{"doi":"10.1016/j.ebiom.2025.105628","title":"Safety, reactogenicity, and immunogenicity of MTBVAC in infants: a phase 2a randomised, double-blind, dose-defining trial in a TB endemic setting","abstract":"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).","journal":"EBioMedicine","year":2025,"id":512420,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9621,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":577007,"name":"Virginie Rozot","orcid":"0000-0001-9757-1501","position":1,"is_corresponding":false},{"id":1239882,"name":"Claire Imbratta","orcid":null,"position":2,"is_corresponding":false},{"id":252311,"name":"Hennie Geldenhuys","orcid":"0000-0002-2221-8997","position":3,"is_corresponding":false},{"id":252290,"name":"Simon C. 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