Sexual dimorphism is a recognized source of variation in the immune system. In response to vaccines and infection, men experience dysbalanced inflammatory responses, more Treg differentiation and lower antibody titers, while women exhibit higher inflammation, better antigen presentation but more T cell exhaustion. The specific contributions of chromosomal and hormonal factors are incompletely understood but can be investigated in transgender persons receiving gender-affirming hormone therapy (GAHT). They experience a hormonal shift towards the experienced gender but retain their chromosomal sex. In an ongoing clinical study, we are vaccinating 60 transgender and 60 cisgender persons with a meningococcal B vaccine, that will serve as a model for immune activation. In this project, we will use a systems vaccinology approach to study vaccine-induced immune response in-depth in this population and unravel the impact of sex hormones. By combining several established methods to study innate and trained immunity (plasma cytokine levels), humoral immunity (hSBA assay) and cellular immunity (intracellular cytokine staining) with novel techniques that allow for genetic and epigenetic investigations (single cell multiome sequencing), we will gain a complete overview of active immune responses for each gender. Beyond advancing our understanding of sex and gender differences in immunity, this study will offer unique insights into how GAHT influences immune function.