Attenuating Mycobacterium tuberculosis for the development

Attenuating Mycobacterium tuberculosis for the development

9th World TB day Berlin 17-18 March 2015
Attenuating Mycobacterium tuberculosis for the
Development of New TB Vaccines Tuberculosis
MTBVAC Carlos Mar-n PRESENT VACCINE BCG:
IS ATTENUATED VACCINE BASED ON Mycobacterium bovis
EFFECTIVE AGAINST SEVERE FORMS OF CHILDHOOD TB
83% COVERAGE GLOBALLY
MAIN GOALS TO IMPROVE BCG :
INCREASE EFFICACY AGAINST ADULT PULMONARY TB
LONG TERM PROTECTION
Mycobacterium tuberculosis Highly clonal population structure
Differential Regions RD1-RD10 M. tuberculosis clinical isolates versus M. bovis (BCG)
TbD 1!
RD 9!
M. tuberculosis RD1 Major virulence factor ESAT6 RD 1!
Brosch et al PNAS 2002
THE M. tuberculosis STRAIN RESPONSIBLE FOR THIS RARE TUBERCULOSIS OUTBREAK SHOWED INCREASED EXPRESSION OF THE phoP GENE A PARTICULAR Mycobacterium bovis STRAIN CAUSED AN UNUSUAL MDR -­‐ XDR TB OUTBREAK… ü  First isolated in 1993 ü  HIV+ve individuals, 114 deaths ü Highly transmissible by aerosol route qRT-­‐PCR western-­‐blot M. bovis
phoP M. bovis “B” strain
IS6110 phoP Samper et al MDR TB AIDS 1997 / Guerrero et al Lancet 1997 / Rivero et al CID 2001 / Soto et al JCM2004 / Samper et al EID 2007 / Gonzalo-­‐Asensio et al PNAS 2014 FINAL CONSTRUCTION OF MTBVAC DELETION OF phoP and fadD26 IN A CLINICAL ISOLATE OF M. tuberculosis Euro-­‐American-­‐Africa linage 4 PhoP-­‐ DAT PAT
Ag85/ESAT6
Ag85 phoP dele3on PhoP of MTBVAC
ESAT6 Samper et al MDR TB AIDS 1997
Guerrero et al Lancet 1997
DIM-­‐ X DIM
fadD26 delePon Camacho et al Mol Microbiol 1999
Cox et al Nature 1999
PHASE I, DOUBLE-BLIND, RANDOMISED, CONTROLLED, SINGLE-CENTRE
STUDY IN HEALTHY ADULTS PI FRANCOIS SPERTINI
SUMMARY OF RELEVANT STUDY PROCEDURES
TIMEPOINTS POSTVACCINATION
SAFETY (AEs, SAEs)
All time points
Microbiological samples (swab, urine, stool)
All time points*
IMMUNOGENICITY 2ARY ENDPOINTS
ELISPOT IFNg (ESAT-6/CFP-10/PPD)
D-3, 0, 28, 90, 210
WBA with MTBVAC & BCG (ICS IL-2, TNF-a, IFNg)
D-3, 0, 28, 90, 210
EXPLORATORY ENDPOINTS
*Except if first two samples negative
Luminex (cytokines in culture) HBHA, Ag85,
ESAT-6,
CFP-10
Dr. Regine Audran D-3, 0, 28, 90, 210
anti–MTBVAC/MTB antibodies
D-3, 0, 28, 56, 90, 210
Transcriptomics (TRANSVAC platform, AGILENT)
All time points
Clinical Development of MTBVAC Phase I Safety /Immunogenicity
Adults Target populaVon MBVAC as prime in newborns Neonates Phase I I Safety /Immunogenicity Dose selecPon EFFICACY (PROTECTION) BETTER OR S AFER THAN BCG “BCG administration as close to birth as possible”
Conclusions: Absence of prior M. tuberculosis infection or
sensitization with environmental mycobacteria is associated with
higher efficacy of BCG against pulmonary tuberculosis and possibly
against miliary and meningeal tuberculosis. Evaluations of new
tuberculosis vaccines should account for the possibility that
prior infection may mask or block their effects.
Mangtani et al CDI 2014 EFFICACY EVALUATION OF A NEW TB VACCINE:
IN A NAÏVE POPULATION
BCG GIVEN AT BIRTH CONFERS COMPARABLE PROTECTION INDEPENDENTLY OF
ENVIRONMENTAL SENSITIZATION (40% SALVADOR AND 36% MANAUS).
Barreto et al Vaccine June 2014
TESTING PRE-EXPOSURE VACCINES IN NEWBORNS ALLOWS RELIABLE EFFICACY DETERMINATION.
EFFICACY EVALUATION OF A NEW TB VACCINE:
IN ADOLESCENTS ?
Previous environmental sensitization:
(e.g., previous BCG vaccination, mycobacterial infection and/or TB contact)
Masking effect:
provides some protective immunity against TB
Blocking effect:
prevents a new vaccine from providing protection
When first dose of BCG WAS GIVEN AT SCHOOL AGE,
protection was highly variable depending on previous
environmental sensitization,
34 % in SALVADOR, sensitization is considered lower
8% IN MANAUS sensitization is considered higher
Barreto et al Vaccine June 2014
EFFICACY STUDIES
Neonates VACCINATION STRATEGY
Neonates + Adolescents Grupo de Genética de Micobacterias
TBVI PDT Dr. Georges Thiry Dr. Roland Dobbelaer Dr. Micha Roumiantzeff Dr. Barry Walker Dr. Mei Mei Ho Dr. Eddy Rommel TBVI CDT Dr Bernard Fritzell Dr. François SperVni Dr. Luc Hessel Dr Emmanuelle Egerdill Carlos Mar-n Dr. Ainhoa Arbués Dr. Jesús Gonzalo Asensio Dr. Juan Ignacio Aguiló SanVago Uranga Dessi Marinova Alberto Cebollada Luis Solans Bernad /Carmen Arnal Esther Brosset/ Samuel Alvarez Ana Belén Gómez, Carlos Lapreave, Ana Pico, Carmen Lafoz !
Esteban Rodriguez Oswaldo Alvarez Dr. Conchita Fernandez Dr. Eugenia Puentes Dr. Alberto Parra Dr. Juana Doce InsPtut Pasteur Paris (FR) Brigice Gicquel Roland Brosh CNRS Toulouse (FR) Christophe Guilhot Wladimir Malaga Health ProtecPon Agency (UK) Ann Rawkins Simon Clark Univerity Sidney (AU) James Triccas Warwick Brigon Universidad Autónoma de México (MX) Rogelio Hernandez Pando InsPtuto Butantan Luciana Leite TBVI (NL) Jelle Thole Douglas Young Nick Draguer Mc Gill University (CA) Marcel Behr Serge Mostowy EPFL (CH) Stewart Cole Claudia Sala Andrej Benjak Biomedical Primate Research Center (NL) Frank Verreck Unitat de Tuberculosi Experimental HUGTP (ES) Pere Joan Cardona CrisVna Vilaplana Vicente Ausina Universidad Autónoma de Madrid (ES) María Jesús García Carmen Menéndez Clinical Development Team
•  Dr. Luc Hessel, chair
•  Dr. Steven Black
•  Dr. Bernard Fritzell
•  Dr. Emanuèle Gerdil
•  Dr. Francois Spertini, Univ. Lausanne