Jaime Esteban <[email protected]>
Madrid, Spain - Thu Jun 26 05:45:13 PDT 1997
I am a MS student and want to pursue a PhD degree in TB research. My research
interests.(1)RFLP analysis of M.tuberculosis.(2)Multi-drug resistance of
M.tuberculosis.(3)Detection of M.tuberculosis by PCR (4)Molecular epidemiology of TB. ***The email user's name is not Chuntao Wu,but Qi-lun Sun. Thank you.
Chuntao Wu <[email protected]>
Beijing, P.R.China - Sun Jun 22 03:57:03 PDT 1997
Diagnosis and treatment
Maria Luigia Lamona <[email protected]>
Caracas, Distrito Federal Venezuela - Mon Jun 16 18:24:23 PDT 1997
tuberculosis:resistance BK (primary and secondary) cancer bronchopulmonary (brachytherapy)
dr. Ciobanu Doru Traian <[email protected]>
Brasov, ROMANIA - Sat Jun 14 01:31:29 PDT 1997
BCG; Tuberculosis innoculations;
Gerri Hynes <[email protected]>
Burlington, Ontario Canada - Fri Jun 6 20:27:01 PDT 1997
Sensitivity of tuberculosis agent to UV-A exposure.
Derek Griffith <[email protected]>
Pretoria, Gauteng South Africa - Wed Jun 4 14:04:33 PDT 1997
More zero band strains of M.tb exists in South India. DR probe has been found to be the ideal
probe for molecular typing of M.tb. Key words: Mycobacterial virulence genes, promoters,
intracellular survival.
Dr. R. Sahadevan <[email protected]>
Madras, Tamil Nadu India - Sat May 31 04:43:56 PDT 1997
Study Results of UV Light Technologies, Management of DOT & DOPT, Community Healthcare
Epidemiology Issues
Kevin A. Gritzke <[email protected]>
St. Louis, MO USA - Tue May 27 17:35:25 PDT 1997
EthnoBios S.R.L. is a small biotech company located in Bolivia working with medicinal plants that
have a history of traditional usage. At this time we are working with the sap of a plant that has a
history in treating TB, rheumatoid arthritis annd verruges. Studies have suggest that this product
induces differnt effects on sveral phases of the immune response which may be compatible with the
reported capacity to resolve the TB process. In addition, these effects (stimulation of splenocytes
and modulation of the marcrophages activity) lead to consider this substance as a promising
candidate to further studies and application as an immunomodulatory product. We have another
that is just as interesting but I have already writen more than a "few lines." Sorry. If anyone is
interested please contact me at [email protected] We lack funding to continue our studies so
any info. would be apprecialted. Thanks, Joseph C. Traini
Lic. Joseph C. Traini <[email protected]>
La Paz, La Paz Bolivia - Tue May 27 12:10:02 PDT 1997
38-kDa antigen, 16-kDa antigen, Diagnosis, Vaccine, TB molecular bilogy
Zengyi Chang, Ph.D. <[email protected]>
Beijing, P.R.China - Thu May 22 16:05:41 PDT 1997
Louisiana Office of Public Health employee in Tuberculosis Control Program interested in learning
more about TB diagnosis and treatment.
Richard Adams <[email protected]>
New Orleans, LA USA - Sun May 18 20:35:21 PDT 1997
INH therapy and longivity further testing once treated
Dawn Bisenius
Peoria, Illinois USA - Sun May 18 20:05:57 PDT 1997
I'm a graduate student who is prepareing a paper on the resurgence of TB and it's effects on the
community. Any information that can be obtained would be very much appreciated
Leslie F. Dowers <Sansouci22>
Rosedale, New York U.S.A. - Sun May 18 19:19:33 PDT 1997
Synthetic organic chemistry. Preparation of tuberculostatic agents having enhanced lipophilicity.
Preparation of antimicrobials having multiple tuberculostatic moieties in one chemical structure.
Near infrared spectroscopy for the analysis of tuberculosis antimicrobials.
M. J. Hearn <[email protected]>
Wellesley, MA USA - Sun May 18 07:22:01 PDT 1997
I would like to receive the lattest news about tuberculosis and the co-infection with AIDS. I´m a
brasilian pulmonologist that work with TB/AIDS. Thank you for your help
Enio Pires Studart <[email protected]>
rio de janeiro, RJ Brasil - Sat May 17 15:33:18 PDT 1997
Mycobacterial genetics and pathogenesis
Ed Swords <[email protected]>
Atlanta, GA USA - Fri May 16 11:42:53 PDT 1997
Use of HPLC for species identification of mycobacteria, susceptibility testing and epidemiology.
