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AbstractObjectivesVaccine‐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.MethodsHerein, 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.ResultsThe 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.ConclusionThis study provides insight into T‐cell responses against the SARS‐CoV‐2 S‐protein following vaccination and subsequent natural infection. We investigated the immunoreactivity of SARS‐CoV‐2 spike protein T‐cell epitopes in individuals who were SARS‐CoV‐2 naive, vaccinated with the AstraZeneca vaccine, and those who became naturally infected after vaccination. While the number of immunoreactive epitopes remained consistent across all groups, we observed a shift in T‐cell responses: naive individuals predominantly recognised HLA‐A‐associated epitopes, vaccination clustered immunoreactive epitopes within two specific regions of the spike protein, and natural infection shifted immunoreactivity towards HLA‐B‐associated epitopes, particularly the B7 supertype. These findings suggest that vaccination and natural infection elicit different T‐cell responses, providing insights that could inform future vaccine design to enhance long‐term immunity against COVID‐19.