Aarhus University Center of Experimental Immunomodulation (AUCEI)

AARHUS UNIVERSITY
CENTER OF EXPERIMENTAL IMMUNOMODULATION
Aarhus University Center
of Experimental Immunomodulation
(AUCEI)
AARHUS UNIVERSITY
CENTER OF EXPERIMENTAL IMMUNOMODULATION
Applicant:
Lars Østergaard MD, PhD, DMSc, Professor/Head
Dept. of Infectious Diseases, Aarhus University Hospital, Skejby Sygehus
DK-8200 Aarhus N, Denmark
Ph.: +45 8949 8300 Fax: +45 8949 8310
e-mail: [email protected]
Page 2
AARHUS UNIVERSITY
CENTER OF EXPERIMENTAL IMMUNOMODULATION
Presentation of the center’s research focus/topic
CONTEXT AND BACKGROUND OF THE PROJECT
Infectious diseases such as pneumonia, hepatitis, and HIV are common, and often life threatening conditions. According to the
WHO, infectious diseases were the most common cause of death globally (25% of all deaths) in 2008.1) Since all age groups are
susceptible to infections, prevention or treatment of infectious diseases has the highest impact of all disease entities with regards to
increasing life span. The severity of infectious diseases depends on the immune system’s capability to maintain a balance between
fighting foreign infectious pathogens, and suppressing harmful self-destruction of the body’s own cells and tissue. This immune
balance can be improved by e.g. vaccines given in advance of exposure, but can also be impaired by either the infection itself (as for
HIV), or by an overshooting inflammatory process leading to self-destruction of host tissue. In order to develop new vaccines and
new drugs providing optimal immune balance, an understanding of the interplay between infectious organisms and the modulations of the immune system is needed.
PRESENTATION OF IDEA/RESEARCH TOPIC
We propose a Center of Experimental Immunomodulation under Aarhus University (AUCEI). The aim of this center is to accelerate the process of identifying and testing novel vaccines and immune modulatory molecules by taking our basic science discoveries
to immediate small scale clinical testing, and generating new basic science on the base of the clinical testing. The idea is to create a
feedback loop between basic science and clinical science in which both entities share and benefit from the newest knowledge, thus
resulting in faster and more efficient development of new therapies, and a deeper scientific understanding of the interplay between
pathogen and host immune response.
RELATION OF IDEA/RESEARCH TOPIC TO EXISTING RESEARCH
We have a longstanding record of initiating and conducting small-scale clinical trials in which novel immune modulatory molecules
and vaccines have been tested, and basic research questions have been solved in our laboratory. We have focused on prevention and
treatment of the most devastating chronic infectious disease, HIV, and the most severe acute infections such as septicemia, pneumonia and meningitis. The center will be a natural extension of these research topics. These diseases have also attracted a great
deal of attention from the international research community, but several questions remain to be answered. For example: we can
stop HIV infection from progressing to AIDS by treatment, but we cannot prevent HIV by vaccination, or cure HIV in an infected
person. However, new international research has identified Histone Deacetylase (HDAC) inhibitors as a novel class of drugs which
has the potential to stimulate HIV expression from latently infected resting cells, thereby reducing the viral reservoir (Archin et al.
AIDS 2009; Matalon et al. Molecular Med 2011). In addition, HDAC inhibitors have been suggested to possess immunomodulating activities independent of their action on HIV replication, which will also be analyzed at the level of signal transduction and
transcription factor activation. However, much remains to be investigated regarding the molecular mechanisms of the clinical and
immunological effects of HDAC inhibitors.
SOCIETAL AND SCIENTIFIC IMPORTANCE (SCHOLARLY RELEVANCE)
Scientifically, AUCEI’s goal is to be at the international front of experimental medicine within infectious diseases, and certain treatment resistant autoimmune conditions. We expect to identify and test novel immune modulatory molecules and pathways that may
have a profound therapeutic potential, and thus be of great innovative and scientific value. Society may potentially benefit from
AUCEI’s work in several ways including economic (new patents), educational (talent development), through improved health care
and quality of life (reduced cost of existing treatment, new prevention, and treatment options).
