A broadly neutralizing antibody recognizes a unique epitope with a signature motif common across coronaviruses

Lei Yan, Fulian Wang, Michelle Hill, Juliane Brun, Ze Liang, Xinyu Shi, Liangminghui Zhang, Xiuxiu He, Yu Li, Qianping Huang, Xuxue Dong, Huanzhen Liu, Yi Zhang, Lili Liu, Raymond A. Dwek, Nicole Zitzmann, Aibin Liang () and Guang Yang ()
Additional contact information
Lei Yan: ShanghaiTech University
Fulian Wang: ShanghaiTech University
Michelle Hill: University of Oxford
Juliane Brun: Oxford Glycobiology Institute
Ze Liang: Nanjing Normal University
Xinyu Shi: Nanjing Normal University
Liangminghui Zhang: Nanjing Normal University
Xiuxiu He: Nanjing Normal University
Yu Li: ShanghaiTech University
Qianping Huang: ShanghaiTech University
Xuxue Dong: ShanghaiTech University
Huanzhen Liu: ShanghaiTech University
Yi Zhang: ShanghaiTech University
Lili Liu: ShanghaiTech University
Raymond A. Dwek: Oxford Glycobiology Institute
Nicole Zitzmann: Oxford Glycobiology Institute
Aibin Liang: Tongji University School of Medicine
Guang Yang: ShanghaiTech University

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Cross-reactive antibodies targeting multiple epitopes have been identified in Sarbecoviruses, but the precise molecular mechanism(s) behind the crossreactivity remain poorly understood. Here, we isolate 3D1, a broadly neutralizing antibody (bnAb) derived from a human combinatorial antibody library targeting the conserved HR1 domain. 3D1 uniquely recognizes a β-turn fold comprising a 6-mer peptide (pepDVVNQN/Q) that forms during a pre-hairpin transition state, occurring exclusively before membrane fusion during viral infection. 3D1 effectively neutralizes a wide range of live SARS-CoV-2 wild-type strains except for Omicron, which evades neutralization due to a detrimental point mutation (Q954H). Notably, this cryptic epitope reveals a signature motif that extends throughout the core region of coronaviruses and is also present in various RNA viruses, including HIV and Marburgvirus. 3D1 functions as a natural or background antibody capable of binding to a diverse array of non-self antigens. 3D1’s cross-reactivity underscores the effectiveness of the library approach, which encompasses the entire antibody repertoire.

Date: 2025
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DOI: 10.1038/s41467-025-63101-1

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