In underdeveloped nations, tuberculosis (TB) continues to be a major source of morbidity and mortality. The currently available vaccine against tuberculosis in endemic areas is mainly ineffective, which triggers the need for a clinically effective vaccine against tuberculosis. In the present review, we emphasized the impact of genetic variations in the BCG strains, which influence the efficacy of BCG vaccines. We also discussed the current status of BCG vaccines and their potential mechanisms on the modulation of B cells and, thereby, humoral immunity, which trigger immune responses against various intracellular pathogens. Further, we also elaborated upon the pre-clinical and clinical studies demonstrating the efficacy and safety of the vaccines. Moreover, we also presented the putative novel targets such as polysaccharide-induced antibodies for the protection against Mtb, PGRS domain as an important target for Humoral immunity, HLA-E pathway-Target strategy for new TB vaccine, Coronin-1a - Novel player for Mycobacterial survival, IRGM, IFN-I3, an autophagy inducer with Irgm1 serving as a core part in the Tuberculosis vaccine development.
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