Patterns of restricted TCR usage following SARS-CoV-2 vaccination and severe disease

Introduction: T cells influence COVID-19 severity and establish long-lasting immune memory in response to vaccination and infection. The diversity of the T cell repertoire, and complexity of T cell epitope recognition, make it challenging to define protective epitope-specific T cells. In this study, we created a highly specific TCR meta-database to identify T cell epitopes from the nearly complete SARS-CoV-2 proteome and determine whether vaccination with mRNA vaccines influenced the TCR repertoire. Methods: Using this meta-database, we analyzed immunosequencing data of genomic DNA to define the variable region of T cell receptor (TCR) b chain (TCRB) sequences among participants in a longitudinal COVID-19 cohort study. The TCR repertoire was compared between participants who were vaccinated or unvaccinated against SARS-CoV-2 and stratified by disease severity. TCR diversity was measured using clonality, an index defined as the inverted normalized Shannon entropy. Results: Highly clonal TCR repertoires correlated with age and comorbidities. Using our meta-database approach, we found that vaccinated participants hospitalized with infection had the most restricted SARS-CoV-2-specific CD8 TCR repertoire. However, TCRB with predicted specificity to non-spike SARS-CoV-2 proteins dominated the response, even in vaccinated participants. We identified a peptide sequence in the ORF10 accessory protein that was more frequently recognized in study participants with mild disease. Conversely, CD8 T cell recognition of a peptide sequence in ORF1ab more closely correlated with severe disease. Discussion: Overarchingly, TCR repertoire analysis revealed that CD8 T cells responding to SARS-CoV-2 broadly recognize epitopes across the SARS-CoV-2 proteome, and provided opportunities to identify epitopes associated with disease.