David Fett <[email protected]>
madison, wi wi - Thu May 15 13:00:37 PDT 1997
Gene expression of Mycobacteria. analysis of limiting amounts of RNA using novel techniques.
Microarray hybridization to study gene expression patterns.
Joe Mangan <[email protected]>
London, England - Wed May 14 08:22:48 PDT 1997
I am a PhD student in Economics at the University of York. analysis of the spread and control of
tuberculosis in developing countries (case study: South - Africa), mathematical models of
population dynamics, rural-urban migration (** edited for length **)
Doriana Delfino <[email protected]>
York, UK Europe - Mon May 12 11:32:32 PDT 1997
Protein Crystallography, Structure-based drug design, Identification of Novel drug targets in
M.tuberculosis, Understanding the molecular mechanisms of drug resistance in tuberculosis,
evolution of TB as well as that of drug resistant species.
Shekhar C. Mande <[email protected]>
Chandigarh, INDIA - Sun May 11 02:12:51 PDT 1997
I work as Lecturer in Preventive and Social Medicine in Government Medical College, Nagpur,
INDIA. My interests are DOTS and epidemiologic models of tuberculosis.
Hemant Kulkarni <[email protected]>
Chapel Hill, North Carolina USA - Sat May 10 13:20:44 PDT 1997
My academic unit has a growing program of TB research (Adult and pediatric) both in London
and in Central Africa. The work encompasses immunology, epidemiology, immunotherapy and
pathology. Keywords: TB, Adult, Pediatric, Central Africa, London, Epidemiology, immunology,
microbiology
Dr.Alimuddin Zumla PhD.MD.FRCP <[email protected]>
London W1P 6DB, United Kingdom - Sat May 10 06:04:35 PDT 1997
TB-HIV; TB prevention and control in Latin America
Kathy DeRiemer <[email protected]>
Brasil - Fri May 9 21:52:39 PDT 1997
Access to TB care / control programmes in developing countries
Dr Bertie Squire <[email protected]>
Liverpool, U.K. - Fri May 9 01:46:48 PDT 1997
Pathology of T.B, Fingerprinting, PCR for diagnosis of T.B from PBMC.
Shaper Mirza <[email protected]>
Birmingham, AL USA - Wed May 7 14:51:20 PDT 1997
I am a respiratory care student interested in information about TB. I am especially interested in
the connection between AIDS and TB.
Heather Hall <[email protected]>
Indianapolis, Indiana USA - Tue May 6 20:42:20 PDT 1997
I am a 16 year-old high school student from Denver who is interested in learning about TB and the
reasons for its resurgence in the past ten years, as well as multi-drug resistant tuberculosis. If
anyone has information on this topic, it would be much appreciated.
Merrill Abrams <[email protected]>
Denver, CO USA - Mon May 5 13:34:05 PDT 1997
I am particularly interested in multi-drug resistant TB, DNA based assay for rapid detection of
multidrug-resistant TB or rifampin resistant strains, molecular aspects of TB also ,,,and possibly
virulence
Ma. Sheila Mangalonzo-de Jesus <[email protected]>
Cupang, Muntinlupa City, 1771 Philippines - Mon May 5 07:43:34 PDT 1997
My interest is Epidemiology of tuberculosis control. TB DNA fingerprinting is one of the most
fascinating new technologies for us.
Toru Mori <[email protected]>
Kiyose, Tokyo 204 Japan - Sat May 3 04:54:11 PDT 1997
I AM A PHYSICIAN FROM INDIA AND AM INTERESTED IN RESEARCH IN T.B. WHICH IS
VERY RAMPANT IN INDIA HAVING SEEN A LOT OF TB AND WORKED VERY CLOSELY
WITH THESE PATIENTS ,I WOULD BE VERY HAPPY IF YOU COULD HAVE ANY
OPPORTUNITIES FOR THE SAME.
murtuza bahrainwala h. <[email protected]>
kew-gardens, ny-11415 U.S.A - Fri May 2 16:21:19 PDT 1997
diagnostic tests PCR-based molecular epidemiology
Caterina Mammina, MD <[email protected]>
Palermo, Italy - Fri May 2 08:03:46 PDT 1997
Direct detection of Mycobacterium species. Speciation by HPLC. Quantitative analysis of clinical
specimens.