SUPPORTING MATERIALS AND METHODS
In addition to our Bio-safety level 3 facility,2) we are equipped with a modern laboratory, and use state of the art technology,
including Realtime qPCR (polymerase chain reaction), transcription factor analysis (TRANS-AM, phosho-flow reporter assays),
ELISA, multiplex bead analysis (Luminex), flow cytometry, cell sorting facility (FACS), siRNA technology, sequencing, and confocal microscopy. The proposed research idea requires use of all of these techniques but all methods can be established within the
existing laboratories and equipemnt. Further, in the project group are clinicians, post-docs, and PhD students with strong backgrounds in immunology, virology, cell biology, and clinical studies.
__________
1) World Health Organization, Global Health Observatory Data Repository, Cause-specific mortality 2008. Available at: http://apps.who.int/ghodata/
2) A biosafety level (BSL) is the level of the biocontainment precautions required to isolate dangerous biological agents in an enclosed facility. The levels of
containment range from the lowest biosafety level 1 to the highest at level 4.
AARHUS UNIVERSITY
Page 3
CENTER OF EXPERIMENTAL IMMUNOMODULATION
Project plan and expected results
PERSPECTIVES FOR/IMPLICATIONS OF IDEA/RESEARCH QUESTION, AT PRESENT AND IN THE LONG TERM.
We propose that AUCEI has three main research topics during the pilot phase: New pharmacological interventions aimed at curing
HIV infection, new therapeutic options for recurrent fever syndromes (familial Mediterranean fever), and development of vaccines for immune compromised individuals. To explore these ideas we have proposed three specific research aims (detailed research
protocols can be requested):
I.
II.
III.
Identification and use of histone deacetylase inhibitors (HDACi) for the eradication of latent HIV infection.
Mechanisms and use of interleukin-1 beta (IL-1β) antagonists in recurrent fever syndromes (familiar Mediterranean fever)
Development and use of novel vaccines and Toll-like receptor (TLR) vaccine adjuvants
In the short term, focusing on these three niches will allow AUCEI to be at the forefront of the scientific field because these goals
are based on our existing expertise and knowledge. The prospect for the coming three years is to establish AUCEI as an international top level research center by strengthening our research network within AU, and with our international collaborators. The key
is to focus on novel research ideas (I-III) which are likely to generate new scientific discoveries with major potential for patenting
and further clinical development. This goal is achieved through collaborations with both academic and industrial partners. Besides
generating new patents, we expect to publish at least 15 papers in major international journals. In addition, new discoveries within
one area (I-III) will feed new knowledge into all clinical and basic science aspects of the other research areas.
In the long term (10 years) the proposed center will be an internationally renowned research institute. By focusing on research
questions that are of paramount scientific interest and health impact, AUCEI will be able to attract both internationally established
researchers as well as the most promising research talents. In addition, integrating basic science into clinical science and vice versa
can bridge the gap between AU basic science institutes and the clinical departments under Aarhus University Hospital. This will
strengthen the scientific network at AU, and pave the way for new research collaborations and scientific discoveries.
MILESTONES WITHIN THE PROJECT PERIOD.
As depicted below, we have several milestones during the project period.
AARHUS UNIVERSITY
CENTER OF EXPERIMENTAL IMMUNOMODULATION
HDACi preclinical testing
Effects on HDACi on HIV latency
Clinical HDACi testing
Experimental IL-1ß inhibition
Characterization of IL-1ß inh. effects and new potential drug targets
TLR adjuvanted HPV trial
HIV trial vaccine
I
II
III
Characterization of TLRs effect on innate and adaptive immunity
Jan 2012
Jan 2013
Jan 2014
EXPECTED RESULT AT CONCLUSION OF PROJECT PERIOD.
The following scientific results are expected at the end of 2014:
i.
ii.
iii.
Identification of the most potent HDACi for HIV eradication in vitro and in vivo.
A new therapeutic option for patients with recurrent fever syndromes (familial mediterranean fever)
A completed trial with conclusive results of a therapeutic HIV vaccine and a TLR adjuvant HPV vaccine trial.
Jan 2015
AARHUS UNIVERSITY
Page 4
CENTER OF EXPERIMENTAL IMMUNOMODULATION
Clinical goals:
Basic science goals
2012 A trial of TLR-adjuvant Human Papilloma Virus vaccination among 100 HIV patients. Experimental use of IL-1β
antagonists in selected patients (e.g. colchicin-resistant familial
mediterranean fever).
