The SARS-CoV-2 Omicron variant (B.1.1.529) contains mutations that mediate escape from antibody responses, although the extent to which these substitutions in spike and non-spike proteins affect T-cell recognition is unknown. Here we show that T-cell responses in individuals with prior infection, vaccination, both prior infection and vaccination, and boosted vaccination are largely preserved to Omicron spike and non-spike proteins. However, we also identify a subset of individuals (∼21%) with a >50% reduction in T-cell reactivity to the Omicron spike. Evaluation of functional CD4+ and CD8+ memory T cell responses confirmed these findings and reveal that reduced recognition to Omicron spike is primarily observed within the CD8+ T cell compartment potentially due to escape from HLA binding. Booster vaccination enhanced T-cell responses to Omicron spike. In contrast to neutralizing immunity, these findings suggest preservation of T-cell responses to the Omicron variant, although with reduced reactivity in some individuals.

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The emergence of SARS-CoV-2 variants that escape convalescent and vaccine-induced antibody responses has renewed focus on the development of broadly protective T cell-based vaccines. Here we apply structure-based network analysis and assessments of HLA class I-peptide stability to define mutationally constrained CD8 + T cell epitopes across the SARS-CoV-2 proteome. Highly networked residues are conserved temporally among circulating variants and across the Sarbecovirus subgenus, and disproportionately impair Spike pseudotyped lentivirus infectivity when mutated. Evaluation of HLA class I stabilizing activity for 18 globally prevalent alleles identifies CD8 + T cell epitopes within highly networked regions with limited mutational frequencies in circulating SARS-CoV-2 variants and deep-sequenced primary isolates. Moreover, these epitopes elicit demonstrable CD8 + T cell reactivity in convalescent individuals but reduced recognition in mRNA-based vaccine recipients. These data thereby elucidate key mutationally constrained regions and immunogenic epitopes in the SARS-CoV-2 proteome for a global T cell-based vaccine against emerging variants and sarbecoviruses.