1. Annual TBVAC2020 Meeting, Les Diablerets, 29th Jan – 1st Feb 2018
“Therapeutic vaccination and host-directed (immuno) therapy against TB”
A Phase 2a
RIA 2016V_1637
MTBVAC in Newborns
WORKING TOGETHER FOR A HEALTHIER WORLD

2. RIA 2016V-1637 – MTBVAC Newborns
Index
MTBVAC Introduction
MTBVAC A new TB vaccine
Preclinical studies
Clinical development
MTBVAC – Efficacy Evaluation of a New Vaccine
RIA2016V-1637 – MTBVAC Phase 2a in newborns
Objectives
Key Parameters
Schedule
Work Plan
Organogram
Partnerships & Collaborations

3. MTBVAC A new TB vaccine
BCG 
1084 epitopes
MTBVAC 
1603 epitopes
A total of 433 T cell-epitopes present in RD regions absent in BCG
Gonzalo- Asensio et al Frontiers in Immunology 15 Dec 2017

4. MTBVAC GENEVA CONSENSUS CRITERIA: CONSTRUCTION OF MTBVAC
TWO STABLE INDEPENDENT MUTATIONS
NO ANTIBIOTIC RESISTANCE MARKERS
MTBVAC
fadD26
phoP 4 4 4

5. Collaborative work over time
PRECLINICAL STUDIES MTBVAC
FROM 2001 to 2012
ATTENUATION
SCID
Aerosol / IV
SC 50 dose 6 Months
Collaborative work over time
BalbC/ IT
2001
2012
C57/BL6 aerosol Protection
Transgenic p25 Ag85B
Memory T cells
Aerosol Low dose
High dose H37Rv
NHP IT Erdman
C57/BL6 in H37Rv
PROTECTION
IMMUNOGENICITY
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

6. Long-term, real time stability studies
MTBVAC CLINICAL DEVELOPMENT
2011
2012
2013
2014
2015
2016
2017
2010
MTBVAC
final lot
May 2011
Long-term, real time stability studies
Non-clinical studies
to support clinical
evaluation
25 Aug’10 – 20 Dec’11
First history time of APPROVAL for a M. tuberculosis vaccine in human clinical trial TIME OF
TBVI PDT
TBVI CDT
Phase I CTA Preparation
Oct’11 – April ’12
CTA Evaluation
Approval
3 Oct 2012
CTA Evaluation
11 May 2015
Approval
13 May 2015
HREC+ DAFF
5 Aug 2015
PHASE Ia HEALTHY ADULTS
in CHUV Switzerland
PPD-, BCG-, HIV-
(18-45 yrs)
Vaccination phase:
23 Jan - 6 Nov 2013
Last visit V10
End of study
6 Jun 2014
Unblinded data
March 2015
Published Nov 2015
The Lancet Respi Medi
PHASE Ib in NEWBORNS
With a safety arm in adults (BCG+, PPD-, HIV-)
Sept Jan 2016
ClinicalTrials.gov: NCT
Vaccination phase 16 feb - 21 Sep 2016
ClinicalTrials.gov NCT

7. MTBVAC - EFFICACY EVALUATION OF A NEW TB VACCINE
Transmission
of TB
Burden of TB in age groups
NEWBORN
INFANT
ADOLESCENT
ADULT
ELDERLY
BCG
ADULTS/ ADOLESCENTS
NEWBORN
Impact
Disease
Disease, transmission
Two main vaccine targets - MTBVAC
1. NEWBORNS: Pre-exposure vaccines could allow for reliable efficacy determination. BCG replacement
2. ADULTS/ADOLESCENTS: Post exposure, vaccinated with BCG, infected with MTB or other mycobacteria

8. RIA 2016V_1637 – MTBVAC Newborns Phase 2a
VACCINATION AT BIRTH (NEONATES):
Dose-Defining Safety and Immunogenicity Study and Capacity Building to Support Vaccine Efficacy Trials in TB-Endemic Regions of Sub-Saharan Africa
PI: Dr. Michele Tameris Clinical Study Advisor: Mark Hatherill
DOSE SELECTION Safety, Reactogenicity and Immunogenicity
Participants
Biofabri / Spain / Coordinator
TuBerculosis Vaccine Initiative (TBVI) / Netherlands
Universidad de Zaragoza / Spain
University of Cape Town (UCT) / South Africa
Center de Recherche Biomedicale Espoir Pour La Santé (BRC-EPLS)/ Senegal
Institut Pasteur de Madagascar (IPM)/ Madagascar

9. RIA 2016V_1637 – MTBVAC Newborns Objectives
A Phase 2a Randomised Controlled Dose-Defining Trial of the Safety and Immunogenicity of MTBVAC in Healthy, BCG Naïve, HIV Unexposed, South African Newborns
Co-primary:
To evaluate safety and reactogenicity of MTBVAC at three escalating dose levels, compared to BCG vaccine
To evaluate the immunogenicity of MTBVAC at three escalating dose levels compared to BCG vaccine
Secondary:
To evaluate QFT conversion and reversion rates in neonates receiving escalating dose levels of MTBVAC
Exploratory: (Thomas Scriba)
To evaluate differences in major histocompatibility (MHC)-restricted T-cell responses induced by MTBVAC and BCG vaccination.
To evaluate differences in donor-unrestricted T-cell responses induced by MTBVAC and BCG vaccination

