Resistance potential of the HLA-A2-restricted immunodominant SARS-CoV-2-specific CD8+ T cell receptor repertoire to antigenic drift

A major concern of COVID-19 is immune escape. While T cells are implicated in protection against severe disease, direct evaluation of their capacity to specifically target SARS-CoV-2 variants remains limited. We aim to narrow this gap by profiling the ability of CD8+ T cells to recognize SARS-CoV-2 mutations after vaccination and observe a high degree of phenotype and repertoire diversity. To better understand the breadth of antigen repertoire coverage, we interrogate the ability of SARS-CoV-2 specific TCRs to bind all point mutations of the immunodominant HLA-A2:S269-277 epitope. While mutation space coverage is surprisingly vast, specific substitutions are not recognized by the vaccine-elicited repertoire. Structural analyses reveal a TCR sequence-based antigen recognition limitation intrinsic to vaccination. Further investigation reveals that this repertoire ‘hole’ is not present in the naive repertoire, suggesting future immune escape through these potential escape mutations could be relieved by modifications to vaccines. It remains elusive whether the T cell repertoire will cover all point mutations of a major epitope. The authors here show that COVID vaccine–induced CD8⁺ T cells detect most YLQ peptide variants except R5, but naïve T cells fill this gap by responding to R5 despite abundant WT-specific cells, ensuring broad coverage to prevent viral immune-escape.