Cross-Reactivity Assessment of Vaccine-Derived SARS-CoV-2 T Cell Responses against BA.2.86 and JN.1

Abstract

The SARS-CoV-2 Omicron sub-variants BA.2.86 and JN.1 contain multiple mutations in the spike protein that were not present in previous variants of concern and Omicron sub-variants. Preliminary research suggests that these variants reduce the neutralizing capability of antibodies induced by vaccines, which is particularly significant for JN.1. This raises concern as many widely deployed COVID-19 vaccines are based on the spike protein of the ancestral Wuhan strain of SARS-CoV-2. While T cell responses have been shown to be robust against previous SARS-CoV-2 variants, less is known about the impact of mutations in BA.2.86 and JN.1 on T cell responses. We evaluate the effect of mutations specific to BA.2.86 and JN.1 on experimentally determined T cell epitopes derived from the spike protein of the ancestral Wuhan strain and the spike protein of the XBB.1.5 strain that has been recommended as a booster vaccine. Our data suggest that BA.2.86 and JN.1 affect numerous T cell epitopes in spike compared to previous variants; however, the widespread loss of T cell recognition against these variants is unlikely.

Keywords: BA.2.86; COVID-19; JN.1; SARS-CoV-2; T cell epitopes; immune escape; mutations; vaccines.

Figure 1

Overview of S-specific SARS-CoV-2 T cell epitopes across SARS-CoV-2 variants. (A,B) show the fractions of CD4+ and CD8+ S-specific SARS-CoV-2 T cell epitopes with and without mutations across SARS-CoV-2 variants.

Figure 2

Mapping of mutations in the BA.2.86 and JN.1 variants onto the spike crystal structure. Mutations affecting numerous T cell epitopes are annotated. The additional phenotypic effects of these mutations are also noted. The crystal structure was obtained from www.rcsb.org (PDB ID: 7XIX) accessed 10 November 2023. RBD: receptor-binding domain; NTD: N-terminal domain; nAbs: neutralizing antibodies.

Figure 3

Predicted effect on the HLA binding of S-specific epitope mutants of BA.2.86 and JN.1. (A,B) show breakdowns of BA.2.86 epitopes for which HLA association is known, along with the predicted effect of Omicron BA.2.86 mutations on peptide–HLA binding. (C,D) show lists of epitopes in JN.1 (additional to those in BA.2.86) with known HLAs, along with their predicted effect on peptide–HLA binding. The complete list of CD4+ and CD8+ (mutant) epitope–HLA pairs and their predictions is provided in Supplementary Tables S3 and S4.