Ancestral SARS-CoV-2-specific T cells cross-recognize the Omicron variant

Abstract

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron (B.1.1.529) variant of concern (VOC) has destabilized global efforts to control the impact of coronavirus disease 2019 (COVID-19). Recent data have suggested that B.1.1.529 can readily infect people with naturally acquired or vaccine-induced immunity, facilitated in some cases by viral escape from antibodies that neutralize ancestral SARS-CoV-2. However, severe disease appears to be relatively uncommon in such individuals, highlighting a potential role for other components of the adaptive immune system. We report here that SARS-CoV-2 spike-specific CD4⁺ and CD8⁺ T cells induced by prior infection or BNT162b2 vaccination provide extensive immune coverage against B.1.1.529. The median relative frequencies of SARS-CoV-2 spike-specific CD4⁺ T cells that cross-recognized B.1.1.529 in previously infected or BNT162b2-vaccinated individuals were 84% and 91%, respectively, and the corresponding median relative frequencies for SARS-CoV-2 spike-specific CD8⁺ T cells were 70% and 92%, respectively. Pairwise comparisons across groups further revealed that SARS-CoV-2 spike-reactive CD4⁺ and CD8⁺ T cells were functionally and phenotypically similar in response to the ancestral strain or B.1.1.529. Collectively, our data indicate that established SARS-CoV-2 spike-specific CD4⁺ and CD8⁺ T cell responses, especially after BNT162b2 vaccination, remain largely intact against B.1.1.529.

Fig. 1. Cross-reactive CD4⁺ T cell responses against B.1.1.529.

a, Representative flow cytometry plots showing spike-specific CD4⁺ T cell responses (CD69⁺CD154⁺) to peptide pools representing wild-type SARS-CoV-2 (WT) or B.1.1.529. b, Frequencies of all spike-specific CD4⁺ T cells in BNT162b2-vaccinated, convalescent and seronegative individuals. Numbers indicate median reduction in the frequency of detected responses. Comparisons used two-sided Wilcoxon signed rank tests. *P = 0.012. c, Stimulation indices calculated as fold change in frequency relative to the negative control. Numbers indicate the percentage of individuals with a detectable response. d, Cross-reactive responses depicted on an individual basis as percentage B.1.1.529/wild-type. e, Helper polarization of spike-specific CD4⁺ T cells with representative gating and dot plots showing the distribution of subsets across individuals with detectable responses. Pie charts show the mean frequency of each subset across all individuals in each group. f, Canonical memory differentiation profiles of spike-specific CD4⁺ T cells with representative gating and dot plots showing the distribution of subsets across individuals with detectable responses. g, Functional profiles of spike-specific CD4⁺ T cell responses in BNT162b2-vaccinated individuals with representative gating and pie charts showing the mean frequency for each combination. Polyfunctional responses were compared using a permutation test. Data in dot plots are shown as median ± interquartile range. Each dot represents one donor.

Fig. 2. Cross-reactive CD8⁺ T cell responses against B.1.1.529.

a, Representative flow cytometry plots showing spike-specific CD8⁺ T cell responses (CD69⁺CD137⁺) to peptide pools representing wild-type SARS-CoV-2 (WT) or B.1.1.529. b, Frequencies of all spike-specific CD8⁺ T cells in BNT162b2-vaccinated, convalescent and seronegative individuals. Numbers indicate median reduction in the frequency of detected responses. Comparisons used two-sided Wilcoxon signed rank tests. c, Stimulation indices calculated as fold change in frequency relative to the negative control. Numbers indicate the percentage of individuals with a detectable response. d, Cross-reactive responses depicted on an individual basis as percentage B.1.1.529/wild-type. e, Canonical memory differentiation profiles of spike-specific CD8⁺ T cells with representative gating and dot plots showing the distribution of subsets across individuals with detectable responses. f, Functional profiles of spike-specific CD8⁺ T cells in BNT162b2-vaccinated individuals with representative gating and pie charts showing the mean frequency for each combination. Polyfunctional responses were compared using a permutation test. Data in bar charts are shown as mean ± 95% confidence intervals, and data in dot plots are shown as median ± interquartile range. Each dot represents one donor. GrzB, granzyme B; NS, not significant.

Extended Data Fig. 1. Peptide validation experiments.

a, Representative flow cytometry plots showing the gating strategy used to assess spike-specific CD4⁺ and CD8⁺ T cell responses to peptide pools representing wild-type SARS-CoV-2 (WT) or B.1.1.529. b,c, Frequencies of spike-specific CD4⁺ (b) and CD8⁺ T cells (c) in BNT162b2-vaccinated individuals, comparing test 15mer peptide pools versus validation 20mer peptide pools representing wild-type SARS-CoV-2 (WT) or B.1.1.529. d, Pairwise analysis of spike-specific CD4⁺ (red lines) and CD8⁺ T cell responses (blue lines) in BNT162b2-vaccinated and convalescent individuals. Data in dot plots are shown as median ± IQR. Each dot represents one donor. **P = 0.007 (Two-sided Wilcoxon signed rank test). ns, not significant.