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 than males. 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 (i.e. estrogen) in enhanced immunity we propose to study the immune responses of adult transgender women who use hormone replacement therapy (HRT) 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 HRT with estrogen. We hypothesize that transgender women who use HRT with estrogen will develop enhanced immune responses similarly to women who do not use HRT. Untangling the relationship between immune response and HRT 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 such as women experiencing severe peri- and postmenopausal symptoms (45% of women above age 50), men with low testosterone (0.9-2.9% of men), people with certain medical conditions such as endometriosis and uterine leiomyomas, individuals with certain cancers (e.g., prostate cancer), and those seeking contraception or fertility treatments. We will compare the humoral and cellular responses in adult transgender women using HRT (21-49 years) before and after immunization with the updated seasonal COVID-19 vaccine, when offered, with those elicited in clinically- and age-matched women and men 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. Our study comprises a critical first step towards determining if HRT with estrogen has immunoenhancing effects. Clear association of estrogen hormone levels with immune responses to vaccines will provide important insights into the impact exogenous vs. endogenous hormone levels have 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 also inform healthcare strategies based on exogenous hormone use, ultimately benefiting public health for all Americans.