mRNA vaccine-induced SARS-CoV-2 spike-specific IFN-γ and IL-2 T-cell responses are predictive of serological neutralization and are transiently enhanced by pre-existing cross-reactive immunity.

The contributions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells to vaccine efficacy and durability are unclear. We investigated relationships between mRNA vaccine-induced spike-specific interferon- gamma (IFN-γ) and interleukin-2 (IL-2) T-cell responses and neutralizing antibody development in long-term care home staff doubly vaccinated with BNT162b2 or mRNA-1273. The impacts of pre-existing cross-reactive T-cell immunity on cellular and humoral responses to vaccination were additionally assessed. Mathematical modeling of the kinetics of spike-specific IFN-γ and IL-2 T-cell responses over 6 months post-second dose was bifurcated into recipients who exhibited gradual increases with doubling times of 155 and 167 days or decreases with half-lives of 165 and 132 days, respectively. Differences in kinetics did not correlate with clinical phenotypes. Serological anti-spike IgG, anti-receptor binding domain (RBD) IgG, anti-spike IgA, and anti-RBD IgA antibody levels otherwise decayed in all participants with half-lives of 63, 57, 79, and 46 days, respectively, alongside waning neutralizing capacity ( IMPORTANCE: Our findings provide valuable insights into the potential contributions of mRNA vaccine-induced spike-specific T-cell responses to the durability of neutralizing antibody levels in both uninfected and hybrid immune recipients. Our study additionally sheds light on the precise impacts of pre-existing cross-reactive T-cell immunity to severe acute respiratory syndrome coronavirus 2 on the magnitude and kinetics of cellular and humoral responses to vaccination. Accordingly, our data will help optimize the development of next-generation T cell-based coronavirus vaccines and vaccine regimens to maximize efficacy and durability.