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Both SARS-CoV-2 infection and COVID-19 vaccines elicit memory T cell responses. Here, we report the development of two pools of experimentally-defined SARS-CoV-2 T cell epitopes, that in combination with spike, were used to discriminate four groups of subjects with different SARS-CoV-2 infection and COVID-19 vaccine status. The overall T cell-based classification accuracy was 89.2% and 88.5% in the experimental and validation cohorts. This scheme was applicable to different mRNA vaccines, different lengths of time post-infection/post-vaccination, and yielded increased accuracy when compared to serological readouts. T cell responses from breakthrough infections were also studied, and effectively segregated from vaccine responses, with a combined performance of 86.6% across all 239 subjects from the five groups. We anticipate that a T cell-based immunodiagnostic scheme to classify subjects based on their vaccination and natural infection history will be an important tool for longitudinal monitoring of vaccination and establishing SARS-CoV-2 correlates of protection.

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Conflict of interest disclosure statement D.V.Z., D.S.D., and K.R.B. hold patents for the discovery and development of immunotherapies for cancer, including patents related to GPC2-directed immune-based therapies. K.R.B. receives research funding from Tmunity for research on GPC2-directed chimeric antigen receptor T cells and D.V.Z., D.S.D., and K.R.B. receive royalties from Tmunity for licensing of GPC2-related intellectual property.