Sher-Hwin Chiu <[email protected]>
Austin, Texas USA - Thu May 1 19:09:58 PDT 1997
High-output UV for HVAC air disinfection
Tom Schaefer <8009250440>
Cincinnati, OH United States - Thu May 1 16:34:32 PDT 1997
Main interests: National TB Programmes, DOTS, TB and NGOs, training health workers. Visit the
tbNET website at http://www.south-asia.com/ngo-tb
Ian Smith <[email protected]>
Kathmandu, Nepal - Wed Apr 30 09:29:53 PDT 1997
New treatment methods for Pulmonary Tuberculosis
Han Yu-ling <[email protected]>
Jinan, Shandong P.R.China - Wed Apr 30 09:00:54 PDT 1997
Developing appropriate diagnostic tests for TB
Dr. Leslie A. Stringfellow <[email protected]>
San Diego, CA USA - Tue Apr 29 11:48:15 PDT 1997
Areas of interest: Molecular Biology, Pathogenesis, Drug development
Juan A. Ayala <[email protected]>
Madrid, Madrid Spain - Tue Apr 29 10:21:41 PDT 1997
Bacterial lipoglycans (eg. mycobacterial LAMs) and lipoproteins
Iain Sutcliffe <[email protected]>
- Tue Apr 29 08:40:38 PDT 1997
DOTS,TB/HIV-AIDS,TB researches,
Petchawan Pungrassami ,M.D. <[email protected]>
Hatyai District, Songkla Province THAILAND - Tue Apr 29 08:36:21 PDT 1997
Looking for info on the recovery time from TB in insulin dependent diabetes.
Nancy Conner <[email protected]>
Birmingham, AL US - Tue Apr 29 08:23:27 PDT 1997
Dept. of Biochem., Baylor college of Medicine. Interests: pathogenesis, virulence. Have isolated and
characterized the oligomeric state and chaperone activity of the 16 kDa antigen from M. tb.
Todd P. Primm <[email protected]>
Houston, Texas USA - Mon Apr 28 11:07:36 PDT 1997
Gerard Cangelosi, Ph.D. Seattle Biomedical Research Institute Department of Pathobiology
University of Washington [email protected] Interests: molecular diagnosis,
pathogenesis, drug development
Gerard Cangelosi <[email protected]>
Seattle, WA USA - Mon Apr 28 10:51:50 PDT 1997
automated fragment-based DNA genotype matching, computational methods, IS6110 fingerprint
clustering methods, Please visit my web pages by following the link from my name.
Hugh Salamon <[email protected]>
Stanford, California USA http://www.stanford.edu/group/molepi/guestbook.html (57 of 58) [05/01/06 2:27:11]
You may email me regarding this website!
Hugh Salamon, Ph.D. <[email protected]>
Stanford, California USA -
●
●
Stanford Center for Tuberculosis Research
Scripts and Guestbook created by Matt Wright and can be found at Matt's Script Archive
Stanford University and individuals maintaining this page are not to be held responsible for any
consequences whatsoever resulting from any and all words or other information on this page, or any
actions taken as a result of contacting individuals listed herein.
Click on this icon to return to the top of the home page.
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Speaks on TB/HIV
More Videos ...
Partner Highlight
News & Announcements
World TB Day 2006 is coming!
23 December 2005
In end-January 2006, the Stop TB
Partnership will release The Global
Plan to Stop TB 2006-2015. In setting
out the resources needed for action,
the Plan will serve as a powerful
advocacy tool that outlines regional
and global scenarios for impact and
costs of planned activities, and
strategic plans for the Partnership’s
seven Working Groups for the next
decade. The thematic focus for World
TB Day 2006 is built on the Global Plan
advocacy strategy, key messages and
action points around the theme Actions
for Life: towards a world free of
tuberculosis as a basis for campaign
development.
Field testing the revised TB recording
and reporting forms
20 December 2005
The Stop TB Department of WHO, in
collaboration with partners, convened
three informal expert consultations in
Geneva, Switzerland in April, May and
September, 2005. The expert group
has issued revised TB recording and
reporting forms and registers to
facilitate building consensus at
national level on a minimum
standardized monitoring tool that
complies with the Stop TB Strategy.
The main changes in the information
system forms are the inclusion of
TB/HIV collaborative activities; culture
for diagnosis and drug resistance
testing; and the management of
patient drug kits. The revision also
aims to strengthen links with all care
providers, civil society and the national
health management information
system (HMIS).
New tuberculosis therapy offers
http://www.stoptb.org/ (1 of 6) [05/01/06 2:29:28]
Stop TB Partnership
Destination Santé
We are a multimedia press
agency in French, Arabic,
Dutch and English, devoted to
health information for mass
audiences. Destination Santé
feeds over 130 newspapers in
Europe, Africa and the Middle
East. Prominent portals (Yahoo, Google, Algérie
Presse Service, Menara…) rely on Destination
Santé material on a daily basis. We are an
exclusive producer of the WHO radio programs
in French (700 stations, 45 countries) and
Arabic (125 stations, 11 countries). As of 1
January 2006, these programs are broadcast by
Destination Santé as an independent press
agency, keeping a strong connection with WHO
program units.
