SARS-CoV-2 Breakthrough Infections Enhance T Cell Response Magnitude, Breadth and Epitope Repertoire

Abstract

Little is known about the effect of SARS-CoV-2 (SARS2) vaccine breakthrough infections (BTIs) on 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 nonS (Spike) SARS2 antigens, consistent with previous undiagnosed asymptomatic SARS2 infections. Following symptomatic BTI, we observed: i) enhanced S-specific CD4 and CD8 T cell responses in donors without previous asymptomatic infection. ii) Expansion of CD4 and CD8 T cell responses to non-S targets (M, N and nsps) independent of SARS2 variant, and iii) 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 vaccineinduced immune responses by increasing the magnitude and by broadening the repertoire of T cell antigens and epitope recognized.

Note:
Funding Information: This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. 75N93021C00016 to A.G. and Contract No. 75N9301900065 to A.S. A.T. was supported by NIH T32AI125179. This work was funded by NIH NIAID award AI142742 (Cooperative Centers for Human Immunology) (S.C., A.S.).

Declaration of Interests: A.S. is a consultant for AstraZeneca Pharmaceuticals, Calyptus Pharmaceuticals, Inc, Darwin Health, EmerVax, EUROIMMUN, F. Hoffman-La Roche Ltd, Fortress Biotech, Gilead Sciences, Granite bio., Gritstone Oncology, Guggenheim Securities, Moderna, Pfizer, RiverVest Venture Partners, and Turnstone Biologics. A.G. is a consultant for Pfizer. S.C. has consulted for GSK, JP Morgan, Citi, Morgan Stanley, Avalia NZ, Nutcracker Therapeutics, University of California, California State Universities, United Airlines, Adagio, and Roche. LJI has filed for patent protection for various aspects of T cell epitope and vaccine design work. All the other authors declare no conflict of interest.

Ethics Approval Statement: Blood samples from healthy adult donors were obtained by donation and collected at the La Jolla Institute Clinical Core in San Diego, California. The study protocol was approved by the local ethic committee under the La Jolla Institute for Immunology Institutional Review Board (IRB#VD-214). All enrolled patients provided informed consent.

Keywords: Breakthrough infection, T cells, B cells, Covid-19 vaccination, SARS-CoV-2, Delta, Omicron, de novo responses, coronavirus