Antibodies utilizing VL6-57 light chains target a convergent cryptic epitope on SARS-CoV-2 spike protein and potentially drive the genesis of Omicron variants

Qihong Yan, Xijie Gao, Banghui Liu, Ruitian Hou, Ping He, Yong Ma, Yudi Zhang, Yanjun Zhang, Zimu Li, Qiuluan Chen, Jingjing Wang, Xiaohan Huang, Huan Liang, Huiran Zheng, Yichen Yao, Xianying Chen, Xuefeng Niu, Jun He (), Ling Chen (), Jincun Zhao () and Xiaoli Xiong ()
Additional contact information
Qihong Yan: the First Affiliated Hospital of Guangzhou Medical University
Xijie Gao: The Fifth Affiliated Hospital of Guangzhou Medical University
Banghui Liu: Chinese Academy of Sciences
Ruitian Hou: Guangzhou Medical University
Ping He: Guangzhou National Laboratory
Yong Ma: Chinese Academy of Sciences
Yudi Zhang: Chinese Academy of Sciences
Yanjun Zhang: the First Affiliated Hospital of Guangzhou Medical University
Zimu Li: Chinese Academy of Sciences
Qiuluan Chen: Bioland Laboratory (Guangzhou Regenerative Medicine and Health - Guangdong Laboratory)
Jingjing Wang: Chinese Academy of Sciences
Xiaohan Huang: the First Affiliated Hospital of Guangzhou Medical University
Huan Liang: the First Affiliated Hospital of Guangzhou Medical University
Huiran Zheng: the First Affiliated Hospital of Guangzhou Medical University
Yichen Yao: ShanghaiTech University
Xianying Chen: the First Affiliated Hospital of Guangzhou Medical University
Xuefeng Niu: the First Affiliated Hospital of Guangzhou Medical University
Jun He: Chinese Academy of Sciences
Ling Chen: the First Affiliated Hospital of Guangzhou Medical University
Jincun Zhao: the First Affiliated Hospital of Guangzhou Medical University
Xiaoli Xiong: Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Continued evolution of SARS-CoV-2 generates variants to challenge antibody immunity established by infection and vaccination. A connection between population immunity and genesis of virus variants has long been suggested but its molecular basis remains poorly understood. Here, we identify a class of SARS-CoV-2 neutralizing public antibodies defined by their shared usage of VL6-57 light chains. Although heavy chains of diverse genotypes are utilized, convergent HCDR3 rearrangements have been observed among these public antibodies to cooperate with germline VL6-57 LCDRs to target a convergent epitope defined by RBD residues S371-S373-S375. Antibody repertoire analysis identifies that this class of VL6-57 antibodies is present in SARS-CoV-2-naive individuals and is clonally expanded in most COVID-19 patients. We confirm that Omicron-specific substitutions at S371, S373 and S375 mediate escape of antibodies of the VL6-57 class. These findings support that this class of public antibodies constitutes a potential immune pressure promoting the introduction of S371L/F-S373P-S375F in Omicron variants. The results provide further molecular evidence to support that antigenic evolution of SARS-CoV-2 is driven by antibody mediated population immunity.

Date: 2024
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DOI: 10.1038/s41467-024-51770-3

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