Services related to TB
- In close cooperation with the WHO TB
Strategy & Operations Unit, Destination Santé
designed a special 10 minute feature in French
and Arabic dedicated to World TB Day: over 100
hours of educational information were
broadcast worldwide on this occasion.
- Since Destination Santé joined the Stop TB
Partnership (2003), over 60 news items related
to TB diagnosis, treatment and prevention have
been disseminated.
View the text in French
View the text in Arabic
View their partner profile
potential shorter treatment
17 December 2005
Clinical results on a new combination
treatment that could dramatically
shorten the length of tuberculosis (TB)
treatment were presented today at the
45 th Annual Interscience Conference
on Antimicrobial Agents and
Chemotherapy in Washington, D.C.
Printable Version
The Special Programme for Research
and Training in Tropical Diseases
(TDR)
L'institut de recherche pour le
développement
Stop TB Partnership Indonesia
launches web site, and successfully
holds first-ever National TB Congress
attended by over 1000.
6 December 2005
The Stop TB
Partnership Indonesia
web site will serve as a
comprehensive public
information tool for
tuberculosis in Indonesia. The web site
was launched in coordination with the
first-ever Indonesian National TB
Congress, that took place in Jakarta,
Indonesia, 18-19 November 2005. The
TB Congress drew over 1000 health
professionals, politicians, healthcare
providers, NGO activists, and TB staff
from throughout the country. The
participants reviewed the national TB
partnership movement, Gerdunas.
Meeting agenda items included new
mechanisms for supporting the 5-year
national TB plan 2006-2010, progress
and opportunities in clinical aspects of
TB, community involvement, and the
International Standards of TB Care.
Indonesia launched Gerdunas in 1999.
Indonesia was the first country in the
world to establish a national Stop TB
partnership.
Stop TB Partnership
World AIDS Day
1 December 2005
The TB community is committed
to the theme of this World AIDS
Day by collaborating with the HIV
community to provide universal
access to comprehensive TB and HIV
prevention, treatment and care
services. In highly HIV endemic
countries TB programmes can raise
awareness about TB/HIV co-infection,
provide HIV counselling and testing
and provide HIV prevention methods
as well as antiretroviral therapy for TB
patients who are also HIV positive. TB
programmes can help keep the promise
and Stop AIDS!
UNAIDS web site
TB/HIV Working Group November
2005 Information Circular
Stop TB Partnership Executive
Secretary addresses World Summit of
Nobel Peace Laureates
24-25 November 2005
The Executive Secretary of the Stop TB
Partnership, Dr. Marcos Espinal, was
invited to make a special presentation
on the global TB epidemic and regional
TB emergency in Africa at the 2005
World Summit of Nobel Peace
Laureates in Rome, Italy on 24-25
November. The summit was organized
by the Gorbachev Foundation and
sponsored by the Municipality of Rome,
this year's theme being "Africa
Emergency: From Attention to Action."
The gathering attracted a number of
Nobel Peace laureates including
Mikhail Gorbachev, Frederik Willem De
Klerk, Adolfo Perez Esquivel, John
Hume, Mairead Corrigan Maguire, Betty
Williams, Rigoberta Menchù Tum, and
Lech Walesa, as well as special guests
Bob Geldolf, Robert F. Kennedy Jr.,
Carla Del Ponte and others.
Italy urges tuberculosis to become a
Stop TB Partnership
priority for the G8 in 2006
(AGI) - Rome, Italy, Nov 10 2005
The Italian Government is to call on G8
countries to intensify global efforts on
TB control and ensure it is included as
a priority in the 2006 summit agenda.
In a statement distributed by the
Prime Minister's Office, Giuseppe
Drago warned that "TB risks being
forgotten" despite two million people
dying from the disease every year. He
also warned of the challenges of
addressing TB in Africa where rates
continue to rise, the threat of drug
resistance, especially in the former
Soviet Union, and the urgent need to
find effective vaccines.
Addressing delegates at the Stop TB
Partnership's Coordinating Board
meeting at Assisi in November, Mr
Drago confirmed Italy's commitment to
TB by announcing that his government
will "take up the duty of informing
other members of the G8 so that the
fight against TB, in particular in Africa,
becomes one of the priorities of the
next summit at Saint Petersburg".
More News ...
