Booster mRNA vaccination post-SARS-CoV-2 infection enhances functional qualities of T cell immunity

Abstract T cells are critical to generate protection from severe respiratory viral disease. Whether repeated SARS-CoV-2 antigen exposure through vaccination causes T cell exhaustion or gain of functions remains debated. In this study, we sampled SARS-CoV-2 convalescent donors before and after vaccination to determine the functional consequences of hybrid immunity. Donors were sampled at 6 months and 18 months convalescence and divided according to their history of mild or severe/hospitalized disease (n = 44 and 45 respectively). In between the two sampling timepoints, donors also received mRNA vaccination through the national COVID-19 vaccination program. Using activation-induced marker assays, intracellular cytokine staining, single-cell transcriptomics and single-cell T-cell receptor sequencing analyses, we show that spike-specific T cells increase in magnitude but, importantly, also gain highly functional characteristics. By contrast, T cell responses to non-spike proteins were diminished or remained unchanged. Elevated interferon-gamma expression was a common hallmark of CD4+ and CD8+ T cells post-mRNA-vaccination. These responses were founded on both pre-expanded and newly detected CD8+ T cell clones after vaccination. Collectively, these data demonstrate the cumulative benefits of booster vaccinations, leading to increased quantity and quality of cell-mediated immunity. Supported by a grant from Karolinska Institutet Research foundation grants (2022-01708)