Parallel detection of SARS-CoV-2 epitopes reveals dynamic immunodominance profiles of CD8 T memory cells in convalescent COVID-19 donors.

Objectives: High-magnitude CD8 T cell responses are associated with mild COVID-19 disease; however, the underlying characteristics that define CD8 T cell-mediated protection are not well understood. The antigenic breadth and the immunodominance hierarchies of epitope-specific CD8 T cells remain largely unexplored and are essential for the development of next-generation broad-protective vaccines. This study identified a broad spectrum of conserved SARS-CoV-2 CD8 T cell epitopes and defined their respective immunodominance and phenotypic profiles following SARS-CoV-2 infection.

Methods: CD8 T cells from 51 convalescent COVID-19 donors were analysed for their ability to recognise 133 predicted and previously described SARS-CoV-2-derived peptides restricted by 11 common HLA class I allotypes using heterotetramer combinatorial coding, which combined with phenotypic markers allowed in-depth profiling of CD8 T cell responses at quantitative and phenotypic levels.

Results: A comprehensive panel of 49 mostly conserved SARS-CoV-2-specific CD8 T cell epitopes, including five newly identified low-magnitude epitopes, was established. We confirmed the immunodominance of HLA-A*01:01/ORF1ab and B*07:02/N and identified B*35:01/N as a third epitope with immunodominant features. The magnitude of subdominant epitope responses, including A*03:01/N and A*02:01/S, depended on the donors' HLA-I context. All epitopes expressed prevalent memory phenotypes, with the highest memory frequencies in severe COVID-19 donors.

Conclusion: SARS-CoV-2 infection induces a predominant CD8 T memory response directed against a broad spectrum of conserved SARS-CoV-2 epitopes, which likely contributes to long-term protection against severe disease. The observed immunodominance hierarchy emphasises the importance of T cell epitopes derived from nonspike proteins to the overall protective and cross-reactive immune response, which could aid future vaccine strategies.