Sex Differences in Vaccine-Induced Immunity and Protection Against Mycobacterium tuberculosis

Tuberculosis (TB) remains a leading global cause of death, with approximately 1.3 million fatalities annually. While males are more susceptible to TB, the underlying immune differences and their impact on vaccine efficacy are not fully understood. In this study, we vaccinated male and female C57BL/6 mice with BCG and 2 recombinant derivatives, VPM1002 and BCGΔBCG1419c, and assessed their protection against Mycobacterium tuberculosis (Mtb) HN878. While all 3 vaccines showed comparable efficacy in females, BCG did not protect males from Mtb-induced death. Instead, recombinant vaccines provided improved protection in males. Vaccination of males with BCGΔBCG1419c, but not BCG, enhanced CD8 T-cell and B-cell recall responses in vaccine-draining lymph nodes, and reduced lung inflammation after Mtb challenge. These findings underscore the impact of sex differences on vaccine efficacy and suggest that future research should consider sex as a biological variable to optimize TB vaccination strategies.