Effects of Exogenous Hormone Treatment on Vaccine Responses - ABSTRACT: Sex differences in immunity are dynamic throughout the lifespan and contribute to heterogeneity in risk of infectious diseases and response to vaccination. Sexual dimorphism is, in part, driven by sex hormones and has been demonstrated in both innate and adaptive immunity; testosterone has an immunosuppressive effect while estrogen is immunoenhancing. Thus, females tend to mount stronger immune responses, exhibit lower infection rates for a variety of pathogens, and demonstrate elevated responses to vaccination. However, the molecular mechanisms driving enhanced immunity in females are not well understood, and the degree to which exogenous sex hormones contribute to immune response is unknown. To dissect the role of female sex hormones in enhanced immunity we propose to study the immune responses of adult transgender women (TW, individuals who identify as women but were assigned male at birth) undergoing gender-affirming hormone therapy (GAHT) with estrogen. This will provide a unique opportunity to understand the impact of sex hormones on the immune system generally, and more specifically, in response to the updated seasonal COVID-19 vaccines. No studies have examined interactions between COVID-19 vaccines and exogenous sex hormone replacement therapies (HRT). We hypothesize that TW undergoing feminizing GAHT with estrogen will develop enhanced immune responses that align more with their gender identity than their biological sex. Untangling the relationship between immune response and gender in TW may facilitate and improve evidence-based outcomes for those who receive the seasonal COVID-19 vaccines in this population, and in future studies also in other populations that receive exogenous sex hormone treatments. We will compare the humoral and cellular responses in adult TW (21-49 years) before and after immunization with the updated seasonal COVID-19 vaccine, when offered, with those elicited in clinically- and age-matched cisgender men and women with similar COVID-19 vaccine uptake and prior infections histories, and who are planning to receive the updated vaccine and be bled prior to immunization (baseline) followed by three bleeds 7-, 28- and 180-days post vaccination. Together, the aims comprise a critical first step towards determining if GAHT with estrogen has immunoenhancing effects. Clear association of sex hormone levels with immune responses to vaccines will provide important insights into the impact of endogenous and exogenous sex hormones on immune health. We posit that providing accurate, unbiased, biologically sound, evidence-based information about vaccine benefits or risks will support personal decision-making regarding wellness and disease prevention and may inform healthcare strategies based on sex and exogenous hormone use, ultimately benefiting public health for all Americans.