Highlighted Projects
Panos and Stop TB Partnership
journalism fellowships
The Panos Global AIDS Programme and
the Stop TB Partnership awarded
fellowships for print and photo
journalists in the South to raise local
debate and understanding of TB and, in
particular, its link with poverty and
HIV/AIDS. The fellowships were
awarded to local journalists in India,
Bangladesh, Pakistan, the Philippines,
Indonesia, Zambia, Malawi, Ethiopia
and Haiti. Articles and photos will be
published in the Fellow's local
newspapers, and a best practice
Stop TB Partnership
reporting guide on TB and photo
exhibition based on the Fellows' work
will be subsequently published by
Panos.
TB Emergency in Africa
In August 2005, TB was declared to be
an emergency in the African region by
The World Health Organization (WHO)
Regional Committee for Africa - a
response to an epidemic that has more
than quadrupled the annual number of
new TB cases in most African countries
since 1990 and is continuing to rise
across the continent, killing more than
half a million people every year.
Recent Publications
Communiqué, Issue No.43
December 2005
Italy urges tuberculosis to
become a priority for the G8 in
2006
Sustaining the Gains
October 2005
National Self-Sufficiency for TB
Drug Access
A Global Drug Facility Strategy
Stop TB Partnership Annual
Report 2004 - Introductory
page
May 2005
Our Annual Report 2004 looks
at the Stop TB Partnership's major
achievements in core areas of work,
including governance, advocacy and
communication, partnership building,
access to lifesaving TB drug treatments
and resource mobilization.
Stop TB Partnership
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Tuberculosis - A Global Emergency
9 million people develop active TB each year than one hour at
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and 2 million die - yet TB is curable. Read
more...
more
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Multi-Drug Resistant TB
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out TB
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Occupational deaths among healthcare workers
By John G. Bartlett M.D.
posted 12/21/2005
The authors estimated the annual death rate for health
care workers from occupational events based on data
from federal sources and estimates based on prevalence
and natural history. The most recent major relevant
event was SARS. There were 8,098 cases and 774
(9.6%) died; health care workers accounted for 1,707
(21%) of cases, but the number of deaths in this group is
not known. The resource expected to provide substantial
data is the National Institute for Occupational Safety and
Health (NIOSH) which is a branch of the CDC and
responsible for research on prevention of work place
injury and illness. However, infectious diseases are not
included in the illness report. Other conditions which are
included are hypersensitivity pneumonitis, mesothelioma
and occupational pneumoconiosis...more
Literature Review
■
■
■
The Antibiotic Guide:
■
■
Novel, single-dose microsphere formulation of
azithromycin versus 7-day levofloxacin therapy for
treatment of mild to moderate community-acquired
pneumonia in adults
By John G. Bartlett M.D.
posted 12/21/2005
The authors report the results of a randomized, doubleblind, comparative trial of single dose azithromycin (2 gm
microsphere in an oral slurry) compared to levofloxacin
(500 mg po/day times 7 days) in patients with "mild-tomoderate CAP." Eligibility criteria included x-ray evidence
of pneumonia, and a PSI score of less than 90 (category IIII in the Fine PSI mortality risk scale). Microbiology
assessment included sputum cultures, urine antigen
assay for S. pneumoniae, blood cultures and serology
plus PCR for M. pneumoniae and C. pneumoniae. The
results show equivalence in the two drugs with no
statistically significant difference in clinical cure rates of
94% in the 214 patients treated with levofloxacin vs.
90% in the 213 patients given azithromycin...more
http://hopkins-abxguide.org/ (1 of 2) [05/01/06 2:33:23]
Occupational Deaths among Healthcare Workers
posted 12/21/2005
S aureus, Panton-Valentine Leukocidin, and
Necrotizing Pneumonia
posted 12/21/2005
Single-Dose Microsphere Azithromycin vs 7-Day
Levofloxacin for Mild to Moderate CommunityAcquired Pneumonia
posted 12/21/2005
archive
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health care professional should use his/her best medical judgement in determining appropriate patient care or treatment. Full Disclaimer >>
http://hopkins-abxguide.org/ (2 of 2) [05/01/06 2:33:23]
-» ´ä ¨¾ À÷ ¤ß Å¦ ¤Î ¯Ý ¯f ¨ó ·|
-» ´ä ÆW ¥J ¬Ó ¦Z ¤j ¹D ªF 266 ¸¹
¹q ¸Ü ¸¹ ½X : (852) 2572 3466
¶Ç ¯u ¸¹ ½X : (852) 2834 0711
¹q ¤l ¶l ¥ó : [email protected]
»Õ ¤U ¬O ²Ä
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http://www.ha.org.hk/org/antitb/default.htm [05/01/06 2:38:17]
The Indian Journal of Chest Diseases and Allied Sciences
Current Issue
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Current Issue
Jul - Sept 2002
http://www.indegene.com/ijcd/indIJCDHome.html [05/01/06 2:40:31]
Past Issues
Oct - Dec 2000 Onwards
The Vaccine Fund
1/5/2006 GMT
The Campaign for Child
Immunization
About The Vaccine Fund
The Global Need
The Vaccine Fund's Mission
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Support The Vaccine Fund
Highlights
9 September 2005
Key European Nations Join UK
and France to Commit Nearly
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click here.
