Cross-reactive CD4+T cells enhance SARS-CoV-2 immune responses upon infection and vaccination

The newly emerged coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused a global pandemic challenging economy and health systems. Initially, it was assumed that SARS-CoV-2 encountered an immunologically unprotected population, however, SARS-CoV-2 displays considerable homologies with endemic, seasonal common cold endemic coronaviruses (HCoVs). We and others could demonstrate the existence of cellular and humoral cross-reactivity to SARS-CoV-2, still the role of cross-reactive immunity in SARS-CoV-2 infection and vaccination is under debate. We comprehensively determined HCoV-reactivity and SARS-CoV-2-cross-reactivity in unexposed individuals and COVID-19 convalescents. Pre-existing cross-reactive memory T cells were efficiently recruited into mild SARS-CoV-2 infections and their abundance correlated with higher S1 IgG and neutralizing antibodies titers. Importantly, the cells were also reactivated after primary BNT162b2 COVID-19 mRNA vaccination in which their kinetics resembled that of secondary immune responses. Our results highlight the functional importance of pre-existing spike-cross-reactive T cells in SARS-CoV-2 infection and vaccination. Abundant cross-immunity may be responsible for the unexpectedly high efficacy of current vaccines even with single doses and the high rate of asymptomatic/mild infection courses.