Personalized HLA-aware TCR measure predicts the risk of symptomatic SARS-CoV-2 infection following booster vaccination

HLA-driven heterogeneity and limitations of live T cell functional assays routinely thwart assessment of cell-mediated immunity in vaccination trials. To address this, we developed a T-cell receptor (TCR)-based measure of immunogen recognition and evaluated it in COV-BOOST, a third-dose COVID-19 vaccine trial, during the Delta and Omicron waves (2021-2022, United Kingdom). We estimated HLA-aware Spike-reactive T cell (HA-TS) breadth from participant HLA genotypes, TCRβ repertoires, and a novel SARS-CoV-2 S HLA-linked reference catalog. Higher post-boost HA-TS breadth was associated with lower symptomatic infection risk (HR 0.58, 95% CI 0.39-0.86). This association persisted after adjustment for neutralizing antibody titers and IFN-γ responses. Examination of HA-TS across prior studies showed that it reflects participant genotype, exposure intensity, and time from exposure to sampling. These findings highlight the possibility that estimates of antigen-specific T cell repertoire breadth could serve as a correlate of protection to accelerate vaccine development.