SARS-CoV-2 vaccination diversifies the CD4+ spike-reactive T cell repertoire in patients with prior SARS-CoV-2 infection

COVID-19 mRNA vaccines elicit strong T and B cell responses to the SARS-CoV-2 spike glycoprotein in both SARS-CoV-2 naïve and experienced patients. However, it is unknown whether the post-vaccine CD4+ T cell boost, critical for virus-specific immune memory, seen in patients with a history of COVID-19 is due to restimulation of T cell clonotypes that were first activated during SARS-CoV-2 primary infection or is the result of new clones that are activated by the vaccine. We identified both new and preexisting T cell receptor clonotypes and found that vaccination significantly broadens the SARS-CoV-2-reactive CD4+ T cell repertoire in patients with a history of COVID-19. Additionally, we demonstrated that the vaccine preferentially induces T cells that only recognize SARS-CoV-2 antigens, rather than the less-avid SARS-CoV-2/common cold coronavirus (CCC) cross-reactive responses. These data demonstrate that SARS-CoV-2 vaccination induces a distinct antigen-specific repertoire relative to natural infection and increases the breadth of the SARS-CoV-2-reactive T cell response.