Safety, reactogenicity, and immunogenicity of MTBVAC in infants: a phase 2a randomised, double-blind, dose-defining trial in a TB endemic setting.

BACKGROUND: Safer and more effective tuberculosis (TB) vaccines than Bacille Calmette Guérin (BCG) are needed. We evaluated the safety, reactogenicity, and immunogenicity of three dose levels of the live-attenuated Mycobacterium tuberculosis (Mtb) vaccine, MTBVAC, compared to BCG, in South African infants. METHODS: Healthy, HIV-unexposed, BCG-naïve infants were randomised to receive a single intradermal dose of BCG (2.5 × 10(5) CFU, n = 24) or MTBVAC (2.5 × 10(4), 2.5 × 10(5), or 2.5 × 10(6) CFU, each n = 25). Safety endpoints were solicited systemic, solicited injection site, and unsolicited adverse events (AE), and serious AE (SAE). Immunogenicity was measured using interferon-γ release assay (IGRA) and whole blood intracellular cytokine staining assay. Follow-up was 12 months post-vaccination. FINDINGS: Ninety-nine infants were enrolled between 18 February 2019 and 08 March 2021. Seventy-eight infants experienced reactogenicity AE (all mild except one grade 2 erythema). Induration, swelling, and erythema were more frequent as MTBVAC dose increased. All reactogenicity events were less frequent in infants receiving MTBVAC 2.5 × 10(5) CFU compared with BCG. Twelve infants (three BCG and nine MTBVAC recipients) experienced 14 vaccine-unrelated SAE, including one death due to bronchopneumonia (MTBVAC recipient). Eight infants were treated for unconfirmed pulmonary TB (four BCG and four MTBVAC 2.5 × 10(4) CFU recipients); one BCG recipient was treated for unconfirmed TB meningitis. MTBVAC was immunogenic at all 3 doses, inducing predominantly Th1-cytokine-expressing CD4 T cells, which peaked at Day 56. The 2.5 × 10(5) and 2.5 × 10(6) CFU MTBVAC doses induced similar response magnitudes and were more immunogenic than BCG. Day 56 IGRA conversion was observed in 61 (87.4%) infants receiving any MTBVAC dose, but only 28 (42.4%) remained positive by Day 365. INTERPRETATION: MTBVAC appeared safe, well-tolerated, and immunogenic at doses between 2.5 × 10(4) and 2.5 × 10(6) CFU in South African infants. The 2.5 × 10(5) CFU MTBVAC dose, being less reactogenic and more immunogenic than BCG, was selected for a multi-centre, phase 3 trial. FUNDING: This trial was funded by the European and Developing Countries Clinical Trials Partnership (EDCTP).