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The Vaccine Fund
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http://www.vaccinefund.org/ (2 of 2) [05/01/06 2:48:10]
Tinplate Hospital (BCG Vaccine)
Vaccine
BCG Vaccine - for prevention of TUBERCULOSIS
Home
Vaccine
BCG
DPT
Background and General Guidelines
BCG, or bacille Calmette-Guérin, is a vaccine for tuberculosis (TB)
disease. BCG is used in many countries, but it is not generally
recommended in the United States because of the low risk of
infection with M. tuberculosis, the variable effectiveness of the BCG
vaccine against pulmonary TB, and the vaccine’s interference with
tuberculin reactivity.
Oral Polio
Varicella
Measles
Hepatitis-A
Hepatitis-B
Typhoid Fever
MMR
Haemo Influenza-B
BCG vaccines are live vaccines derived from a strain of
Mycobacterium bovis that was attenuated by Calmette and Guerin at
the Pasteur Institute in Lille, France (29). BCG was first administered
to humans in 1921. Many different BCG vaccines are available
worldwide. Although all currently used vaccines were derived from
the original M. bovis strain, they differ in their characteristics when
grown in culture and in their ability to induce an immune response to
tuberculin. These variations may be caused by genetic changes that
occurred in the bacterial strains during the passage of time and by
differences in production techniques. The vaccine currently available
for immunization in the United States, the Tice strain, was developed
at the University of Illinois (Chicago, Illinois) from a strain originated
at the Pasteur Institute. The Food and Drug Administration is
considering another vaccine, which is produced by Connaught
Laboratories, Inc., for licensure in the United States. This vaccine
was transferred from a strain that was maintained at the University
of Montreal (Montreal, Canada).
BCG vaccination does appear to lower the risk of serious
complications of primary TB in children. But in the United States, the
consideration of BCG vaccination is recommended only for children
http://www.tinplatehospital.com/bcg.asp (1 of 3) [05/01/06 2:50:28]
TT (Tetanus)
Surgeries/Procedures
Obstestrics and Gyneac
Orthopeadic
General Surgeries
Urological
Gastrointestinal
Other Operations
ENT
Eye
Pathology
Dental
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News/Articles
Incinerator for TPH
New Facility for
Sr.Citizen
who have negative tuberculin skin test results, and who cannot be
given treatment for latent TB infection but are at high risk for
continuous exposure to infectious TB or to TB that is resistant to
isoniazid and rifampin. BCG is no longer recommended for health
care workers or other adults who are likely to be exposed to TB.
However, vaccination of health care workers should be considered on
an individual basis in settings in which
A New lease of life
(1) a high percentage of TB patients are infected with M. tuberculosis
strains resistant to both isoniazid and rifampin,
(2) transmission of such drug-resistant M. tuberculosis strains to
health care workers and subsequent infection are likely, and
(3) comprehensive TB infection-control precautions have been
implemented and have not been successful.
A typical delivery case
TPH rises from Ashes
ETech. in eye surgery
New Annexe for TPH
Case Studies
Gynaec tumor surgery
Remedy from Squint
Other Links
Best Indian Hospitals
Jamshedpur hospitals
Dhanbad hospitals
Furthermore, BCG should not be given to persons who are
immunosuppressed, such as persons who are infected with HIV. It
should not be given to pregnant women, even though no harmful
effects of BCG vaccination on the fetus have been observed.
Ranchi hospitals
Ranchi Nursing homes
Community/Health
Family Welfare
Interpreting Tuberculin Skin Test Results in BCG-Vaccinated Persons
In persons vaccinated with BCG, sensitivity to tuberculin is highly
variable, depending upon the strain of BCG used and the group
vaccinated. The presence or size of a postvaccination tuberculin skintest reaction does not predict whether BCG will provide any
protection against TB disease.
Bagbera Dispensary
Lafarge OHC
Tariffs
Bed charges
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General working hours
Furthermore, the size of a tuberculin skin-test reaction in a BCGvaccinated person is not a factor in determining whether the reaction
is caused by M. tuberculosis infection or the prior BCG vaccination.