HDACi preclinical screening and testing to identify the most suitable compound for clinical use. Characterization of IL-1β antagonist therapy on innate and adaptive immune signalling.
2013 Trial of HDACi treatment for HIV eradication. Initiation of
therapeutic HIV vaccine trial.
Identifying new potential drug targets for patients with autoimmune diseases. Characterization of TLRs effect on signalling and
function of the innate and adaptive immune system.
2014 Completion of therapeutic HIV vaccine trial.
Explorative analyses of HDACi treatment’s impact on latent HIV
reservoir and the adaptive immune system. Further in vitro characterization of TLR agonists and IL-1β inhibition immunological
effects and evaluation of new drug targets.
The following scientific achievements are expected by the end of 2014:
I.
II.
III.
IV.
At least three top-level international researchers have a working contract with the center
At least three patent applications are filed
At least ten manuscripts are submitted / published in scientific journals with an impact factor above 5.
At least 4 PhD students and 6 research year students are working within the scope of the center.
INTERNATIONAL AND NATIONAL COLLABORATION.
We have a strong pre-existing network of collaborators that enables AUCEI to compete at the highest international level. The academic and industrial collaborators include:
Dept. of Clinical
Microbiology
(AUH)
Søren Paludan
Dept. of
Biomedicine (AUH)
Dept. of
Nephrology
(AUH)
NATIONAL
Dept. of Clinincal
Immunology
(AUH)
Dept. of
Dermatology
(AUH)
COLLABORATORS
Klaus Überla
Andreas Kaufmann
Sharon Lewin
Expert in Molecular & MedicalVirology
Ruhr University, Bochum
Expert in Cervial Tumorimmunology
Charité, Berlin
Expert in Infections & HIV latency
Monash University, Melbourne
INTERNATIONAL
EXPECTED TALENT-DEVELOPMENT CONTRIBUTION.
Our goal is to recruit and educate at least 2 Post docs, 4 PhD students, and 6 pre-graduate students from Jan 2012 to Jan 2015. As
part of the AUCEI talent development we also expect to recruit foreign PhD students, and allow our own students and post docs
to engage in research stays with our collaborators.
FUTURE PLANS (ORGANISATIONAL, FINANCIAL, RESEARCH) IF EXPECTED RESULTS ARE ACHIEVED.
After the pilot phase, the center will be considered an upcoming international renowned institution for fast and efficient approach
in testing research questions related to immune balancing with high scientific standards. This will allow us to attract future financial
support from 3 potential sources: 1) As the center will be of international standard with international collaborators, research grants
will be obtained from international funds such as the Gates Foundation, NIH and EU, and 2) Revenue from new public-private
partnerships as offspring from our research activities (e.g. preclinical development and early phase testing of new potent HDACi
analogues 3) Revenue from trial site activities in phase 2b and 3 trial through collaborations with major pharmaceutical companies
(e.g. GSK, Pfizer, MSD).).
The proposed center has overlapping interests in immunology and immunomodulation with many of the other medical specialties
within Inflammatory Section such as Dermatology, Rheumatology, Oncology, and Hematology and the para-clinical specialties
such as Clinical Microbiology, Clinical Genetics and Clinical Immunology. It is therefore obvious to include these specialties in the
research during the later phases of research.
AARHUS UNIVERSITY
Page 5
CENTER OF EXPERIMENTAL IMMUNOMODULATION
Organization of the Center
FORMS OF COLLABORATION (INTERDISCIPLINARY, INTERNATIONAL)
AUCEI’s scientific foundation is a team of dynamic researchers at the Department of infectious
diseases, Aarhus University Hospital. To add additional international scientific quality to this
group, professor Charles Dinarello has agreed to join AUCEI as chief scientific advisor. Prof.
Dinarello will come as visiting professor to AUCEI 3-4 times each year for periods of 2 weeks.
Additionally, Prof. Dinarello will regularly participate in teleconferences and will be available for
e-mail correspondence.
AUCEI’s scientific management board will consist of Prof. Lars Østergaard (Director), Prof.
