Uncovering the role of antigen-specific T cells in SARS-CoV-2 breakthrough infection 3518

Abstract Description Breakthrough infections of SARS-CoV-2 in vaccinated individuals underscore the need to evaluate the quantitative and qualitative assessment of vaccine-induced T-cell immunity. To understand the epitope-specific CD8+ T-cell responses, we studied SARS-CoV-2 vaccinated (infection naive before vaccination) individuals up to 2 years post-vaccination, and longitudinally profiled 139 immunogenic CD8 T-cell epitopes using DNA-barcoded pMHC multimers. Furthermore, in SARS-CoV-2 breakthrough infections, we comprehensively evaluated vaccine- and infection-induced T-cells using in-house developed single-cell compatible pMHC multimers in combination with single-cell RNA sequencing (scRNA-seq), single-cell T-cell receptor sequencing (scTCRseq), and cellular indexing of transcriptomes and epitopes by sequencing (CITEseq). We identified antigen-specificities of vaccine-induced immunodominant T-cells and their implications in establishing long-term CD8+ T-cell memory. Importantly, we observed significant clonal expansion of vaccine-induced T-cells as well as non-spike-specific T-cells in breakthrough infection. Furthermore, pre-infection samples were enriched with antigen-specific naïve T cells, whereas post-infection samples showed increased expression markers and gene signatures associated with T-cell cytotoxicity. These insights into the TCR repertoire and antigen specificity provide valuable guidance for improved vaccine design and immune protection strategies. Funding Sources Grants: - REACT - Horizon Europe - Grant agreement No 101057129 - DFF Sapere Aude Topic Categories Viral Immunology (VIR)