Tuberculin skin testing is not contraindicated for persons who have
been vaccinated with BCG, and the skin-test results of such persons
are used to support or exclude the diagnosis of M. tuberculosis
infection.
A diagnosis of M. tuberculosis infection and the use of treatment of
latent TB infection should be considered for any BCG-vaccinated
person who has a tuberculin skin-test reaction of >=10 mm of
induration, especially if any of the following circumstances are
present:
The vaccinated person is a contact of another person who has
infectious TB, particularly if the infectious person has transmitted M.
tuberculosis to others;
The vaccinated person was born or has resided in a country in which
the prevalence of TB is high; or
The vaccinated person (e.g., some health care workers, employees
and volunteers at homeless shelters, and workers at drug-treatment
centers) is exposed continually to populations in which the
prevalence of TB is high.
Treatment of latent TB infection should be considered for BCG-
Clinical working hours
Immunizational clinics
ICU/Trauma center
ICU
Trauma center
T C John center
Health Care
Patient's Feedback
vaccinated persons who are infected with HIV and who are at risk for
M. tuberculosis infection if they have a tuberculin skin-test reaction
of >= 5 mm induration.
BCG-vaccinated persons who have a positive reaction to the
tuberculin skin test, but who do not have TB disease, should be
evaluated for treatment of latent TB infection. The possibility of TB
disease should be considered for BCG-vaccinated persons who have
symptoms suggestive of TB.
Tinplate Hospital
P.O.Golmuri, Jamshedpur
Phone: +91-0657-2340512, EPABX: 2340713-720
Site Developed by MSD(TCIL)
OI: Turberculosis -- ÆGIS
Turberculosis
"TB"
"MDR-TB" (multi-drug resistant TB)
This is part of a series on Opportunistic Infections ("OIs"). Please note that -1. This Page Is Just A Starting Point: ÆGIS is a great place for you to find overview
information about HIV and opportunistic infections, but it is not a substitute for getting
medical advice from a doctor who specializes in treating HIV.
2. Finding The Latest Information: Advances in treating opportunistic infections can
happen at any time, so the material on this page may be outdated. Some links in the see
also section at the bottom of this page are actually special database links. They may
contain information published after this page was written.
Tuberculosis (TB) is a dangerous -- often deadly -- disease. Testing, preventative measures,
and aggressive treatment are important. TB is the most common opportunistic infection.
Classification
Infection with Mycobacterium tuburculosis
Description
●
●
Infection: TB is transmitted when a person with active TB coughs or sneezes, releasing
microscopic particles into the air. These particles, also called droplet nuclei, contain live
tubercle bacteria, and may result in infection when inhaled by another person. Once
infected by TB, most people, remain healthy and develop only latent infection. People with
latent infection are neither sick nor infectious. However, they do have the potential to
become sick and infectious with active TB. (GMHC)
An earli OI: Active TB often occurs early in the course of HIV infection, often months or
years before other OIs. In fact, TB may be the first indication that a person is HIV-infected.
TB also causes disease outside the lungs of HIV-infected people, particularly in the later
stages of AIDS. (NIH)
http://www.aegis.com/topics/oi/oi-tb.html (1 of 3) [05/01/06 2:52:55]
●
●
●
●
●
Multi-drug Resistant TB: Of particular concern for people with AIDS is multi-drugresistant TB (MDR-TB). MDR-TB occurs when patients fail to take their TB medicine for
the prolonged periods necessary to destroy all parts of the TB organism and it becomes
resistant to the drugs. These resistant organisms can be spread to other people. Even with
treatment, for individuals coinfected with HIV and MDR-TB, the death rate may be as high
as 80 percent, as opposed to 40 to 60 percent for people with MDR-TB alone. The time
from diagnosis to death for some patients with HIV and MDR-TB may be only months as
they are sometimes left with no treatment options. (NIH)
In about half of the HIV+ people with TB, the infection involves more than just the lungs.
Other targets include the lymphatic system.
Symptoms include: cough, fever, night sweats, weight loss, fatigue.
Diagnosis is usually made with a skin test.
The US Centers For Disease Control considers TB an AIDS-defining condition.
Danger Zone
●
TB is more frequent for those with CD4+ cells less than 200/mm but can occur at any
CD4+ count.
NOTE: If you are undergoing treatment that has increased your CD4+ levels, see the important
note on Naive T-Cells. There is some evidence that you should use the lowest CD4+
level you ever had when considering your risk for some opportunistic infections.
