mRNA vaccination boosts S-specific T cell memory and promotes expansion of CD45RA_int T_EMRA-like CD8⁺ T cells in COVID-19 recovered individuals

SARS-CoV-2 infection and mRNA vaccination both elicit spike (S)-specific T cell responses. To analyze how T cell memory from prior infection influences T cell responses to vaccination, we evaluated functional T cell responses in naive and previously infected vaccine recipients. Pre-vaccine S-specific responses are predictive of subsequent CD8⁺ T cell vaccine-response magnitudes. Comparing baseline with post-vaccination TCRβ repertoires, we observed large clonotypic expansions correlated with the frequency of spike-specific T cells. Epitope mapping the largest CD8⁺ T cell responses confirms that an HLA-A∗03:01 epitope was highly immunodominant. Peptide-MHC tetramer staining together with mass cytometry and single-cell sequencing permit detailed phenotyping and clonotypic tracking of these S-specific CD8⁺ T cells. Our results demonstrate that infection-induced S-specific CD8⁺ T cell memory plays a significant role in shaping the magnitude and clonal composition of the circulating T cell repertoire after vaccination, with mRNA vaccination promoting CD8⁺ memory T cells to a T_EMRA-like phenotype.