Globally, Mycobacterium tuberculosis (Mtb) remains the leading cause of death from a single infectious agent. The only licensed vaccine, Bacillus Calmette–Guérin (BCG), was developed over a century ago and does not provide consistent protection against pulmonary tuberculosis (TB). Efforts to develop more effective vaccines are hindered by an incomplete understanding of the correlates of protection and by the pathogen’s sophisticated immune-evasion strategies. Mtb systematically undermines host defenses, reprograms host cell biology, and interferes with cell–cell communication to establish a permissive niche and sustain chronic infection. An effective vaccine must elicit immune responses capable of overcoming these bacterial strategies across diverse host and pathogen backgrounds. Traditional approaches focused on boosting T cell responses have proven inadequate. In this review, we summarize innate and adaptive immune mechanisms that contain Mtb, examine how bacterial immune subversion and host–pathogen heterogeneity complicate vaccine design, and highlight emerging concepts and strategies to guide TB vaccine development.
Prasad et al. (2026) studied this question.