Landscape of T cell epitopes displays hot mutations of SARS‐CoV‐2 variant spikes evading cellular immunity

Abstract

AbstractThe continuous evolution of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has been accompanied by the emergence of viral mutations that pose a great challenge to existing vaccine strategies. It is not fully understood with regard to the role of mutations on the SARS‐CoV‐2 spike protein from emerging viral variants in T cell immunity. In the current study, recombinant eukaryotic plasmids were constructed as DNA vaccines to express the spike protein from multiple SARS‐CoV‐2 strains. These DNA vaccines were used to immunize BALB/c mice, and cross‐T cell responses to the spike protein from these viral strains were quantitated using interferon‐γ (IFN‐γ) Elispot. Peptides covering the full‐length spike protein from different viral strains were used to detect epitope‐specific IFN‐γ+ CD4+ and CD8+ T cell responses by fluorescence‐activated cell sorting. SARS‐CoV‐2 Delta and Omicron BA.1 strains were found to have broad T cell cross‐reactivity, followed by the Beta strain. The landscapes of T cell epitopes on the spike protein demonstrated that at least 30 mutations emerging from Alpha to Omicron BA.5 can mediate the escape of T cell immunity. Omicron and its sublineages have 19 out of these 30 mutations, most of which are new, and a few are inherited from ancient circulating variants of concerns. The cross‐T cell immunity between SARS‐CoV‐2 prototype strain and Omicron strains can be attributed to the T cell epitopes located in the N‐terminal domain (181–246 aa [amino acids], 271–318 aa) and C‐terminal domain (1171–1273 aa) of the spike protein. These findings provide in vivo evidence for optimizing vaccine manufacturing and immunization strategies for current or future viral variants.