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

## TL;DR

The study identifies key T cell epitopes in SARS-CoV-2 Omicron infections after inactivated vaccination, highlighting conserved immune responses and potential vaccine targets.

## Contribution

The work systematically identifies immunodominant T cell epitopes and their HLA associations in vaccinated individuals infected with Omicron, revealing conserved epitopes across variants.

## Key findings

- Inactivated vaccination primes CD4+ T cells for conserved epitopes in S1-NTD, M protein β-sandwich, and N-CTD.
- XBB.1.5 and BA.2.86 mutations partially evade T cell immunity but a conserved HLA-DRB1∗09:01 epitope remains effective.
- Epitope-specific T cell responses show variable durability over 10 months post-infection.

## Abstract

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.

•Characterizing dominant HLA-epitope pairs by inactive vaccine and Omicron infection•Inactive vaccination elicits broad-spectrum CD4+ T but not CD8+ T cell response•Mutated S152–160, S360–370, and S126–140 in XBB.1/BA2.86 variant impair T cell recognition•SARS-CoV-2 T cell clones show varying durability based on epitopes

Characterizing dominant HLA-epitope pairs by inactive vaccine and Omicron infection

Inactive vaccination elicits broad-spectrum CD4+ T but not CD8+ T cell response

Mutated S152–160, S360–370, and S126–140 in XBB.1/BA2.86 variant impair T cell recognition

SARS-CoV-2 T cell clones show varying durability based on epitopes

Molecular biology; Immunology; Virology