SARS-CoV-2 breakthrough infections enhance T cell response magnitude, breadth, and epitope repertoire
Alison Tarke, Parham Ramezani-Rad, Tertuliano Alves Pereira Neto, Yeji Lee, Vanessa Silva‐Moraes, Benjamin Goodwin, Nathaniel I. Bloom, Leila Siddiqui, Liliana Avalos, April Frazier, Zeli Zhang, Ricardo da Silva Antunes, Jennifer M. Dan, Shane Crotty, Alba Grifoni, Alessandro Sette
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 T cell 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 T cell responses in donors without previous asymptomatic infection, (2) expansion of CD4 and CD8 T cell responses to non-S targets (M, N, and nsps) independent of SARS2 variant, and (3) generation of novel epitopes recognizing variant-specific mutations. These variant-specific T cell 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 T cell antigens and epitopes recognized.