Unique binding pattern for a lineage of human antibodies with broad reactivity against influenza A virus

Xiaoyu Sun, Caixuan Liu, Xiao Lu, Zhiyang Ling (), Chunyan Yi, Zhen Zhang, Zi Li, Mingliang Jin, Wenshuai Wang, Shubing Tang, Fangfang Wang, Fang Wang, Sonam Wangmo, Shuangfeng Chen, Li Li, Liyan Ma, Yaguang Zhang, Zhuo Yang, Xiaoping Dong, Zhikang Qian, Jianping Ding, Dayan Wang (), Yao Cong () and Bing Sun ()
Additional contact information
Xiaoyu Sun: Chinese Academy of Sciences; University of Chinese Academy of Sciences
Caixuan Liu: Chinese Academy of Sciences
Xiao Lu: Chinese Academy of Sciences; University of Chinese Academy of Sciences
Zhiyang Ling: Chinese Academy of Sciences; University of Chinese Academy of Sciences
Chunyan Yi: Chinese Academy of Sciences; University of Chinese Academy of Sciences
Zhen Zhang: Chinese Academy of Sciences; University of Chinese Academy of Sciences
Zi Li: Chinese Center for Disease Control and Prevention
Mingliang Jin: Chinese Academy of Sciences
Wenshuai Wang: Chinese Academy of Sciences; University of Chinese Academy of Sciences
Shubing Tang: Fudan University
Fangfang Wang: The National Facility for Protein Science in Shanghai (NFPS)
Fang Wang: Chinese Academy of Sciences; University of Chinese Academy of Sciences
Sonam Wangmo: Chinese Academy of Sciences; University of Chinese Academy of Sciences
Shuangfeng Chen: Chinese Academy of Sciences; University of Chinese Academy of Sciences
Li Li: ShanghaiTech University
Liyan Ma: Chinese Academy of Sciences; University of Chinese Academy of Sciences
Yaguang Zhang: Chinese Academy of Sciences; University of Chinese Academy of Sciences
Zhuo Yang: Chinese Academy of Sciences; University of Chinese Academy of Sciences
Xiaoping Dong: Chinese Center for Disease Control and Prevention
Zhikang Qian: University of the Chinese Academy of Sciences
Jianping Ding: Chinese Academy of Sciences; University of Chinese Academy of Sciences
Dayan Wang: Chinese Center for Disease Control and Prevention
Yao Cong: Chinese Academy of Sciences
Bing Sun: Chinese Academy of Sciences; University of Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract Most structurally characterized broadly neutralizing antibodies (bnAbs) against influenza A viruses (IAVs) target the conserved conformational epitopes of hemagglutinin (HA). Here, we report a lineage of naturally occurring human antibodies sharing the same germline gene, VH3-48/VK1-12. These antibodies broadly neutralize the major circulating strains of IAV in vitro and in vivo mainly by binding a contiguous epitope of H3N2 HA, but a conformational epitope of H1N1 HA, respectively. Our structural and functional studies of antibody 28-12 revealed that the continuous amino acids in helix A, particularly N49HA2 of H3 HA, are critical to determine the binding feature with 28-12. In contrast, the conformational epitope feature is dependent on the discontinuous segments involving helix A, the fusion peptide, and several HA1 residues within H1N1 HA. We report that this antibody was initially selected by H3 (group 2) viruses and evolved via somatic hypermutation to enhance the reactivity to H3 and acquire cross-neutralization to H1 (group 1) virus. These findings enrich our understanding of different antigenic determinants of heterosubtypic influenza viruses for the recognition of bnAbs and provide a reference for the design of influenza vaccines and more effective antiviral drugs.

Date: 2022
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DOI: 10.1038/s41467-022-29950-w

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