Multi‐Omics Analysis Reveals Sex‐Specific Signatures for BCG Vaccine Efficacy

Vaccines are a cornerstone of global public health, but their efficacy can vary significantly among individuals. Bacille Calmette-Guérin (BCG) vaccine against tuberculosis is one of the most used vaccines, and its efficacy is influenced by numerous factors, including sex, age, and geographical location. Systematic investigations using large-scale multi-omics analyses to dissect sex-specific determinants of vaccine efficacy remain limited. To better understand this variability and improve vaccine efficacy, we analyzed multi-omics data from a cohort of 321 healthy individuals vaccinated with BCG, integrating immune cell frequencies, single-cell RNA sequencing, plasma proteins, metabolites, and DNA methylation profiles. Our findings revealed significant sex-specific differences in immune pathways that contribute to BCG efficacy. In males, pre-vaccination signatures were associated with a stronger pro-inflammatory response, highlighting the importance of an innate-driven immune response, while females exhibited enhanced antigen presentation pathways and adaptive immune responses. This study underscores the need for understanding individual baseline immune status in relation to biological sex, an approach that could represent a promising path to optimizing vaccine effectiveness.