The functional relevance of preexisting cross-immunity to severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) is a subject of intense debate. Here, we show that human endemiccoronavirus (HCoV)–reactive and SARS-CoV-2–cross-reactive CD4+T cells are ubiquitous but decreasewith age. We identified a universal immunodominant coronavirus-specific spike peptide (S816-830)and demonstrate that preexisting spike- and S816-830–reactive T cells were recruited into immuneresponses to SARS-CoV-2 infection and their frequency correlated with anti–SARS-CoV-2-S1-IgGantibodies. Spike–cross-reactive T cells were also activated after primary BNT162b2 COVID-19messenger RNA vaccination and displayed kinetics similar to those of secondary immune responses.Our results highlight the functional contribution of preexisting spike–cross-reactive T cells inSARS-CoV-2 infection and vaccination. Cross-reactive immunity may account for the unexpectedly rapidinduction of immunity after primary SARS-CoV-2 immunization and the high rate of asymptomatic ormild COVID-19 disease courses.
