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Human neutralizing antibodies target a conserved lateral patch on H7N9 hemagglutinin head

Author

Listed:
  • Manxue Jia

    (Columbia University Vagelos College of Physicians and Surgeons)

  • Hanjun Zhao

    (University of Hong Kong
    Hong Kong Science and Technology Park)

  • Nicholas C. Morano

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University)

  • Hong Lu

    (Columbia University Vagelos College of Physicians and Surgeons)

  • Yin-Ming Lui

    (University of Hong Kong)

  • Haijuan Du

    (National Institutes of Health)

  • Jordan E. Becker

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University)

  • Kwok-Yung Yuen

    (University of Hong Kong
    Hong Kong Science and Technology Park
    University of Hong Kong-Shenzhen Hospital)

  • David D. Ho

    (Columbia University Vagelos College of Physicians and Surgeons)

  • Peter D. Kwong

    (Columbia University Vagelos College of Physicians and Surgeons
    National Institutes of Health)

  • Lawrence Shapiro

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University
    National Institutes of Health)

  • Kelvin Kai-Wang To

    (University of Hong Kong
    Hong Kong Science and Technology Park
    University of Hong Kong-Shenzhen Hospital)

  • Xueling Wu

    (Columbia University Vagelos College of Physicians and Surgeons)

Abstract

Avian influenza A virus H7N9 causes severe human infections with >30% fatality. Currently, there is no H7N9-specific prevention or treatment for humans. Here, from a 2013 H7N9 convalescent case in Hong Kong, we isolate four hemagglutinin (HA)-reactive monoclonal antibodies (mAbs), with three directed to the globular head domain (HA1) and one to the stalk domain (HA2). Two clonally related HA1-directed mAbs, H7.HK1 and H7.HK2, potently neutralize H7N9 and protect female mice from lethal H7N9/AH1 challenge. Cryo-EM structures reveal that H7.HK1 and H7.HK2 bind to a β14-centered surface and disrupt the 220-loop that makes hydrophobic contacts with sialic acid on an adjacent protomer, thereby blocking viral entry. Sequence analysis indicates the lateral patch targeted by H7.HK1 and H7.HK2 to be conserved among influenza subtypes. Both H7.HK1 and H7.HK2 retain HA1 binding and neutralization capacity to later H7N9 isolates from 2016–2017, consistent with structural data showing that the antigenic mutations during this timeframe occur at their epitope peripheries. The HA2-directed mAb H7.HK4 lacks neutralizing activity but when used in combination with H7.HK2 moderately augments female mouse protection. Overall, our data reveal antibodies to a conserved lateral HA1 supersite that confer neutralization, and when combined with a HA2-directed non-neutralizing mAb, augment protection.

Suggested Citation

  • Manxue Jia & Hanjun Zhao & Nicholas C. Morano & Hong Lu & Yin-Ming Lui & Haijuan Du & Jordan E. Becker & Kwok-Yung Yuen & David D. Ho & Peter D. Kwong & Lawrence Shapiro & Kelvin Kai-Wang To & Xueling, 2024. "Human neutralizing antibodies target a conserved lateral patch on H7N9 hemagglutinin head," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48758-4
    DOI: 10.1038/s41467-024-48758-4
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    1. Rong Hai & Mirco Schmolke & Victor H. Leyva-Grado & Rajagowthamee R. Thangavel & Irina Margine & Eric L. Jaffe & Florian Krammer & Alicia Solórzano & Adolfo García-Sastre & Peter Palese & Nicole M. Bo, 2013. "Influenza A(H7N9) virus gains neuraminidase inhibitor resistance without loss of in vivo virulence or transmissibility," Nature Communications, Nature, vol. 4(1), pages 1-9, December.
    2. Zhe Chen & Jianmin Wang & Linlin Bao & Li Guo & Weijia Zhang & Ying Xue & Hongli Zhou & Yan Xiao & Jianwei Wang & Fan Wu & Ying Deng & Chuan Qin & Qi Jin, 2015. "Human monoclonal antibodies targeting the haemagglutinin glycoprotein can neutralize H7N9 influenza virus," Nature Communications, Nature, vol. 6(1), pages 1-10, November.
    3. Jianfang Zhou & Dayan Wang & Rongbao Gao & Baihui Zhao & Jingdong Song & Xian Qi & Yanjun Zhang & Yonglin Shi & Lei Yang & Wenfei Zhu & Tian Bai & Kun Qin & Yu Lan & Shumei Zou & Junfeng Guo & Jie Don, 2013. "Biological features of novel avian influenza A (H7N9) virus," Nature, Nature, vol. 499(7459), pages 500-503, July.
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