A broadly neutralizing antibody recognizes a unique epitope with a signature motif common across coronaviruses
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 (pep<sup>DVVNQN/Q</sup>) 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.
Authors
- Fulian Wang (ORCID: https://orcid.org/0000-0001-6571-6147)
- Liangminghui Zhang
- Nicole Zitzmann (ORCID: https://orcid.org/0000-0003-1969-4949)
- Aibin Liang (ORCID: https://orcid.org/0000-0002-8978-1987)
- Xinyu Shi (ORCID: https://orcid.org/0000-0001-9586-2460)
- Huanzhen Liu
- Xuxue Dong
- Michelle L. Hill (ORCID: https://orcid.org/0000-0002-9289-5811)
- Raymond A. Dwek (ORCID: https://orcid.org/0000-0001-9989-2245)
- Juliane Brun (ORCID: https://orcid.org/0000-0002-0964-3681)
- Guang Yang (ORCID: https://orcid.org/0000-0001-7379-6810)
- Qianping Huang (ORCID: https://orcid.org/0009-0001-7130-1279)
- Lili Liu (ORCID: https://orcid.org/0000-0002-5881-7908)
- Yi Zhang (ORCID: https://orcid.org/0000-0002-8228-2560)
- Yu Li (ORCID: https://orcid.org/0000-0001-5000-2758)
- Xin He (ORCID: https://orcid.org/0000-0002-8602-5166)
- Lei Yan (ORCID: https://orcid.org/0000-0003-1775-5533)
- Zhiqiang Liang
Institutions
- Tongji University (CN)
- Nanjing Normal University (CN)
- ShanghaiTech University (CN)
- University of Oxford (GB)
- Tongji Hospital (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-15
- DOI
- https://doi.org/10.1038/s41467-025-63101-1
- Citations
- 6
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 8.38
Funders
- University of Oxford
- Ministry of Science and Technology of the People's Republic of China
- Jiangsu Science and Technology Department