Syncytia Formation Promotes Virus Resistance to Interferon and Neutralizing Antibodies (preprint)

SARS-CoV-2, like many viruses, generates syncytia. Using SARS-CoV-2 and S (S) expressing recombinant vesicular stomatitis and influenza A viruses, we show that S-mediated syncytia formation provides resistance to interferons in cultured cells, human small airway-derived air-liquid interface cultures and hACE2 transgenic mice. Amino acid substitutions that modulate fusogenicity in Delta- and Omicron-derived S have parallel effects on viral interferon resistance. Syncytia formation also decreases antibody virus neutralization activity in cultured cells. These findings explain the continued selection of fusogenic variants during SARS-CoV-2 evolution in humans and, more generally, the evolution of fusogenic viruses despite the adverse effects of syncytia formation on viral replication in the absence of innate or adaptive immune pressure.

Broadly neutralizing antibodies target the coronavirus fusion peptide (preprint)

The potential for future coronavirus outbreaks highlights the need to develop strategies and tools to broadly target this group of pathogens. Here, using an epitope-agnostic approach, we identified six monoclonal antibodies that bound to spike proteins from all seven human-infecting coronaviruses. Epitope mapping revealed that all six antibodies target the conserved fusion peptide region adjacent to the S2' cleavage site. Two antibodies, COV44-62 and COV44-79, broadly neutralize a range of alpha and beta coronaviruses, including SARS-CoV-2 Omicron subvariants BA.1 and BA.2, albeit with lower potency than RBD-specific antibodies. In crystal structures of Fabs COV44-62 and COV44-79 with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine at the S2' cleavage site. Importantly, COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings identify the fusion peptide as the target of the broadest neutralizing antibodies in an epitope-agnostic screen, highlighting this site as a candidate for next-generation coronavirus vaccine development.