SARS-CoV-2 responsive T cell numbers are associated with protection from COVID-19: A prospective cohort study in keyworkers

Background: Immune correlates of protection from COVID-19 are important, but incompletely understood. Methods: We conducted a prospective cohort study in 2,826 participants working in hospitals and Fire and Police services in England, UK during the pandemic (ISRCTN5660922). Of these, 2,672 were unselected volunteers recruited irrespective of previous SARS-CoV-2 RT-PCR test results, and 154 others were recruited separately specifically because they previously tested positive. At recruitment in June 2020, we measured numbers of interferon-y; secreting, SARS-CoV-2 responsive T cells using T-SPOT Discovery SARS-CoV-2 kits (Oxford Immunotec Ltd), and antibodies to SARS-CoV-2 proteins using commercial immunoassays. We then described time to microbiologically confirmed SARS-CoV-2 infection, stratified by immunological parameters. Results: T cells responsive to the spike (S), nuclear (N) and membrane proteins (M) dominated the responses measured. Using the sum of the spots (responsive cells within each well of 250,000 peripheral blood mononuclear cells) for S, N and M antigens minus the control, the 2,672 unselected participants were divided into those with higher responses (n=669, 25.4%; median 30 spots (IQR 18,54)) and those with low responses (n=2016, 76.7%, median 3 (IQR 1,6)), the cutoff we derived being 12 spots. Of the participants with higher T cell responses, 367 (53%) had detectable antibodies against the N or S proteins. During a median of 118 days follow-up, 20 participants with lower T cell responses developed COVID-19, compared with none in the population with high T cell responses (log-rank test, p=6x10-3). Conclusions: Peripheral blood SARS-CoV-2 responsive T cell numbers are associated with risk of developing COVID-19.