Leveraging <scp> <i>Mycobacterium tuberculosis</i> Rv1507A </scp> Protein for Improved Immunogenicity in <scp> <i>Mycobacterium bovis</i> BCG </scp> Vaccine

Tuberculosis (TB) remains a global health burden, particularly because of the limited efficacy of the Bacillus Calmette-Guérin (BCG) vaccine against adult pulmonary TB. To improve immunogenicity, we developed a recombinant BCG strain expressing the M. tuberculosis -specific antigen Rv1507A (rBCG_Rv1507A) and evaluated its immune-enhancing potential. rBCG_Rv1507A-infected human PBMCs and murine macrophages exhibited enhanced co-stimulatory marker expression and Th1-skewed cytokine profiles in vitro. The vaccine stimulated the expansion of T follicular helper (TFH) cells and both central and effector memory T cells. Intratracheal immunisation induced systemic and mucosal antibody responses, localized memory B cell formation, and enrichment of lung-resident memory T cells in vivo. Importantly, rBCG_Rv1507A promoted macrophage apoptosis and suppressed autophagy, which may support cross-antigen presentation. Furthermore, it induces features of trained immunity, including hematopoietic progenitor expansion and metabolic reprogramming of macrophages. These immunological enhancements were compartmentalized to the lungs, the primary site of TB infection, due to mucosal delivery. Collectively, rBCG_Rv1507A demonstrated potential as a next-generation TB vaccine by integrating durable adaptive memory with innate immune training. However, further studies are required to confirm its protective efficacy.