Systematic profiling of SARS-CoV-2 structural protein-specific T cell epitopes in Omicron infections following inactivated vaccination.

Comprehensive identification of T cell epitopes is crucial for understanding SARS-CoV-2-specific T cell immunity and guiding vaccine development. Epitope-specific T cells primed by inactivated vaccination (IV)-widely administered in China-followed by Omicron breakthrough infection (BI)-remain poorly characterized. Using hierarchical epitope screening in the IV-BI cohort, we systematically validated known epitope-HLA interactions and uncovered previously unrecognized associations, revealing immunodominant epitopes in conserved regions (S1-NTD, M protein β-sandwich, and N-CTD). Based on these epitopes, analysis of cohort samples before and after BI revealed that certain epitope-specific, CD4+ T cells were initially primed by IV. Longitudinal analysis revealed epitope-specific temporal dynamics in SARS-CoV-2-specific T cell immunity, with certain subsets declining over 10 months post-infection. While XBB.1.5 and BA.2.86 subvariant-harboring mutations partially evaded T cell immunity, a conservative HLA-DRB1∗09:01-restricted epitope was identified across ancestral and Omicron strains. These findings delineate regionally prevalent HLA-associated immunodominant epitope frameworks and highlight pan-variant epitope candidates for vaccine development and T cell immunity monitoring.