Sex differences in vaccine induced immunity and protection against Mycobacterium tuberculosis

Tuberculosis (TB) is a disease that has evolved with humankind for millennia, causing approximately 1.3 million deaths worldwide per annum. Although increased male affliction for TB and other infections were long known from an epidemiological perspective, our mechanistic understanding of the underlying immunological divergences is relatively recent. As such, there is insufficient knowledge regarding the sexually dimorphic immune response to TB vaccines, where no accepted correlates of protection are yet available. In this context, our goal was to explore how individual sex influences the protective effects of TB vaccines. For this purpose, we vaccinated female and male C57BL/6 mice with Bacille Calmette-Guérin (BCG) and two recombinant derivatives, VPM1002 and BCGΔBCG1419c, to analyse their protective efficacy against challenge with Mycobacterium tuberculosis HN878. We found poor efficacy of BCG in males and the ability of next generation vaccine candidates to improve protection specifically in males. To determine the underlying mechanisms for the differences in survival upon vaccination between females and males, as well as, among different vaccine candidates, we analysed the distribution and persistence of the vaccine strains, in addition to vaccine-induced immune responses at various time points in draining lymph nodes and spleen. We identified sex specific differences in CD8 T cell proliferation in response to mycobacterial antigens ex vivo , 90 days post-vaccination, that associates with vaccine mediated protection against HN878. By integrating our multi-parametric datasets into principal component analysis, followed by extraction of high-variance features, we have uncovered an additional significant association of early CD4 T cell responses with late CD8 T cell responses as well as with survival post HN878 infection. In addition, we have also identified specific clusters of responding CD8 T cells in spleen post-vaccination, that are globally deficient in males as compared to females, irrespective of the BCG strain administered.