Browne, Daniel J., Crooks, Pauline, Smith, Corey, and Doolan, Denise L. (2025) Differential reactivity of SARS-CoV-2 S-protein T-cell epitopes in vaccinated versus naturally infected individuals. Clinical & Translational Immunology, 14 (5). e70031.

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Abstract

Objectives: Vaccine-induced protective immunity against SARS-CoV-2 has proved difficult to sustain. Robust T-cell responses are thought to play an important role, but T-cell responses against the SARS-CoV-2 spike protein (S-protein), the core vaccine antigen, following vaccination or natural infection are incompletely understood. Methods: Herein, the reactivity of 170 putative SARS-CoV-2 S-protein CD8⁺ and CD4⁺ T-cell peptide epitopes in the same individuals prior to vaccination, after COVID-19 vaccination, and again following subsequent natural infection was assayed using a high-throughput reverse transcription-quantitative PCR (HTS-RT-qPCR) assay. Results: The profile of immunoreactive SARS-CoV-2 S-protein epitopes differed between vaccination and natural infection. Vaccine-induced immunoreactive epitopes were localised primarily into two extra-domanial regions. In contrast, epitopes recognised following natural infection were spread across the antigen. Furthermore, T-cell epitopes in naïve individuals were primarily recognised in association with HLA-A, while natural infection shifted epitope associations towards HLA-B, particularly the B7 supertype. Conclusion: This study provides insight into T-cell responses against the SARS-CoV-2 S-protein following vaccination and subsequent natural infection.

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