MTBVAC in Newborns: Description and objectives
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. Safety and immunogenicity of MTBVAC was demonstrated in BCG naïve adults; and MTBVAC appears safe in a 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.
EDCTP supports this 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.
The 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.
Aims of the project are:
- To evaluate safety and reactogenicity of MTBVAC at three escalating dose levels, compared to BCG vaccine, in healthy, BCG naïve, HIV unexposed, South African newborns;
- To evaluate the immunogenicity of MTBVAC at three escalating dose levels in healthy, BCG naïve, HIV unexposed, South African newborns.
A secondary aim of the project is:
- To evaluate immunogenicity of MTBVAC at escalating dose levels as compared to BCG
- To evaluate the dynamics of MTBVAC vaccine-induced QFT conversion and reversion in healthy, BCG naïve, HIV unexposed, South African newborns.
Project duration 36 months.
Work package 1: MTBVAC Phase 2a in newborns
A randomized, controlled, double blind trial will evaluate the safety, reactogenicity, immunogenicity, and potential for QFT conversion and reversion of the candidate TB vaccine MTBVAC in BCG naïve newborns, administered in 3 cohorts at a single intradermal dose of 2.5 x 104, 2.5 x 105 or 2.5 x 106 CFU, compared to BCG vaccine at a dose of 2.5 x 105 CFU.
The hypothesis is, that the optimal safe and immunogenic MTBVAC dose for infants lies in the range of 2.5 x 104 (10-fold lower than BCG) to 2.5 x 106 CFU (10-fold higher than BCG). Therefore, this proposed infant trial aims to define the MTBVAC dose-response curve above and below the optimal MTBVAC dose, straddling a 3-log dose range.
In addition, given the crucial importance of confirming that MTBVAC vaccine-induced QFT conversion occurs in infants, understanding the immunological basis for MTBVAC vaccine-induced QFT conversion, and defining the time course and magnitude (IFN-g concentration) of MTBVAC vaccine-induced QFT conversion and reversion events, serial QFT assays will be performed in parallel with whole blood T cell assays.
Study Design: Ninety-nine HIV unexposed, BCG naïve, newborns without known household exposure to M.tuberculosis will be randomized to receive either BCG standard dose at 2.5 x 105 CFU (n=24) or MTBVAC at one of three different dose levels (n=75).
The work package is subdivided into three sub-work packages:
1. Study start-up
2. Study conduct
3. Study close out
Work package 2: Capacity building and Technology Transfer for Infant Efficacy Trials
The clinical development consortium will prepare for the planned MTBVAC newborn efficacy trials by establishing a network of three sites in three African countries; i.e. South Africa: South African Tuberculosis Vaccine Initiative (SATVI) at the University of Cape Town (UCT); Senegal: Centre de Recherche Biomédicale (CRB-EPLS) and Madagascar: Institut Pasteur de Madagascar (IPM). These three sites, which include Francophone and Anglophone institutions in Southern, East and West Africa, have been selected to offer optimal genetic, epidemiologic, and demographic diversity in the study population for future efficacy testing. Each site has an established research infrastructure. In order to establish readiness for clinical trials of TB vaccines, the Senegal and Madagascar sites will, under this project, further develop immunology laboratory capacity through technology transfer and training.
The primary capacity building goals include:
1) To standardize immunological assay techniques;
2) To harmonize common operational practices and standard operating procedures.
Capacity building will be ensured through several phases:
1. Training phase by SATVI for technicians from CRB-EPLS and IPM
2. Local transposition and translation of Standard Operating Procedures
3. Technology transfer phase
4. Validation phase
Work package 3: Site Preparation Study: Epidemiology of Childhood TB in partner sites
A cross–sectional childhood TB prevalence survey will be conducted in Senegal and Madagascar to collect information on the local TB epidemic to inform site selection, sample size, and recruitment strategies for a future efficacy trial of MTBVAC in young children. These studies are focused on estimating likely accrual of childhood TB disease endpoints in targeted study communities.
Specifically, these studies will provide targeted prevalence estimates among high-risk sub-communities who would be identified for recruitment in an efficacy trial. This WP will build upon the enhanced laboratory capacities acquired in WP2 to conduct a cross-sectional survey of age-specific M. tuberculosis infection rates during which additional epidemiological data will be gathered on TB disease prevalence.
The objectives are to provide epidemiological data on childhood TB disease prevalence to prepare for future efficacy trials with MTBVAC at the Senegal and Madagascar study sites:
- Define local age-specific prevalence rates of TB infection and disease in children by respectively QuantiFERON® assay and available data from the local, regional, or national TB Control Program;
- Establish the respective endpoints of future Prevention of Infection (POI) and Prevention of Disease (POD) efficacy trials.
- Infer burden of TB transmission and local childhood TB incidence;
This work package is subdivided into three sub-work packages:
- Establishment of the protocol and approvals
- Cross-sectional childhood TB prevalence survey
- Data management and analysis
Work package 4: Project management
To ensure and manage the expected project objectives, a project management structure is established in order to:
- Establish and implement management infrastructure (Steering Committee, Project management team, Scientific and Clinical Advisory Team, Project management tools (administration, financial, dissemination and communication);
- Scientific and technical coordination of the project activities;
- Financial and contractual management;
- Monitor project progress, and provide reports;
- Monitor data management and impact;
- Implement dissemination and communication activities;
- Monitor ethical issues.
This work package will be distributed into two sub-work packages:
- Establish organizational structure including its bodies
- Implementation of the coordination and project management activities