Prevention
●
●
●
The US CDC recommends treatment for any HIV+ person with latent (inactive, no
symptoms) M. tuberculosis. That diagnosis is made using skin tests.
Prophylaxis (prevention) is usually isoniazid.
Outside the US, BCG vaccination has been used for the prevention of TB.
NOTE: Many HIV experts stress that it is important that anyone newly diagnosed as being HIVpositive be given a "TB with anergy" test. That is a test for TB, mumps, and candida. Those with
severely damaged immune systems can show false negative results on the TB test.
1. If you test positive for TB, you are infected with TB.
2. If you test negative for TB but positive for mumps or candida, you do not have TB. This is
the result you want! Those with functioning immune systems will test positive for mumps,
candida, or both ... so a positive result on these tests means the negative TB test can be
trusted.
3. If you test negative for all three, then you have anergy, which means your immune system
is to damaged to respond to common antigens.
Treatment
■
■
■
■
Treatment usually includes multiple drugs: isoniazid, rifampin, pyrazinamide,
ethambutol (or streptomycin).
Some mutations of TB are resistant to some of the common drugs. There are
susceptibility tests that can show which drugs will work on a particular strain.
The US CDC recommends DOT (directly observed therapy) -- where a nurse
watches each drug dose being taken. The biggest reason for TB treatment
failure is a failure to take the medicines.
Some with late-stage AIDS have trouble absorbing the drugs. Doctors can
sometimes run tests to see if malabsorption is a problem.
See Also...
■
■
■
■
■
■
■
ÆGIS Knowledgebase: TB Drugs
ÆGIS Knowledgebase: TB Clinical Trials
ÆGIS Knowledgebase: AIDSline TB Articles
Being Alive newsletter: TB Screening
NIAID Alert: TB and HIV Replication
GMHC: What TB Is (1993)
Yahoo! Tuberculosis web sites
This information is designed to support, not replace, the relationship that exists between you and your doctor.
©1998. AEGIS.
Tuberculosis Association of Ohio County
Tuberculosis Association of Ohio County
HOME
HOLIDAY SEALS
PROGRAMS
HISTORY
TB FACTS
LOCATION
CONTACT
LINKS
TB is at the lowest rate of increase since it's emergence in the 1980's according to the CDC.
The Tuberculosis Association of Ohio County is a nonprofit organization located in Wheeling, West Virginia. The association
has been providing programs and services for the residents of Ohio
County since 1909.
●
Our mission is to combat tuberculosis and other primary
lung diseases in the Ohio county area through prevention,
treatment, and education.
Unlike many organizations which funnel contributions to a national headquarters, we use our funds
locally, to benefit Ohio County residents. The money is not used for high administrative salaries and
bureaucratic costs; it is used almost exclusively to fund preventive medical programs, scholarships and
community service projects in Ohio County.
Generous local donors can see the good things their contributions accomplish.
http://www.tboc.org/ [05/01/06 2:54:46]
Home Page
TB All Time Low in
Chicago in 2001
Click on the dancing drug on bug icon to enter
Web site for TB Chicago is hosted as a service to the public and is not an agency
of any governmental organization
Sponsors: Drs. Bapu P. and Vijaya L. Arekapudi
Lake Shore Medical Associates, Ltd.
Webmaster & Hostmaster: Bapu P. Arekapudi, M.D
Disclaimer
http://www.tbchicago.org/ [05/01/06 3:14:43]
TBC India
Procurement Info | Method of Calculation
TUBERCULOSIS CONTROL - INDIA
WHO-recommended
Directly Observed
Treatment, Short Course
(DOTS) strategy was
launched formally as
Revised National TB Control
programme in India in
1997 after pilot testing
from 1993-1996. Since
then DOTS has been widely
advocated and successfully
applied.
In terms of population coverage, India
now has the second largest DOTS
(Directly Observed Treatment, Short
course) programme in the world.
However, India's DOTS programme is
the fastest expanding programme, and
the largest in the world in terms of
patients initiated on treatment, placing
more than 100,000 patients on
treatment every month. This site
provides information about tuberculosis
and its control in India.
Click here to see RNTCP
implementation in India
DOTS is the most effective
strategy available for
controlling TB
Indian TB
Programme officers
The five key components
More..
Strategic Vision Document of the RNTCP
http://www.tbcindia.org/ [05/01/06 3:16:46]
In India today, like any other
day this year, more than
1,000 people will die from
tuberculosis (TB) But these
deaths can be prevented.
With proper care and
treatment, TB patients can
be cured and the battle
against TB can be won...
More...

TUBERCULOSIS

Transcription

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