Project: MTBVAC in Newborns: Phase 2a Dose-Defining Safety and Immunogenicity Study and Capacity Building to Support Vaccine Efficacy Trials in Tuberculosis-Endemic Regions of Sub-Saharan Africa

Acronym MTBVAC-Newborns (Reference Number: RIA2016V-1637)
Duration 01/01/2018 - 31/12/2020
Project Topic A new effective tuberculosis (TB) vaccine is essential to achieve World Health Organization End TB goals and eliminate TB by 2050. The optimal long-term strategy would be a combination of serial mass campaigns in adults, coupled with universal newborn vaccination. Newborns are the only human population without prior mycobacterial exposure in TB endemic countries and as such, live attenuated mycobacterial vaccines may offer better protection to this naïve population compared to adults. MTBVAC is a novel TB vaccine candidate based on an attenuated M. tuberculosis clinical isolate of the Euro-American lineage containing two independent, stable genetic deletions of the genes phoP and fadD26 coding for two major virulence factors, the transcription factor PhoP and the cell-wall lipids PDIM, respectively. MTBVAC contains most of the genes deleted from BCG and presents a wider collection of mycobacterial antigens to the host immune system. Safety and immunogenicity of MTBVAC was demonstrated in BCG naïve adults; and MTBVAC appears safe in a small ongoing Phase 1b study in South African newborns. Definitive demonstration of safety and immunogenicity at the optimal MTBVAC dose is key to progression into multi-centre efficacy trials in infants. This EDCTP project will support a Phase 2a dose-defining study of MTBVAC to evaluate the safety, reactogenicity, immunogenicity, and potential for IGRA conversion and reversion, of MTBVAC in South African newborns. Ninety-nine HIV unexposed, BCG naïve newborns will be randomized to receive either BCG standard dose (n=24) or MTBVAC at one of three dose levels (n=75). Allocation will be double blind and enrolment sequential into 3 cohorts of increasing MTBVAC dose (n=33 per cohort, 25 MTBVAC and 8 BCG): Cohort 1 MTBVAC 2.5x104; Cohort 2 MTBVAC 2.5x105; Cohort 3 MTBVAC 2.5x106. Dose escalation will be staggered to allow gradual evaluation of safety. Final selection of Cohort 3 dose will be based on all available safety and immunogenicity data in newborns and adults. If safety criteria for the highest 2.5x106 CFU dose are not fulfilled, the lowest (2.5x103 CFU) MTBVAC dose would be selected. Our clinical development consortium will prepare for an infant efficacy trial of MTBVAC by establishing a network of three African sites in South Africa, Senegal and Madagascar. Each site has established research infrastructure. Senegal and Madagascar will, under this project, acquire immunology laboratory technology transfer and training; and collect crucial TB epidemiological data to enable swift transition into a Phase 3 infant trial, pending favourable data from this project.
Network EDCTP2
Call Vaccines for poverty-related diseases (PRDs)

Project partner

Number Name Role Country
1 Biofabri S.L. Coordinator Spain
2 Stichting tuBerculosis Vaccine Initiative Partner Netherlands, The
3 Universidad de Zaragoza Partner Spain
4 University of Cape Town Partner South Africa
5 Centre de Recherche Biomédicale Espoir Pour La Santé Partner Senegal
6 Institut Pasteur de Madagascar Partner Madagascar