One to neutralize all.

A strategy to mitigate outbreaks of emerging coronaviruses with pandemic potential is the development of pan-coronavirus vaccines and broadly neutralizing antibodies (bnAbs). The SARS-CoV-2 spike glycoprotein, in particular the receptor-binding site, is the primary target of nAbs; but, owing to selection pressure, neutralization escape variants emerge. Previously it was shown that a bnAb, CC40.8, from a COVID-19-convalescent donor exhibits broad reactivity with human betacoronaviruses. This study reports that CC40.8 targets an S2 stem–helix epitope, which is part of the fusion machinery. The contact residues between the peptide–antibody complex were largely conserved between betacoronaviruses, and CC40.8 neutralized diverse betacoronaviruses and SARS-CoV-2 variants of concern in vitro. Finally, CC40.8 reduced weight loss and SARS-CoV-2 titres in animal models. The findings might guide pan-coronavirus vaccine development and antibody-based intervention strategies.