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

Abstract T cells are critical to providing protection from severe COVID-19. However, whether repeated SARS-CoV-2 vaccination post-infection fuels T cell exhaustion or reshapes functionality remains debated. Here, we sampled SARS-CoV-2 convalescent donors of different COVID-19 disease severity before and after subsequent mRNA vaccination to determine the functional consequences of hybrid immunity. Using combined single-cell protein and transcriptional analysis of T cells targeting different regions of the SARS-CoV-2 genome, we identified that spike-specific T cells increased in magnitude but, notably, also gained improved polyfunctional characteristics. In contrast, T cell responses targeting non-spike proteins diminished with time and functionally remained unchanged. Elevated IFN-γ expression was a common hallmark of CD4+ and CD8+ T cell responses in mRNA-vaccinated individuals after SARS-CoV-2 infection. These responses were founded on both pre-expanded and newly detected CD8+ T cell clones after vaccination. Elevated IFN-γ production and magnitude of SARS-CoV-2-specific CD4+ and CD8+ T cells were also found in patients with B cell abnormalities (chronic lymphocytic leukemia; CLL) after booster mRNA vaccination (four doses). Collectively, these data demonstrate limited signs of functional exhaustion and instead cumulative benefits of booster vaccination post-infection, increasing the quantity and quality of cell-mediated immunity.