Sex differences in vaccine induced immunity and protection against Mycobacterium tuberculosis

Abstract

Tuberculosis (TB), a disease killing over a million people per annum, shows a strong male preponderance in disease development. Although increased male affliction for TB has long been known from an epidemiological perspective, the mechanistic understanding of those differences is relatively recent. The only approved vaccine for TB, Bacillus Calmette Guérin (BCG), shows high variability in its protective efficacy – necessitating the development of effective vaccine candidates. However, whether the male-biased susceptibility to TB also applies to the efficacy of the BCG vaccine, has been scarcely explored. In the current study, a male specific failure of BCG is demonstrated in the C57BL/6 mouse model. However, two recombinant derivatives of BCG (rBCGs) - VPM1002 and BCGΔBCG1419c - were found to ameliorate this male specific vulnerability of BCG by significantly improving survival rates in males upon Mycobacterium tuberculosis (Mtb) challenge. The disparities in survival between rBCGs and BCG vaccinated males were not attributable to their ability to reduce lung colony forming units (CFUs). Further analysis revealed that BCGΔBCG1419c, used as a representative of VPM1002 and BCGΔBCG1419c, significantly enhances CD8 T cell responses 90 days post vaccination compared to BCG, specifically in males. This enhancement shows a strong positive correlation with improved survival following Mtb challenge. In addition, significant positive correlations were identified between the CD4 T cell response on day 28 post-vaccination and the CD8 T cell response on day 90 post-vaccination, as well as between the CD4 T and B cell responses on day 28 post-vaccination. The CD4 T cell response at day 28 post-vaccination also showed a significant direct correlation with survival following Mtb challenge. Lastly, 28 days post-vaccination, CD8 T cell populations in the spleen showed distinct global differences between sexes, with specific clusters varying between males and females, independent of vaccine type. In summary, the current study identified a male specific failure of BCG in the C57BL/6 mouse model of TB and the ability of rBCGs to significantly improve the protective efficacy specifically in males. The underlying differences in post-vaccine immune responses that correlate with vaccine efficacy, as well as, those differences between sexes were identified. Elucidating how sex-specific differences in CD8 T cell responses influence vaccine efficacy, as well as the potential role of CD4 T cells and B cells in the sex-specific development of different CD8 T cell populations open new avenues for future studies.