Post on 14-Oct-2018
“MTBVAC. A live attenuated M. tuberculosis vaccine
in clinical trials”
MTBVAC
Nacho Aguiló Universidad de Zaragoza
http://genmico.unizar.es/
3rd December 2015
VPM1002 recombinant BCG (rBCG) + Listeriolysin
(L. monocytogenes) rBCGDUreaseC : (MPIIB)
rBCG KNOCK-IN strategy: Listeriolysin O (clinical development, phase IIa)
Brosch et al PNAS 2007 BCG Pasteur 1173 SEQUENCE
Live attenuated MTB strategy
95% of TB cases in humans are caused by M. tuberculosis
BCG Genome: Diminishing of T-Cell Epitopes
Copin et al Vaccine October 2014
Compared 1.530 human T cell epitopes in BCG with MTBC 23% OF THE KNOWN T CELL EPITOPES
ARE ABSENT IN BCG (358/1530)
2001 2012
PRECLINICAL STUDIES FROM 2001 to 2012
PROTECTION IMMUNOGENICITY
C57/BL6 in H37Rv Aerosol Low dose High dose H37Rv NHP IT Erdman
C57/BL6 aerosol Protection
Transgenic p25 Ag85B
Memory T cells
BalbC/ IT SCID
Aerosol / IV SC 50 dose 6 Months
Perez et al Mol Micro 2001, Williams et al Tuberculosis 2005, Martín et al Vaccine 2006, Aguilar et al CEI
2007, Cardona et al Vaccine 2009, Verreck et al PLOs ONE 2009, Nambiar et al Eur J Immunology 2012
ATTENUATION, SAFETY AND BIODISTRIBUTION
SO2: prototype vaccine with identical phenotype as MTBVAC
Randomize and Allocate BCG control 3:1
Primary Endpoints: Safety &
Reactogenicity
Vaccination & Evaluation
Data Analysis and Study
Conclusion
Safety
Review
Team
Local
Safety
Monitor
36 HEALTHY PPD-, BCG-, HIV- (6 months follow-up)
MTBVAC PHASE 1 CLINICAL EVALUATION
Secondary Endpoint:
Immunogenicity
MTBVAC 5x103, 5x104, 5x105
BCG: 5x105
(CFU in 0.1ml)
Phase I
Prof. F. Spertini
PRIMARY ENDPOINT: SAFETY
Spertini et al 2015 Lancet Respiratory Medicine
No adverse events were associated with vaccination
• All volunteers were negative for ESAT-6, CFP10 at day 210, the end of active
follow-up study.
Spertini et al 2015 Lancet Respiratory Medicine
ESAT6-CFP10 IGRA CONVERSION
0 28 90 210 0 28 90 210 0 28 90 210 0 28 90 210
-0.1
0.0
0.1
0.2
0.3
0.4
0.5 0.0809
*
0.0169
*
0.0006
***
0.0038
* *
days
1/94/9 2/9 1/9
MTBVAC
5.103
BCG
5.105
MTBVAC
5.104
MTBVAC
5.105
0 28 90 210 0 28 90 210 0 28 90 210 0 28 90 210-0.05
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35 0.1149 0.0615 0.0017
*** *
0.0396
*
3/9
days
2/9 0/9 1/9
MTBVAC
5.103
BCG
5.105
MTBVAC
5.104
MTBVAC
5.105
live MTBVAC-specific response live BCG-specific response
me
mo
ryC
D4
Tc
ell
s
ex
pre
ss
ing
3c
yto
kin
es
(%)
3 CYTOKINES (IFNg , IL2, TNF a) POLYFUNCTIONAL CD4+ T CELL
Spertini et al 2015 Lancet Respiratory Medicine
Whole Blood Assay
stimulation with BCG
or MTBVAC
SECONDARY ENDPOINT: IMMUNOGENECITY
EXPLORATORY ENDPOINTS: ONGOING
TBVAC-H2020 PROJECT
PBMCs. DIFFERENTIAL ANTIGEN-SPECIFIC IMMUNOGENECITY: • ESAT6 (RD1) • CFP10 (RD1) • MTP64 (RD2)
• HBHA
• AG85A/B
• LATENCY ANTIGENS
• OTHERS
Aaby and Benn PNAS | October 23, 2012
EVALUATION OF MTBVAC IN NEWBORNS (naïve population)
• Adult safety arm vaccination completed (November 2015)
VACCINE EFFICACY
http://www.ndm.ox.ac.uk/who-tb-day-2014
EVALUATION OF MTBVAC IN ADOLESCENTS
• BCG VACCINATED
• ENVIROMENTAL MYCOBACTERIA
• HIGH PREVALENCE OF QFT+ INDIVIDUALS
IMPACT IN TB TRANSMISSION
Nacho Aguiló
José Antonio Aínsa*
Henar Alonso
Esther Broset
Carmen Arnal
Rebeca Bailo
Alberto Cebollada
Ana Belén Gómez
Jesús Gonzalo
Begoña Grácia
Daniel Ibarz Bosque
Mª José Iglesias Gozalo*
Carmen Lafoz
* IP coordinadores de línea
Carlos Lampreave
Dessi Marinova
Isabel Millan
Isabel Otal*
Ana Pico
Sara Sagasti
Sofía Samper *
Luis Solans
Santiago Uranga
Samuel Álvarez
Liliana Rodrigues
Grupo de Genética de Micobacterias http://genmico.unizar.es
Microbiología Clínica
Mª José Revillo Pinilla
Asunción Vitoria
Dirección General de Salud Pública
Grupo de Apoptosis, Inmunidad y
Cancer
Alberto Anel
Julian Pardo
Centro de Encefalopatías y
Enfermedades Emergentes
Marta Monzón
Juan J Badiola
Universidad Autónoma de México (MX) Rogelio Hernandez Pando
Universidad Autónoma de Madrid (ES) María Jesús García Carmen Menéndez
Unitat de Tuberculosi Experimental HUGTP (ES) Pere Joan Cardona Cristina Vilaplana Vicente Ausina
Public Health England (UK) Ann Rawkins Simon Clark
Biomedical Primate Research Center (NL) Frank Verreck
Institut Pasteur Paris (FR) Brigitte Gicquel Roland Brosh
Mc Gill University (CA) Marcel Behr
Serge Mostowy
TBVI (NL) Jelle Thole Douglas Young Nick Draguer
CNRS Toulouse (FR) Christophe Guilhot Olivier Neyrolles
EPFL (CH) Stewart Cole Claudia Sala Andrej Benjak
Univerity Sidney (AU) Warwick Britton James Triccas
Instituto Butantan Brazil (BR) Luciana Leite
Clinical Development Team
• Dr. Luc Hessel, chair
• Dr. Steven Black
• Dr. Bernard Fritzell
• Dr. Emanuèle Gerdil
• Dr. Francois Spertini, Univ. Lausanne