“MTBVAC. A live attenuated M. tuberculosis vaccine

in clinical trials”

MTBVAC

Nacho Aguiló Universidad de Zaragoza

http://genmico.unizar.es/

3rd December 2015

1a. Subunit vaccines/adjuvants 1b. Subunit vaccines/viral vectors 2. Live vaccines

Source: TBVI

LIVE VACCINES: • rBCG

• Attenuated MTB

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)

∆phoP ∆fadD26

phoP fadD26

Mycobacterium tuberculosis MT103

MTBVAC

MTBVAC

2008

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