SARS-CoV-2 breakthrough infections enhance T cell response magnitude, breadth, and epitope repertoire

Abstract

Little is known about the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or SARS2) vaccine breakthrough infections (BTIs) on the magnitude and breadth of the Tcell repertoire after exposure to different variants. We studied samples from individuals who experienced symptomatic BTIs during Delta or Omicron waves. In the pre-BTI samples, 30% of the donors exhibited substantial immune memory against non-S (spike) SARS2 antigens, consistent with previous undiagnosed asymptomatic SARS2 infections. Following symptomatic BTI, we observed (1) enhanced S-specific CD4 and CD8 Tcell responses in donors without previous asymptomatic infection, (2) expansion of CD4 and CD8 Tcell responses to non-S targets (M,N, and nsps) independent of SARS2 variant, and (3) generation of novel epitopes recognizing variant-specificmutations. These variant-specific Tcell responses accounted for 9%-15% of the total epitope repertoire. Overall, BTIs boost vaccine-induced immune responses by increasing the magnitude and by broadening the repertoire of Tcell antigens and epitopes recognized.