Sex-specific immune responses to COVID-19 vaccination in end-stage renal disease patients

Abstract Background End-stage renal disease (ESRD) patients have muted memory B cell formation and reduced humoral responses to COVID-19 vaccination; however, early innate immune responses have yet to be characterized. Sex-stratification is also limited in COVID-19 vaccination research. Methods We collected blood before (BD1) and 1-4 days post-dose 1 (PD1) of BNT162b2 vaccination for RNA-sequencing in ESRD patients (n = 35 BD1; 18 PD1) and healthy controls (HC) (n = 31 BD1; 30 PD1). Additionally, 20 plasma cytokines were quantified in ESRD patients (n = 39 BD1, 35 PD1) and HC (34 BD1, 15 PD1). Results Transcriptional profiling of vaccine responses identified 125 significantly differentially expressed genes (DEG) (padj<0.04) in ESRD patients and 107 DEGs (padj<0.05) in HC. 71 DEGs were shared, 54 unique to ESRD, and 36 unique to HC. DEG, pathway analyses, and cytokine responses in the combined dataset showed ESRD patients were more inflamed than HC at baseline, with an elevated inflammatory cytokine profile compared to HC. These results were driven by female ESRD patients where IL-2, IL-10, and IP-10 were more significant in females (p < 0.001) compared to males (p < 0.01). While IL-6, IFN-γ, IL-13, eotaxin, were exclusively associated in females (p < 0.05). Healthy females also had a stronger immunological response to vaccination compared to healthy males. Conclusions Despite baseline inflammation, ESRD patients were able to mount similar early immune responses to vaccination as HC, with females in both populations more reactogenic than males. Sex-stratification is recommended for ongoing immunological research to better understand unique responses to COVID-19 vaccination. Key messages • End-stage renal disease patients have similar early innate immune responses to COVID-19 vaccination as healthy controls. • Sex-stratification is important to identify unique immunological responses that may be leveraged for sex-specific vaccination strategies.