Charles Dinarello (Chief scientific advisor), Ole Schmeltz Søgaard, MD PhD, Trine Hyrup
Mogensen, MD PhD, and Martin Tolstrup, Cand Scient PhD. Board meetings will be held on
the first Thursday of every second month. OSS (I), THM (II), and MT (III) are responsible for
presenting and supervising their research area A thorough discussion of progresses and challenges
within each of the three focus areas will take place at each meeting. Prof. Dinarello and Prof. Østergaard are responsible for the
overall scientific strategy and for decisions regarding patenting and publication. Prof. Østergaard is responsible for financial management of AUCEI.
AUCEI plans to consolidate already existing national collaborations with our partners at Aarhus University and with Prof. Paludan
in particular, as well as the interdisciplinary collaborations with the Department of Clinical Immunology, Department of Nephrology, and Department of Clinical Microbiology at Aarhus University Hospital.
Chief Scientific Advisor
AARHUS UNIVERSITY
Prof. Charles Dinarello
CENTER OF EXPERIMENTAL IMMUNOMODULATION
PhD
Pre graduate
research
Prof. Lars Østergaard
Professor of Medicine
Colorado University, Denver
I - HDACi
Associate
professors
* Leading
Director of AUCEI center
Professor, Clinical institute
Aarhus University Hospital
II - IL-1beta antagonist
III - Novel vaccines
& adjuvants
Ole Schmeltz Søgaard*
Jesper Melchjorsen
Martin Tolstrup
TBA (new)
Trine Hyrup Mogensen*
Carsten Schade Larsen
Søren Fangel-Jensen
Martin Tolstrup*
Jesper Melchjorsen
Søren Jensen-Fangel
Thomas Aagaard Rasmussen
Rune Rønhave (new)
Randi Berg
TBA (new)
Lars Toft Nielsen
Lars Dalgaard (new)
TBA (new)
Pregraduate medical and molecular biology students
AUCEI will also use our international partners to establish new methods in assessing humoral and cellular immunity, as well as
identifying new signalling pathways and receptors. In addition, AUCEI will benefit from their expertise and access to novel immunological active compounds (e.g. HDACi through Topotarget/Italfarmaco/Novartis) and vaccines (e.g. therapeutic CTL-based HIV
vaccine through Klaus Überla).
LOCATION
The pre-existing laboratories and research facilities at the Department of Infectious Diseases will form the natural basis for the
majority of AUCEI activities. Certain immunological and virological laboratory analyses will be performed at our collaborator’s
research facilities at AU and internationally. In the long term, AUCEI may move to a new strategic location within the framework
of the inflammatory section under the New Aarhus University Hospital. However, with our previous contributions to biotech startups, we envision novel patents may form the basis for the development of a biotech company located in the Science Park at AU.
The market for prophylactic and therapeutic immune modulatory entities is increasing.
AARHUS UNIVERSITY
Page 6
CENTER OF EXPERIMENTAL IMMUNOMODULATION
Presentation of applicant prof. Lars Østergaard
Lars Østergaard (48) is a professor and chief physician (MD, PhD and DMSc) at Dept. of Infectious Diseases at Aarhus University Hospital, Denmark.
2000: 2000: 1999: 1995: 1990: Specialist in infectious diseases, Danish National Board of Health, Denmark
Diploma in international health, University of Copenhagen, Denmark
DMSc, University of Aarhus, Denmark
Ph.D, University of Aarhus, Denmark
Graduated from Medical School, University of Aarhus, Denmark
Lars Østergaard have been in charge of reseach in infectious diseases in the department for 7 years providing scientific supervision
for 25 medical students taking a research diploma and 15 PhD students within infectious diseases topics. He is a member of several
national and international advisory boards related to infectious diseases. Since 2006 Lars Østergaard has been a board member
(honorary treasurer) in the scientific commitee Nordic Society for Clinical Microbiology and Infectious Diseases. Since 2009 he
serves as chairman of the Danish AIDS foundation.
PREVIOUS RESULTS AND COMPETENCIES
In 2008 Lars Østergaard was appointed by management and employees as one of 12
successful and excellent leaders within the entire public Danish health care system due
to his winning competencies as an authentic leader that handles challenges in a way that
creates commitment and development among those that he works with. He provides
inspiration and the personal space for development for personal qualitication in people
at all levels within the department, creating an atmosphere of presence & a winning
mentality that dare challenge known situations. During his responsibility for research in
department of infectious diseases an increasing number of publications as well as new
research students and PhDs have arised within the department.
