Cytotoxic T cells targeting spike glycoprotein are associated with hybrid immunity to SARS-CoV-2

Abstract mRNA vaccination of individuals with prior SARS-CoV-2 infection provides superior protection against breakthrough infections variants concern compared to in the absence infection. However, immune mechanisms by which this ‘hybrid immunity’ is generated and maintained are unknown. While genetic variation spike glycoprotein effectively subverts neutralizing antibodies, spike-specific T cells generally variants. Thus, we comprehensively profiled cell responses S1 S2 domains a cohort SARS-CoV-2-naïve (n = 13) or convalescent 17) who received two-dose vaccine series were matched age, sex, type. Using flow cytometry, observed that overall functional breadth CD4 as well polyfunctional Th 1responses similar between two groups. cytotoxic both trended higher among subjects. Multi-modal single-cell RNA sequencing revealed diverse programs CD8 displayed enhanced antiviral cytokine production. Taken together, our data suggest targeting may partially account for hybrid immunity SARS-CoV-2.