Science: Broadly neutralizing antibodies target the coronavirus fusion peptide
SCIENCE | VOL 377 | ISSUE 6607 | 12 JUL 2022
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 Kosik, Zhe Hu, Ming Zhao, Divya Mohan, Andrew J. R. Cooper, Mary Peterson,Jeff Skinner, Saurabh Dixit, Erin Kollins, Louis Huzella, Donna Perry, Russell Byrum, Sanae Lembirik, David Drawbaugh, Brett Eaton, Yi Zhang, Eun Sung Yang, Man Chen, Kwanyee Leung, Rona S. Weinberg, Amarendra Pegu, Daniel E. Geraghty, Edgar Davidson, Iyadh Douagi, Susan Moir, Jonathan W. Yewdell, Connie Schmaljohn, Peter D. Crompton, Michael R. Holbrook, David Nemazee, John R. Mascola, Ian A. Wilson, Joshua Tan
Highlights
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 andBA.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.
Introduction
Coronaviruses consist of four genera that infect birds and mammals (1). Seven coronaviruses are known to cause human disease: the alphacoronaviruses HCoV-229E (human coronavirus 229E) andHCoV-NL63 (human coronavirus NL63), as well as the betacoronaviruses HCoV-OC43(human coronavirus OC43), HCoV-HKU1 (human coronavirus HKU1), SARS-CoV (severe acute respiratory syndrome coronavirus),MERS-CoV (Middle East respiratory syndrome coronavirus), and SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2).Whereas the first four coronaviruses generally cause mild disease, the latter three have brought about serious outbreaks in recent years. In particular, the ongoing COVID-19pandemic caused by SARS-CoV-2 has resulted in more than 6 million deaths since the first cases were identified in 2019 (2). The currently dominant SARS-CoV-2 Omicron BA.2,BA.2.12.1, BA.4, and BA.5 subvariants are at least partially resistant to most available vaccines and antibody therapeutics (3–6). Further-more, two coronaviruses previously linked only to animal infection were recently detected in individuals with flu-like symptoms (7,8). These developments highlight the importance of targeting conserved and functionally essential sites on coronaviruses.
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