Potent Cross‐neutralizing Antibodies Reveal Vulnerabilities of Henipavirus Fusion Glycoprotein

Potent Cross‐neutralizing Antibodies Reveal Vulnerabilities of Henipavirus Fusion Glycoprotein

Abstract 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...

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Main Authors: Yi Ren, Pengfei Fan, Xinghai Zhang, Ting Fang, Zhengshan Chen, Yanfeng Yao, Xiangyang Chi, Guanying Zhang, Xiaofan Zhao, Bingjie Sun, Fangxu Li, Zixuan Liu, Zhenwei Song, Baoyue Zhang, Cheng Peng, Entao Li, Yilong Yang, Jianmin Li, Sandra Chiu, Changming Yu
Format: Article
Language:English
Published: Wiley 2025-07-01
Series:Advanced Science
Subjects:
antibodies
cross‐neutralizing
fusion glycoprotein
henipaviruses
protection
vulnerabilities
Online Access:https://doi.org/10.1002/advs.202501996
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Summary:Abstract 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.
ISSN:2198-3844

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