Dominant substitutions underlying the antigenic evolution of H5 influenza virus

Mengyi Zhang, Luyao Qin, Zichen Li, Jiamin Chen, Jincheng Tong, Xiao Ding, Huan Li, Yun Ma, Jingze Liu, Qiuju He, Rong Bi, Weijin Huang, Cheng Bian, Youchun Wang (), Aiping Wu () and Qianqian Li ()
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Mengyi Zhang: Chinese Academy of Medical Science & Peking Union Medical College, State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Medical Biology
Luyao Qin: Chinese Academy of Medical Sciences & Peking Union Medical College, State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine
Zichen Li: Chinese Academy of Medical Science & Peking Union Medical College, State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Medical Biology
Jiamin Chen: Chinese Academy of Medical Science & Peking Union Medical College, State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Medical Biology
Jincheng Tong: Chinese Academy of Medical Science & Peking Union Medical College, State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Medical Biology
Xiao Ding: Chinese Academy of Medical Sciences & Peking Union Medical College, State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine
Huan Li: Chinese Academy of Medical Science & Peking Union Medical College, State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Medical Biology
Yun Ma: Chinese Academy of Medical Sciences & Peking Union Medical College, State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine
Jingze Liu: Chinese Academy of Medical Sciences & Peking Union Medical College, State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine
Qiuju He: Chinese Academy of Medical Science & Peking Union Medical College, State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Medical Biology
Rong Bi: Chinese Academy of Medical Science & Peking Union Medical College, State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Medical Biology
Weijin Huang: Chinese Academy of Medical Sciences & Peking Union Medical College, National Institutes for Food and Drug Control
Cheng Bian: Chinese Academy of Medical Science & Peking Union Medical College, State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Medical Biology
Youchun Wang: Chinese Academy of Medical Science & Peking Union Medical College, State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Medical Biology
Aiping Wu: Chinese Academy of Medical Sciences & Peking Union Medical College, State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine
Qianqian Li: Chinese Academy of Medical Science & Peking Union Medical College, State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Medical Biology

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract Highly pathogenic avian influenza (HPAI) H5 viruses have recently been documented in mammals including humans, posing a major threat to global public health. To prevent a potential H5 pandemic, it is critical to elucidate the antigenic evolutionary pattern and identify key drivers underlying its evolution. In this work, we construct a comprehensive antigenic map of H5 influenza viruses spanning their evolutionary history and classified three antigenic clusters with no cross-neutralization. The first corresponds to ancestral clades, the second to 2.3.4.4* clades being predominant since 2010, and the third to 2.3.4.4 h clade. Despite the gradually increasing genetic distances from ancestral to 2.3.4.4* to 2.3.4.4 h, their antigenic evolution does not follow the same progressive pattern: the antigenic distance between 2.3.4.4 h and ancestral is smaller than that between 2.3.4.4* and ancestral. This divergence is associated with two distinct mutation patterns at six key amino acid positions: (1) persistent mutations at positions 88 (N > R > S), 199 (D > N > S), and 205 (K > N > D), and (2) reversible mutations at positions 131 (Q > L > Q), 139 (S > P > S), and 289 (N > H > N). These findings not only reveal the antigenic evolution mechanism of H5 influenza, but also provide important guidance for vaccine strain selection and broad-spectrum vaccine development.

Date: 2025
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DOI: 10.1038/s41467-025-65730-y

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