KEY PUBLICATIONS
Lars Østergaard has a total of 162 peer-reviewed publications in scientific journals.
Within the last year he has published the following papers which are all related to the
activity of the proposed center. In addition he is co-inventor of six patents of which the
below mentioned is the most relevant for the center:
1: Melchjorsen J, Risør MW, Søgaard OS, O’loughlin KL, Chow S, Paludan SR, Ellermann-Eriksen
S, Hedley DW, Minderman H, Ostergaard L, Tolstrup M. Tenofovir Selectively Regulates Production
of Inflammatory Cytokines and Shifts the IL-12/IL-10 Balance in Human Primary Cells. J Acquir
Immune Defic Syndr. 2011 Aug 1;57(4):265-75.
60
50
40
30
20
10
0
2006
2007
2008
2009
2010
2011
2010
2011
Publications (from Pure)
12
10
8
6
4
2
0
2006
2007
2008
New research year students
2009
New PhD students
2: Kirkegaard T,Wheatley A, Melchjorsen J, Bahrami S, Pedersen FS, Center RJ, Purcell DF, Ostergaard L, Duch M, Tolstrup M. Induction of humoral and cellular immune responses against the HIV-1 envelope protein using gamma-retroviral
virus-like particles.Virol J. 2011 Aug 1;8(1):381.
3: Pedersen RH, Lohse N, Østergaard L, Søgaard OS. The effectiveness of pneumococcal polysaccharide vaccination in HIV-infected adults: a systematic review. HIV Med. 2011 Jul;12(6):323-33.
4: Li JZ, Paredes R, Ribaudo HJ, Svarovskaia ES, Metzner KJ, Kozal MJ, Hullsiek KH, Balduin M, Jakobsen MR, Geretti AM, Thiebaut R, Ostergaard L, Masquelier B, Johnson JA, Miller MD, Kuritzkes DR. Low-frequency HIV-1 drug resistance mutations and risk of NNRTI-based antiretroviral treatment failure: a systematic review and pooled analysis. JAMA. 2011 Apr 6;305(13):1327-35.
5: Agergaard J, Nante E, Poulstrup G, Nielsen J, Flanagan KL, Østergaard L, Benn CS, Aaby P. Diphtheria-tetanus-pertussis vaccine administered
simultaneously with measles vaccine is associated with increased morbidity and poor growth in girls. A randomised trial from Guinea-Bissau.Vaccine.
2011 Jan 10;29(3):487-500.
6: Bukh AR, Melchjorsen J, Offersen R, Jensen JM, Toft L, Støvring H, Ostergaard L, Tolstrup M, Søgaard OS. Endotoxemia is associated with altered innate and adaptive immune responses in untreated HIV-1 infected individuals. PLoS One. 2011;6(6):e21275. Epub 2011 Jun 24.
7: Søgaard OS, Lohse N, Harboe ZB, Offersen R, Bukh AR, Davis HL, Schønheyder HC, Østergaard L. Improving the immunogenicity of pneumococcal conjugate vaccine in HIV-infected adults with a toll-like receptor 9 agonist adjuvant: a randomized, controlled trial. Clin Infect Dis. 2010 Jul
1;51(1):42-50.
8: Søgaard OS, Schønheyder HC, Bukh AR, Harboe ZB, Rasmussen TA, Ostergaard L, Lohse N. Pneumococcal conjugate vaccination in persons with
HIV: the effect of highly active antiretroviral therapy. AIDS. 2010 Jun 1;24(9):1315-22.
Patentnummer:WO2010022740. aug 20, 2008: HIV-1 envelope polypeptides for HIV vaccine. / Duch, Mogens R.; Pedersen, Finn Skou; Bahrami,
Shervin; Villesen, Palle; Wiuf, Carsten Henrik; Østergaard, Lars Jørgen; Tolstrup, Martin.
