Toward tuberculosis elimination: An update on tuberculosis vaccines in clinical trials.

Despite major advances in diagnosis and treatment, tuberculosis (TB) control - and ultimately elimination - will remain unachieved without a vaccine capable of preventing pulmonary disease and transmission. Bacille Calmette-Guérin (BCG), a live attenuated vaccine derived from Mycobacterium bovis and the only licensed TB vaccine, has been widely implemented because of its proven efficacy against severe childhood TB. However, despite global coverage approaching 90%, BCG provides limited and inconsistent protection against pulmonary TB in adolescents and adults, the populations that sustain transmission. In response, a diverse pipeline of novel TB vaccine candidates has emerged across multiple technological platforms. This review provides an updated overview of TB vaccines in clinical development. Currently, sixteen candidates are undergoing clinical evaluation, including four in active Phase 3 efficacy trials. This review also offers critical insights into challenges shaping late-stage TB vaccine development. We argue that evolving understanding of Mycobacterium tuberculosis infection - including heterogeneity within latent infection, the contribution of subclinical disease, and limitations of binary IGRA-based classification - necessitates reassessment of current efficacy endpoints. By examining prevention-of-disease (PoD), prevention-of-infection (PoI), and prevention-of-recurrence (PoR) strategies, we highlight the need for closer alignment between biological insight, trial design, and policy objectives to ensure that new vaccines advance TB elimination.