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

Abstract

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