Broadly neutralizing antibodies target the coronavirus fusion peptide
Cherrelle Dacon, Courtney Tucker, Linghang Peng, Chang‐Chun D. Lee, Ting-Hui Lin, Meng Yuan, Yu Cong, Lingshu Wang, Lauren Purser, Jazmean K. Williams, Chul‐Woo Pyo, Ivan Košík, Zhe Hu, Ming Zhao, Divya Mohan, Andrew J. R. Cooper, Mary Peterson, Jeff Skinner, Saurabh Dixit, Erin Kollins, Louis Huzella, Donna L. Perry, Russell Byrum, Sanae Lembirik, David Drawbaugh, Brett Eaton, Yi Zhang, Eun Sung Yang, Man Chen, Kwanyee Leung, Rona Singer Weinberg, Amarendra Pegu, Daniel E. Geraghty, Edgar Davidson, Iyadh Douagi, Susan Moir, Jonathan W. Yewdell, Connie S. Schmaljohn, Peter D. Crompton, Michael R. Holbrook, David Nemazee, John R. Mascola, Ian A. Wilson, Joshua Tan
Abstract
The potential for future coronavirus outbreaks highlights the need to broadly target this group of pathogens. We used an epitope-agnostic approach to identify six monoclonal antibodies that bind to spike proteins from all seven human-infecting coronaviruses. All six antibodies target the conserved fusion peptide region adjacent to the S2' cleavage site. COV44-62 and COV44-79 broadly neutralize alpha- and betacoronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants BA.2 and BA.4/5, albeit with lower potency than receptor binding domain-specific antibodies. In crystal structures of COV44-62 and COV44-79 antigen-binding fragments with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine residue at the S2' cleavage site. COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings highlight the fusion peptide as a candidate epitope for next-generation coronavirus vaccine development.