Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial

Abstract

Background Infants are a key target population for new tuberculosis vaccines. We assessed the safety and immunogenicity of the live-attenuated Mycobacterium tuberculosis vaccine candidate MTBVAC in adults and infants in a region where transmission of tuberculosis is very high. Methods We did a randomised, double-blind, BCG-controlled, dose-escalation trial at the South African Tuberculosis Vaccine Initiative site near Cape Town, South Africa. Healthy adult community volunteers who were aged 18-50 years, had received BCG vaccination as infants, were HIV negative, had negative interferon-γ release assay (IGRA) results, and had no personal history of tuberculosis or current household contact with someone with tuberculosis were enrolled in a safety cohort. Infants born to HIV-negative women with no personal history of tuberculosis or current household contact with a person with tuberculosis and who were 96 h old or younger, generally healthy, and had not yet received routine BCG vaccination were enrolled in a separate infant cohort. Eligible adults were randomly assigned (1:1) to receive either BCG Vaccine SSI (5 × 10⁵ colony forming units [CFU] of Danish strain 1331 in 0•1 mL diluent) or MTBVAC (5 × 10⁵ CFU in 0•1 mL) intradermally in the deltoid region of the arm. After favourable review of 28-day reactogenicity and safety data in the adult cohort, infants were randomly assigned (1:3) to receive either BCG Vaccine SSI (2•5 × 10⁵ CFU in 0•05 mL diluent) or MTBVAC in three sequential cohorts of increasing MTBVAC dose (2•5 × 10³ CFU, 2•5 × 10⁴ CFU, and 2•5 × 10⁵ CFU in 0•05 mL) intradermally in the deltoid region of the arm. QuantiFERON-TB Gold In-Tube IGRA was done on days 180 and 360. For both randomisations, a pre-prepared block randomisation schedule was used. Participants (and their parents or guardians in the case of infant participants), investigators, and other clinical and laboratory staff were masked to intervention allocation. The primary outcomes, which were all measured in the infant cohort, were solicited and unsolicited local adverse events and serious adverse events until day 360; non-serious systemic adverse events until day 28 and vaccine-specific CD4 and CD8 T-cell responses on days 7, 28, 70, 180, and 360. Secondary outcomes measured in adults were local injection-site and systemic reactions and haematology and biochemistry at study day 7 and 28. Safety analyses and immunogenicity analyses were done in all participants who received a dose of vaccine. This trial is registered with ClinicalTrials.gov, number NCT02729571.

Respiratory Immunization With a Whole Cell Inactivated Vaccine Induces Functional Mucosal Immunoglobulins Against Tuberculosis in Mice and Non-human Primates

“…The present work describes vaccination with a heat-killed (HK) version of the live attenuated M. tuberculosis vaccine MTBVAC (Arbues et al, 2013) both in mice and non-human primates (NHP). MTBVAC is the first and only live attenuated tuberculosis vaccine based on M. tuberculosis that has reached clinical stages of development, and it has shown an excellent safety profile both in adults and newborns, as well as stronger immunogenicity compared to BCG (Spertini et al, 2015;Tameris et al, 2019). Results in the present study demonstrate improved efficacy of MTBVAC HK when given by intranasal route to mice previously vaccinated with subcutaneous BCG.…”

New live attenuated tuberculosis vaccine MTBVAC induces trained immunity and confers protection against experimental lethal pneumonia

“…In order to confirm the relevance of these mechanisms in vivo, a group of C57BL/6 mice were vaccinated with a clinically relevant dose of MTBVAC [8,28,29] or BCG subcutaneously. After 4 weeks, these mice were challenged with LPS, and the levels of their proinflammatory cytokines were measured in serum ( Fig 4A).…”

Update on TB Vaccine Pipeline

“…The primary target population of MTBVAC are neonates; the secondary target population includes adolescents and adults (as a booster vaccine). A Phase Ia trial in adults showed that MTBVAC is safe and immunogenic [56] and a second Phase Ib in neonates in an endemic country showed that MTBVAC is as safe as BCG and more immunogenic [57]. Dose-defining Phase IIa trials in both target populations started in 2019 with funding support from US NIH in collaboration with IAVI in adults (ClinicalTrials.gov NCT02933281) and the EDCTP in collaboration with TBVI in neonates (ClinicalTrials.gov NCT03536117) ( Figure 2).…”