Advancing Tuberculosis Vaccination: Immunological Insights and Emerging Strategies for Improved Protection

Tuberculosis (TB) remains one of the leading causes of infectious disease mortality worldwide despite widespread Bacille Calmette-Guérin (BCG) vaccination and decades of control efforts. The limited and variable efficacy of current vaccination strategies, particularly against adult pulmonary disease, highlights the need for a deeper understanding of the host immune mechanisms that determine protection against Mycobacterium tuberculosis. While traditional approaches to TB vaccine development have largely focused on pathogen-specific immunity and clinical efficacy, emerging evidence suggests that successful TB control may depend equally on the strategic modulation of host immune responses. This narrative review examines the immunological basis of TB vaccination, emphasizing how contemporary vaccine platforms reshape both innate and adaptive immunity. We discuss the roles of trained immunity, T-cell function, immune memory, and mucosal immune responses in mediating protection, as well as the mechanisms by which M. tuberculosis evades immune surveillance. The review further explores next-generation vaccine technologies, including protein-adjuvant, viral-vectored, live-attenuated, and mRNA-based vaccines, highlighting their distinct immunological targets. Particular attention is given to mucosal immunity, systems vaccinology, and the ongoing search for reliable correlates of protection, which collectively offer new opportunities to improve vaccine design and evaluation. Finally, we examine host-directed immunomodulatory approaches, immune-engineering strategies, and precision vaccinology as emerging paradigms for TB prevention. By reframing TB vaccines as instruments for immune reprogramming rather than solely pathogen-specific interventions, this review provides an integrated perspective on how advances in immunology may accelerate progress toward global TB control and the goals of the WHO End TB Strategy.