Abstract / Summary
The relationship between SARS-CoV-2-specific T cell responses and COVID-19 risk is incompletely understood, particularly after variant-adapted booster receipt. We assessed Spike-specific and Nucleocapsid-specific CD4+ and CD8+ T cell responses, measured by validated 27-color intracellular cytokine staining assay, as correlates of COVID-19 risk over 6 months in COVAIL recipients of a second SARS-CoV-2 booster on Day 1 (D1). Among one-dose mRNA recipients, D15 CD4 + T cell IFN-γ and/or IL-2 Spike BA.4/5 responses correlated inversely with COVID-19 risk for previously-infected (non-naïve) [hazard ratio (HR) = 0.62 (95% CI 0.39, 0.99) per 3-fold increase], but not SARS-CoV-2 naïve [HR = 1.03 (0.81, 1.32)], participants (22 non-naïve, 122 naïve cases). Spike-specific CD4+ T cells and neutralizing antibodies each independently predicted COVID-19 in non-naïve participants [Cox bivariate model HRs per standard deviation: D1 Spike CD4 + T cell 0.81 (0.68, 0.96), D15 titer 0.43 (0.27, 0.69), co-correlatep < 0.001]. Among non-naïve participants, high Spike-specific CD4+ T cell responses and neutralizing antibody titers marked low risk, as did polyfunctional Spike-specific CD4+ T cells expressing ≥ three cytokine(s)/markers. At the same high D15 CD4+ Spike-specific T cell levels, risk was lower for non-naïve vs. naïve participants, suggesting that these T cell responses are a proxy for unmeasured protective immune mechanism(s) operant post-SARS-CoV-2 infection. Vaccines to SARS-CoV-2 clearly stimulate virus specific T cell and antibody responses but T cell-mediated protection is challenging to show. Here the authors use PBMC samples from an open-label clinical trial of different prototype and variant-specific COVID-19 vaccine boosters to examine the function and phenotype of T cell populations and how T cell response levels associate with risk of, and with protection against, symptomatic SARS-CoV-2 infection.