Omicron BA.2 breakthrough infection elicits CD8⁺ T cell responses recognizing the spike of later Omicron subvariants

Here, we examine peripheral blood memory T cell responses against the SARS-CoV-2 BA.4/BA.5 variant spike among vaccinated individuals with or without Omicron breakthrough infections. We provide evidence supporting a lack of original antigenic sin in CD8⁺ T cell responses targeting the spike. We show that BNT162b2-induced memory T cells respond to the BA.4/BA.5 spike. Among individuals with BA.1/BA.2 breakthrough infections, IFN-γ–producing CD8⁺ T cell responses against the BA.4/BA.5 spike increased. In a subgroup with BA.2 breakthrough infections, IFN-γ–producing CD8⁺ T cell responses against the BA.2-mutated spike region increased and correlated directly with responses against the BA.4/BA.5 spike, indicating that BA.2 spike–specific CD8⁺ T cells elicited by BA.2 breakthrough infection cross-react with the BA.4/BA.5 spike. We identified CD8⁺ T cell epitope peptides that are present in the spike of BA.2 and BA.4/BA.5 but not the original spike. These peptides are fully conserved in the spike of now-dominant XBB lineages. Our study shows that breakthrough infection by early Omicron subvariants elicits CD8⁺ T cell responses that recognize epitopes within the spike of newly emerging subvariants.