Evolution of SARS-CoV-2 T cell responses as a function of multiple COVID-19 boosters

We investigated the long-term impact of repeated COVID-19 vaccinations on adaptive immunity through a three-year study of 78 individuals without reported symptomatic infections. We observed distinct dynamics in Spike-specific responses across multiple vaccine doses. While antibody levels increased and stabilized with each booster, T cell responses quickly plateaued and remained stable. Notably, approximately 30% of participants showed evidence of asymptomatic infections. Single-cell RNA sequencing revealed a diverse landscape of Spike-specific T cell phenotypes, without signs of exhaustion or functional impairment. Individuals with evidence of asymptomatic infection displayed unique immunological features, including increased frequencies of Th17-like CD4+ T cells and GZMKhi/IFNR CD8+ T cell subsets. In this group, repeated vaccinations correlated with an increase in regulatory T cells, potentially indicating a balanced immune response that may mitigate immunopathology. By regularly stimulating T cell memory, boosters contribute to a stable and enhanced immune response, which may provide better protection against symptomatic infections. Single-cell RNA-seq profiling of CD4+ and CD8+ T cells reactive to SARS-CoV-2 Spike (S) as captured by applying the activation-induced marker (AIM) assay to PBMC samples from multiple visits (time-points) of 54 donors after receiving COVID-19 vaccine boosters and reporting no disease symptoms.