Page 7
AARHUS UNIVERSITY
CENTER OF EXPERIMENTAL IMMUNOMODULATION
Presentation of other members of research group
Prof. Charles Dinarello, 67, received his medical degree from Yale University, and his clinical training at Massachusetts General
Hospital. From 1974-1977 he was senior investigator at the National Institutes of Health in Bethesda. After being Professor of
Medicine and Pediatrics at Tufts University School of Medicine, and a staff physician at the New England Medical Center Hospital
in Boston, he moved to the University of Colorado, Denver School of Medicine in 1996. Dr. Dinarello serves on the editorial board
of the Proceedings of the National Academy of Sciences as well as several other scientific journals. Prof. Dinarello is considered a
founding father of cytokine biology. He purified and cloned IL-1β and established the use of IL-1 inhibitors such as monoclonal
antibodies for therapy. Prof. Dinarello has received numerous prestigious awards for his work including the 2009 Albany Medical Center Prize (the highest value price in medical and biomedical research in the United States), 2009 Crafoord prize, and 2010
Paul Ehrlich und Ludwig Darmstaedter Prize (highest endowed and internationally most distinguished award in medicine in Germany). Prof. Dinarello has published more than 900 papers, and his affiliation would be a great asset to both AUCEI and Aarhus
University in general.
Martin Tolstrup, 36, received his MSc Molecular Biology from the Faculty of Science, Aarhus University in 2003, and did his
PhD in 2004-07 in collaboration with the Department of Infectious Diseases and the Institute of Molecular Biology. He worked
in Australia in 2006-07, and has published 13 papers and has 3 patents. Martin has co-founded the biotech companies SKAU
Vaccines and EnFutech focusing on vaccine and therapeutic interventions towards HIV. The companies have attracted international funding through The International AIDS Vaccine Initiative (IAVI), the EUROStars program as well as a Malaysian Biotech
company Sentinext.
Jesper Melchjorsen, 35, is a senior researcher at Dept. Q. He received his PhD in 2005 in Medical Microbiology from Aarhus
University (Awarded best PhD thesis from Dept of Health Sciences 2005). In 2002 he received his MSc in Molecular Cell Biology
and Virology. Guest researcher abroad: USA and Canada (Flowcytometry, 2010), Australia (vaccine project, 2008) and Finland
(virus project, 2004). Third year chemistry studies (bachelor) completed in Austria (1998-99). He has twenty peer-reviewed publications and one patent (9 first authorships, 6 second), the majority within the field Immunology and Virology.
Ole Schmeltz Søgaard, 35, received his medical degree from Aarhus University in 2005 and did his internship at Aarhus Hospital 2005-06. He was clinical assistant and PhD student at the department of infectious diseases from 2007-2011 and now holds a
joint clinical and research position at the department. He has primarily done research in HIV and novel vaccines and has published
17 papers and 2 patents.
Trine Hyrup Mogensen, 38, received her medical degree from Aarhus University in 2002, earned her PhD in 2003, and a
doctoral degree in 2009. THM has long been working in innate immunity and has contributed with publications on basic and clinical immunology during viral and bacterial infections, as well as several reviews and book chapters. She holds a joint clinical and
research position which is funded by The Medical Research Council (FSS). THM currently runs a group of 4 members with focus
on innate immune responses to HIV infection.
Carsten Schade Larsen, 53, received his medical degree from Aarhus University, and did his clinical training at Aarhus University Hospital and Copenhagen University Hospital. He is a specialist in infectious diseases and internal medicine. 1993 DMSc,
Aarhus University on a thesis entitled: “Transmembrane Signalling in Human T-lymphocytes”. Currently consultant at the Department of Infectious Diseases, Aarhus University Hospital, and Associate Professor, Aarhus University, Chairman of the Danish
Society of Travel Medicine and Fellow of the Royal College of Physicians and Surgeons Glasgow, Faculty of Travel Medicine. He
has published 70 papers.
Søren Jensen-Fangel, 45, received his medical degree from Aarhus University in 1996. DMSc in 2004 defending the thesis
“The effectiveness of highly active antiretroviral therapy in HIV-infected patients”. Holds a joint clinical (consultant) and research
position at the Department of Infectious Diseases Skejby, Aarhus University Hospital. He has primarily done clinical and epidemiological studies in the HIV field as well as vaccine studies after HBV immunization and has publishes 24 papers.