10. RIA 2016V_1637 – MTBVAC Newborns Key Parameters
A Phase 2a Randomised Controlled Dose-Defining Trial of the Safety and Immunogenicity of MTBVAC in Healthy, BCG Naïve, HIV Unexposed, South African Newborns
Trial Population: 99 (75+24)
Cohort 1: n= 25 MTBVAC (2.5 x 104 CFU) and n=8 BCG
Cohort 2: n=25 MTBVAC (2.5 x 105 CFU) and n=8 BCG
Cohort 3: n=25 MTBVAC (*2.5 x 106 or 103 CFU) and n=8 BCG
1 Site: SATVI in Cape Town, SA
Duration: 36 months
DSMB Safety Review before Cohort 3 vaccination

11. RIA 2016V_1637 – MTBVAC Newborns Schedule

12. RIA 2016V_1637 – MTBVAC Newborns Work Plan
Work Package 1 – MTBVAC Phase 2a in newborns
Work Package 2 – Capacity Building and Technology Transfer for Infant Efficacy Trial
Work Package 3 – Epidemiology studies
Work Package 4 – Project Management

13. RIA 2016V_1637 – MTBVAC Newborns Work Plan
Leads: University of Cape Town (UCT)
Dr. Mark Hatherill
Work Package 1 – MTBVAC Phase 2a in newborns
Co-primary:
To evaluate safety and reactogenicity of MTBVAC at three escalating dose levels, compared to BCG vaccine
To evaluate the immunogenicity of MTBVAC at three escalating dose levels compared to BCG vaccine
Secondary:
To evaluate QFT conversion and reversion rates in neonates receiving escalating dose levels of MTBVAC
Exploratory: (Thomas Scriba)
To evaluate differences in major histocompatibility (MHC)-restricted T-cell responses induced by MTBVAC and BCG vaccination
To evaluate differences in donor-unrestricted T-cell responses induced by MTBVAC and BCG vaccination

14. RIA 2016V_1637 – MTBVAC Newborns Work Plan
Leads: Center de Recherche Biomedicale Espoir Pour La Santé (BRC-EPLS)
Dr. Gilles Riveau
Work Package 2 – Capacity Building and Technology Transfer for Infant Efficacy Trial
Objectives
Training to staff of BRC-EPLC and IPM in celular inmunology assays at SATVI
Performing on site training experiments at BRC-EPLC and IPM
Validation steps ensuring proficiency of on-site assays at BRC-EPLS and IPM by SATVI

15. RIA 2016V_1637 – MTBVAC Newborns Work Plan
Leads: Institut Pasteur de Madagascar (IPM)
Dr. Niaina Rakotosamimanana
Work Package 3 – Epidemiology studies of Childhood TB in partner sites
Objectives
Provide epidemiological data on childhood TB disease prevalence Efficacy Trial
Perform cross-sectional childhood TB prevalence survey of M. tuberculosis infection
Define local age-specific prevalence rates of TB infection & disease in children by QFT conversión
Infer burden of TB transmission and local childhood TB incidence
Establish endpoints of future Prevention of Infection and Prevention of Disease
500 CHILDREN IN 4 COHORTS BY AGES (1, 2, 5 & 12 )

16. RIA 2016V_1637 – MTBVAC Newborns Work Plan
Leads: BIOFABRI
Dr. Ingrid Murillo
Work Package 4 – Project Management
Objectives
Establish and implement management infrastructure
Scientific, technical and clinical coordination
Financial and contractual management
Dissemination and communication activities

17. RIA 2016V_1637 – MTBVAC Newborns Organogram
Steering committee
(All partners)
SCAT (UNIZAR,TBVI)
WP leader 3 (IPM)
WP leader 2 (BRC_EPLS)
WP 1 partners:
UCT
Biofabri (TCD)
WP 2 partners:
IPM
BRC-EPLS
WP 3 partners:
WP leader 1 (UCT)
PMT (Biofabri/TBVI/UNIZAR) coordination and project management WP 4

18. RIA 2016V_1637 – MTBVAC Newborns PARTNERSHIPS & COLLABORATIONS.
RIA 2016V_1637 – MTBVAC Newborns
PARTNERSHIPS & COLLABORATIONS
Dr. Gilles Riveau BRC-EPLS (Senegal)
Dr. Jelle Thole advisor on product and clinical development of MTBVAC
Prof. Carlos Martín University of Zaragoza
Mr. Anne Mainema TBVI
Ms. Danielle Roordink TBVI
Dr. Niaina Rakotosamimanana
Institut Pasteur of Madagascar
Dr. Michele Tameris SATVI
Dr. Esteban Rodríguez
Dr. Eugenia Puentes Dr. Juana Doce
Dr. Ingrid Murillo
BIOFABRI
Prof. Mark Hatherill University of Cape Town

19. Thank you!!