Abstract
The COVID-19 pandemic has revealed a range of disease phenotypes in infected patients with asymptomatic, mild, or severe clinical outcomes, but the mechanisms that determine such variable outcomes remain unresolved. In this study, we identified immunodominant CD8 T-cell epitopes in the spike antigen using a novel TCR-binding algorithm. The predicted epitopes induced robust T-cell activation in unexposed donors demonstrating pre-existing CD4 and CD8 T-cell immunity to SARS-CoV-2 antigen. The T-cell reactivity to the predicted epitopes was higher than the Spike-S1 and S2 peptide pools in the unexposed donors. A key finding of our study is that pre-existing T-cell immunity to SARS-CoV-2 is contributed by TCRs that recognize common viral antigens such as Influenza and CMV, even though the viral epitopes lack sequence identity to the SARS-CoV-2 epitopes. This finding is in contrast to multiple published studies in which pre-existing T-cell immunity is suggested to arise from shared epitopes between SARS-CoV-2 and other common cold-causing coronaviruses. However, our findings suggest that SARS-CoV-2 reactive T-cells are likely to be present in many individuals because of prior exposure to flu and CMV viruses.
Highlights
The COVID-19 pandemic has revealed a range of disease phenotypes in infected patients with asymptomatic, mild, or severe clinical outcomes, but the mechanisms that determine such variable outcomes remain unresolved
The results demonstrate that the use of OncoPeptVAC identified potent CD8 T-cell epitopes in the spike antigen that could not have been detected by using large overlapping peptide pools used in T-cell activation assays
Several studies on respiratory viruses have shown the presence of robust virus-specific CD8-T cell responses which have been shown to last for decades
Summary
The COVID-19 pandemic has revealed a range of disease phenotypes in infected patients with asymptomatic, mild, or severe clinical outcomes, but the mechanisms that determine such variable outcomes remain unresolved. Detection of pre-existing immunity in healthy donors using epitopes that favor CD8 T-cell activation may provide a framework to understand the complex immune responses observed in clinical settings. It may shed light on the differences in morbidity and mortality in different population groups across the globe. Our study uncovered strong pre-existing CD8 T-cell immunity against SARS-CoV-2 using a small set of 11 epitopes that engaged cross-reactive TCRs recognizing epitopes from other viruses, not necessarily common cold viruses belonging to the coronavirus family as hypothesized by other studies. Our findings raise the possibility that many individuals carrying antigen-experienced T-cells against other viruses may be naturally protected against COVID-19 without prior SARS-CoV-2 infection
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