Post-pandemic memory T cell response to SARS-CoV-2 is durable, broadly targeted, and cross-reactive to the hypermutated BA.2.86 variant

Abstract

Ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has given rise to recombinant Omicron lineages that dominate globally (XBB.1), as well as the emergence of hypermutated variants (BA.2.86). In this context, durable and cross-reactive Tcell immune memory is critical for continued protection against severe COVID-19. We examined Tcell responses to SARS-CoV-2 approximately 1.5 years since Omicron first emerged. We describe sustained CD4+ and CD8+ spike-specific Tcell memory responses in healthcare workers in South Africa (n= 39) who were vaccinated and experienced at least one SARS-CoV-2 infection. Spike-specific Tcells are highly cross-reactive with all Omicron variants tested, including BA.2.86. Abundant nucleocapsid and membrane-specific Tcells are detectable in most participants. The bulk of SARS-CoV-2-specific Tcell responses have an early-differentiated phenotype, explaining their persistent nature. Overall, hybrid immunity leads to the accumulation of spike and non-spike Tcells evident 3.5 years after the start of the pandemic, with preserved recognition of highly mutated SARS-CoV-2 variants.