TY - JOUR T1 - Broadly neutralizing antibodies target the coronavirus fusion peptide JF - bioRxiv DO - 10.1101/2022.04.11.487879 SP - 2022.04.11.487879 AU - Cherrelle Dacon AU - Courtney Tucker AU - Linghang Peng AU - Chang-Chun D. Lee AU - Ting-Hui Lin AU - Meng Yuan AU - Yu Cong AU - Lingshu Wang AU - Lauren Purser AU - Jazmean K. Williams AU - Chul-Woo Pyo AU - Ivan Kosik AU - Zhe Hu AU - Ming Zhao AU - Divya Mohan AU - Andrew Cooper AU - Mary Peterson AU - Jeff Skinner AU - Saurabh Dixit AU - Erin Kollins AU - Louis Huzella AU - Donna Perry AU - Russell Byrum AU - Sanae Lembirik AU - Yi Zhang AU - Eun Sung Yang AU - Man Chen AU - Kwanyee Leung AU - Rona S. Weinberg AU - Amarendra Pegu AU - Daniel E. Geraghty AU - Edgar Davidson AU - Iyadh Douagi AU - Susan Moir AU - Jonathan W. Yewdell AU - Connie Schmaljohn AU - Peter D. Crompton AU - Michael R. Holbrook AU - David Nemazee AU - John R. Mascola AU - Ian A. Wilson AU - Joshua Tan Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/04/12/2022.04.11.487879.abstract N2 - 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.One-Sentence Summary Rare monoclonal antibodies from COVID-19 convalescent individuals broadly neutralize coronaviruses by targeting the fusion peptide.Competing Interest StatementJT and CD are co-inventors on a provisional patent filed on the mAbs described in this study. JKW and ED are employees of Integral Molecular. YC, SD, EK, LMH, DLP, RSB, SL and MRH performed this work as employees of Laulima Government Solutions, LLC. The content of this publication does not necessarily reflect the views or policies of the DHHS or of the institutions and companies with which the authors are affiliated. All other authors declare no competing interests. ER -