BNT162b2 mRNA vaccine-induced sex differences in the single-cell transcriptome of peripheral blood mononuclear cells in healthy adults

IntroductionMen reportedly experience more severe disease and adverse outcomes from COVID-19, including death. Women report more adverse events (AEs) after vaccination in general. While few studies have addressed sex-specific risk factors or molecular mechanisms behind COVID-19, none have examined sex differences in the response to COVID-19 vaccination. MethodsWe searched AE reporting databases to find sex differences specific to COVID-19 vaccines. We analyzed public datasets to identify baseline sex differences in gene expression across cell types and time points, and sex differences in the response to the second BNT162b2 mRNA vaccine dose. ResultsSex differences in AE rates for mRNA vaccines equaled those for other non-mRNA vaccines. T cells and monocytes showed the greatest number of sexually dimorphic genes. Platelet counts in the study population differed significantly before vaccination (3.6% in females vs 1.8% in males) but not after the second BNT162b2 dose (7.2% vs 7.3%). There were no notable sex differences in the expression of key genes induced by the second dose after exclusion of platelets. BNT162b2 dose 2-specific APOBEC3Ahigh monocytes and the dose 2-induced gene signature persisted for longer in women. Glucocorticoid-responsive TSC22D3, CEBPB/D and DDIT4 were specifically induced in females; the voltage-gated potassium channel regulatory subunit KCNE3 was specifically induced in males. ConclusionsThis sexual dimorphism in both X-linked and autosomal gene transcriptome in PBMCs after mRNA COVID-19 vaccination might explain fatigue, autoimmune, and neurological AEs reported after vaccination at different rates in women and men.