Identifying highly conserved and immunogenic SARS-CoV-2 CD8+ T Cell Epitopes for Vaccine Design

Abstract

Abstract Vaccines to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induce antibody responses against the spike (S) protein. However, the continued emergence of variants such as Omicron (B.1.1.529), with 30 amino acid changes in the S protein, underscores the need to find conserved targets that induce adaptive immunity. Natural infection induces CD8+ T cell activation against the viral proteins S, membrane (M), and nucleocapsid (N) as well as NSPs (non-structural proteins). Our study seeks to find conserved and immunogenic MHC class I epitopes throughout the SARS-CoV-2 peptidome. We used Ensemble MHC, a novel consensus predictive algorithm to select highly immunogenic CD8+ T cell epitopes presented by 52 of the most common HLA-I alleles, covering > 98% of the world’s population. We selected 658 high confidence predicted peptides from the SARS-CoV-2 immunopeptidome and prioritized testing 108 structural epitopes derived from the S, M, N, and E proteins. We collected PBMCs from unexposed, healthy, and convalescent individuals (n=31) covering ~ 85% of HLA alleles in the population, and measured T cell immunity by IFNγ secretion ELISpot and Activation Induced Marker (AIM) flow cytometry. In convalescent individuals, all predicted epitopes tested so far (n=36) were immunogenic (IFNγ response >2 fold than background) but 3/19 tested donors were unreactive. Samples from pre-pandemic (2017–19) unexposed healthy donors are reactive to 42% of tested epitopes, which indicate cross-reactivity to common cold coronaviruses (CCC) and possibly pre-existing protection against SARS-CoV-2. In summary, we have identified 45 highly conserved and immunogenic SARS-CoV-2 CD8+ T cell epitopes as potential targets for vaccine design. Supported by a grant from the Arizona Department of Health Services (AZDHS)