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

Loyal, L.; Braun, J.; Henze, L.; Kruse, B.; Dingeldey, M.; Reimer, U.; Kern, F.; Schwarz, T.; Mangold, M.; Unger, C.; Doerfler, F.; Kadler, S.; Rosowski, J.; Guercan, K.; Uyar-Aydin, Z.; Frentsch, M.; Kurth, F.; Schnatbaum, K.; Eckey, M.; Hippenstiel, S.; Hocke, A.; Mueller, M. A.; Sawitzki, B.; Miltenyi, S.; Paul, F.; Mall, M. A.; Wenschuh, H.; Voigt, S.; Drosten, C.; Lauster, R.; Lachmann, N.; Sander, L.-E.; Corman, V. M.; Roehmel, J.; Meyer-Arndt, L. A.; Thiel, A. M.; Giesecke-Thiel, C.

While evidence for pre-existing SARS-CoV-2-cross-reactive CD4+ T cells in unexposed individuals is increasing, their functional significance remains unclear. Here, we comprehensively determined SARS-CoV-2-cross-reactivity and human coronavirus-reactivity in unexposed individuals. SARS-CoV-2-cross-reactive CD4+ T cells were ubiquitous, but their presence decreased with age. Within the spike glycoprotein fusion domain, we identified a universal immunodominant coronavirus-specific peptide epitope (iCope). Pre-existing spike- and iCope-reactive memory T cells were efficiently recruited into mild SARS-CoV-2 infections and their abundance correlated with higher IgG 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 spike-specific 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.