Association between sex hormones and anti-S/RBD antibody responses to COVID-19 vaccines in healthcare workers

Abstract

Healthcare workers (HCWs) are the target population for vaccination against coronavirus disease (COVID-19) as they are at a high risk of exposure and transmission of pathogens to patients. Neutralizing antibodies developed after COVID-19 vaccination decline within few months of vaccination. Several factors, including age and sex, can affect the intensity, efficacy, and duration of immune response to vaccines. However, sex-specific analyses of humoral responses to COVID-19 vaccines are lacking. This study aimed to evaluate sex-based differences in anti-S/RBD (Receptor Binding Domain) responses at three different time points after the second dose of mRNA COVID-19 vaccine in HCWs in relation to age, and to investigate the role of sex hormones as potential markers of response. Anti-S/RBD levels after two doses of the mRNA vaccine were collected from 521 HCWs naïve to COVID-19, working at two Italian Clinical Centers. Multiple regression analysis was applied to evaluate the association between anti-S levels and sex, age, and plasma levels of sex hormones. Significantly higher anti-S/RBD response to the COVID-19 vaccination was found in female HCWs, and a significant and more abrupt decline in response with time was observed in women than that in men. A novel, positive association of testosterone plasma levels and higher anti-S levels in male HCWs was found, suggesting its potential role as sex specific marker in males. In conclusion, understanding the sex-based differences in humoral immune responses to vaccines may potentially improve vaccination strategies and optimize surveillance programs for HCWs.

Keywords: COVID-19; anti-S/RBD; estrogen; healthcare workers; progesterone; sex difference; testosterone; vaccine.

Figure 1.

Measurements of anti-S/receptor binding domain (RBD) (by natural log transformed values and 95%CI) in the groups classified based on sex and age: (a) overall; (b) 20–44 years; (c) 45–55 years and (d) 56–85 years; p-values by Wilcoxon – Mann–Whitney test are shown for each post-vaccination time point.

Figure 2.

Analysis of sex differences in anti-S/RBD waning. Scatters for the log values of anti-S/RBD antibody levels with the regression lines estimated using mixed regression model for males (M) and females (F), panel (a) all age groups; panel (b) 20–44 years; panel (c) 45–55 years; panel (d) 56–85 years; p-values relative to anti-S/RBD antibody slope differences in M vs F are shown in each panel.

Figure 3.

The effect of sex hormones on the anti-S/RBD response to vaccination. Simple regression models for anti-S/RBD antibody levels applied in a subgroup of healthcare workers (HCWs, n = 112) using the log of sex hormone plasma levels as a covariate; 17-β estradiol: a (females) and B (males); testosterone: C (females) and D (males); progesterone: E (females) and F (males); beta estimates (slopes) with relative p-values obtained using regression models are shown in each panel.