Potent Cross‐neutralizing Antibodies Reveal Vulnerabilities of Henipavirus Fusion Glycoprotein
Hendra and Nipah viruses (HNVs), zoonotic paramyxoviruses with >50% case fatality rates, cause fatal encephalitis and respiratory disease, yet lack approved therapies. Here, nine rhesus-derived monoclonal antibodies (mAbs) targeting the fusion glycoprotein (F) prefusion conformation are developed. Four mAbs exhibit first-rate cross-neutralization against HNVs, with two showing synergistic potency when combined with attachment glycoprotein (G)-specific mAbs. Single-dose administration of mAbs confers robust protection against lethal Nipah virus challenge in hamsters. Structural insights reveal that 8 of the 9 potent mAbs adopt a human IGHV4-59-like framework with protruding CDRH3 loops, forming pushpin-shaped paratopes that stabilize the prefusion F-trimer by occupying vulnerable interprotomer cavities. Systematic mutational profiling identifies 14 prefusion-locking residues within the F ectodomain, classified as i) structural linchpins governing fusogenicity or ii) immunodominant hotspots targeted by cross-neutralizing mAbs. This work delivers promising therapeutic candidates against HNVs and provides blueprints for the rational design of antibodies and vaccines targeting viral fusion machinery.
Authors
- Xiaofan Zhao (ORCID: https://orcid.org/0000-0002-6615-4825)
- Yi Ren (ORCID: https://orcid.org/0000-0002-0075-3454)
- Guanying Zhang (ORCID: https://orcid.org/0000-0003-3372-3355)
- Pengfei Fan (ORCID: https://orcid.org/0000-0002-7212-231X)
- Sandra Chiu (ORCID: https://orcid.org/0000-0001-9034-5755)
- Baoyue Zhang (ORCID: https://orcid.org/0000-0002-4996-6856)
- Entao Li (ORCID: https://orcid.org/0000-0003-0666-8557)
- Zhengshan Chen (ORCID: https://orcid.org/0000-0003-2869-1467)
- Yilong Yang (ORCID: https://orcid.org/0000-0003-3412-0425)
- Xiangyang Chi (ORCID: https://orcid.org/0000-0002-0580-5997)
- Yanfeng Yao (ORCID: https://orcid.org/0000-0002-6175-8590)
- Zixuan Liu (ORCID: https://orcid.org/0000-0001-5690-4808)
- Cheng Peng (ORCID: https://orcid.org/0000-0001-6233-6974)
- Jianmin Li (ORCID: https://orcid.org/0000-0002-2827-2185)
- Xinghai Zhang
- Ting Fang (ORCID: https://orcid.org/0000-0002-8963-7176)
- Zhenwei Song
- Changming Yu
- Fangxu Li (ORCID: https://orcid.org/0009-0008-4837-3849)
- Bingjie Sun (ORCID: https://orcid.org/0009-0003-4999-2063)
Institutions
- University of Science and Technology of China (CN)
- Chinese Academy of Sciences (CN)
- Beijing VDJBio (China) (CN)
- Wuhan Institute of Virology (CN)
- University of Chinese Academy of Sciences (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-04-29
- DOI
- https://doi.org/10.1002/advs.202501996
- Citations
- 1
- Primary Topic
- Virology and Viral Diseases
- Type
- article
- Field-Weighted Citation Impact
- 1.35
Funders
- National Natural Science Foundation of China