Live-attenuated Mycobacterium tuberculosis vaccine, MTBVAC, in adults with or without M tuberculosis sensitisation: a single-centre, phase 1b-2a, double-blind, dose-escalation, randomised controlled trial.

BACKGROUND An effective adult vaccine is needed to control tuberculosis. We evaluated the safety and immunogenicity of a live-attenuated Mycobacterium tuberculosis vaccine (MTBVAC). METHODS This single-centre, phase 1b-2a, double-blind, dose-escalation, randomised controlled trial (NCT02933281) enrolled South African adults previously vaccinated with BCG, who were HIV negative and aged 18-50 years, with or without M tuberculosis sensitisation assessed by QuantiFERON-tuberculosis Gold-Plus assay (QFT). Participants were recruited from the local community and randomly allocated (2:1) to receive MTBVAC (5 × 103, 5 × 104, 5 × 105, or 5 × 106 colony-forming unit [CFU] doses) or BCG revaccination (5 × 105 CFU dose). The primary outcomes were the occurrence of systemic solicited adverse events within 7 days and unsolicited adverse events within 28 days after vaccination, the occurrence of solicited and unsolicited injection-site reactions within 84 days after vaccination, and the occurrence of serious adverse events (SAEs) until the end of study, 365 days after vaccination. Data were analysed per modified intention to treat. The trial is now complete and closed. FINDINGS Between Jan 15, 2019, and Sept 7, 2020, 485 participants provided consent and were screened. 144 participants were enrolled and 143 (99%) were vaccinated. BCG was administrated to 47 (33%) of 143 and MTBVAC to 96 (67%) of 143. 12 participants with QFT-negative results and 12 with QFT-positive results were randomly allocated to receive each dose of MTBVAC and 24 participants with QFT-negative results and 24 with QFT-positive results were randomly allocated to receive BCG revaccination. Injection-site pain, discharge, erythema, and swelling increased with MTBVAC dose level. MTBVAC 5 × 105 CFU recipients reported a similar proportion of related adverse events (23 [96%] of 24) as BCG recipients (45 [96%] of 47). MTBVAC recipients who were QFT positive reported more injection-site reactions (46 [96%] of 48; 95% CI 85·7-99·5) than MTBVAC recipients who were QFT negative (32 [67%] of 48; 51·6-79·6). No vaccine-related SAEs were reported. All doses of MTBVAC were immunogenic; vaccine-induced antigen-specific CD4 T-cell responses peaked 28 days after vaccination. The MTBVAC 5 × 105 and 5 × 106 CFU doses induced T-helper-cell-1 cytokine-expressing CD4 T-cell responses that exceeded BCG-induced responses in participants who were QFT negative and QFT positive. INTERPRETATION MTBVAC at the 5 × 105 dose showed similar safety and reactogenicity and greater immunogenicity when compared to BCG. These results suggest that the 5 × 105 dose of MTBVAC could be selected for a subsequent efficacy evaluation. FUNDING Congressionally Directed Medical Research Programmes and US National Institutes of Health.