Vaccine-induced T cell responses correlate with reduced risk of severe COVID-19 in a placebo-controlled efficacy trial

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BACKGROUND: While vaccine-induced SARS-CoV-2 antibodies provide partial protection against COVID-19, a significant question remains regarding the role of vaccine-induced T cells in combating COVID-19. The purpose of this study is to investigate whether signatures of the T-cell response contribute to protection against (severe) COVID-19. METHODS: T cell receptor (TCR) sequencing was conducted using pre-vaccination and 29 days post-vaccination PAXgene samples from 396 participants in the phase 3 efficacy trial, ENSEMBLE. The dataset consists of 198 individuals who developed breakthrough COVID-19 infections, including 23 severe cases, and an equal number of matched control subjects. Immunosequencing and subsequent computational analysis was performed to identify SARS-CoV-2 and Spike-specific TCRs to quantify SARS-CoV-2 specific T cell breadth, depth, clonal expansion, and a model test score that describes magnitude of cellular response compared to pre-pandemic controls. FINDINGS: Preliminary analyses demonstrated high concordance and correlation between functional T cell responses measured by a standard intracellular cytokine staining and TCR sequencing metrics. Furthermore, vaccine-elicited T cell responses correlated inversely with the risk of developing severe COVID-19, while no strong relation was observed with overall symptomatic COVID-19 risk. A multivariable analysis including neutralizing antibody data and TCR scores indicated that, in addition to humoural responses, T cell responses contribute to protection against severe COVID-19. INTERPRETATION: Our findings show that higher vaccine-elicited T cell responses are significantly correlated with decreased risk of severe COVID-19, but not with risk of any symptomatic COVID-19. These results represent a direct correlation between vaccine-elicited T cell responses and protection from severe COVID-19. FUNDING: This work was fully funded by Janssen Vaccines & Prevention B.V. The samples were sourced from ENSEMBLE, which was partly funded by Biomedical Advanced Research and Development Authority (BARDA), under other transaction agreement HHSO100201700018C.

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