Lineage-specific pathogenicity, immune evasion, and virological features of SARS-CoV-2 BA.2.86/JN.1 and EG.5.1/HK.3

Yuanchen Liu, Xiaoyu Zhao, Jialu Shi, Yajie Wang, Huan Liu, Ye-Fan Hu, Bingjie Hu, Huiping Shuai, Terrence Tsz-Tai Yuen, Yue Chai, Feifei Liu, Hua-Rui Gong, Jiayan Li, Xun Wang, Shujun Jiang, Xiang Zhang, Yanliang Zhang, Xiangnan Li, Lei Wang, Madeline Hartnoll, Tianrenzheng Zhu, Yuxin Hou, Xiner Huang, Chaemin Yoon, Yang Wang, Yixin He, Minmin Zhou, Lianzhao Du, Xiaojuan Zhang, Wan-Mui Chan, Lin-Lei Chen, Jian-Piao Cai, Shuofeng Yuan, Jie Zhou, Jian-Dong Huang, Kwok-Yung Yuen, Kelvin Kai-Wang To, Jasper Fuk-Woo Chan (), Bao-Zhong Zhang (), Lei Sun (), Pengfei Wang () and Hin Chu ()
Additional contact information
Yuanchen Liu: The University of Hong Kong, Pokfulam
Xiaoyu Zhao: Fudan University
Jialu Shi: The University of Hong Kong, Pokfulam
Yajie Wang: Fudan University
Huan Liu: The University of Hong Kong, Pokfulam
Ye-Fan Hu: Pak Shek Kok
Bingjie Hu: The University of Hong Kong, Pokfulam
Huiping Shuai: The University of Hong Kong, Pokfulam
Terrence Tsz-Tai Yuen: The University of Hong Kong, Pokfulam
Yue Chai: The University of Hong Kong, Pokfulam
Feifei Liu: The University of Hong Kong, Pokfulam
Hua-Rui Gong: Chinese Academy of Sciences
Jiayan Li: Fudan University
Xun Wang: Fudan University
Shujun Jiang: Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine
Xiang Zhang: Fudan University
Yanliang Zhang: Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine
Xiangnan Li: Fudan University
Lei Wang: The University of Hong Kong, Pokfulam
Madeline Hartnoll: The University of Hong Kong, Pokfulam
Tianrenzheng Zhu: The University of Hong Kong, Pokfulam
Yuxin Hou: The University of Hong Kong, Pokfulam
Xiner Huang: The University of Hong Kong, Pokfulam
Chaemin Yoon: The University of Hong Kong, Pokfulam
Yang Wang: The University of Hong Kong, Pokfulam
Yixin He: The University of Hong Kong, Pokfulam
Minmin Zhou: The University of Hong Kong, Pokfulam
Lianzhao Du: The University of Hong Kong, Pokfulam
Xiaojuan Zhang: The University of Hong Kong, Pokfulam
Wan-Mui Chan: The University of Hong Kong, Pokfulam
Lin-Lei Chen: The University of Hong Kong, Pokfulam
Jian-Piao Cai: The University of Hong Kong, Pokfulam
Shuofeng Yuan: The University of Hong Kong, Pokfulam
Jie Zhou: The University of Hong Kong, Pokfulam
Jian-Dong Huang: The University of Hong Kong, Pokfulam
Kwok-Yung Yuen: The University of Hong Kong, Pokfulam
Kelvin Kai-Wang To: The University of Hong Kong, Pokfulam
Jasper Fuk-Woo Chan: The University of Hong Kong, Pokfulam
Bao-Zhong Zhang: Chinese Academy of Sciences
Lei Sun: Fudan University
Pengfei Wang: Fudan University
Hin Chu: The University of Hong Kong, Pokfulam

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

Abstract: Abstract SARS-CoV-2 JN.1 with an additional L455S mutation on spike when compared with its parental variant BA.2.86 has outcompeted all earlier variants to become the dominant circulating variant. Recent studies investigated the immune resistance of SARS-CoV-2 JN.1 but additional factors are speculated to contribute to its global dominance, which remain elusive until today. Here, we find that SARS-CoV-2 JN.1 has a higher infectivity than BA.2.86 in differentiated primary human nasal epithelial cells (hNECs). Mechanistically, we demonstrate that the gained infectivity of SARS-CoV-2 JN.1 over BA.2.86 associates with increased entry efficiency conferred by L455S and better spike cleavage in hNECs. Structurally, S455 altered the mode of binding of JN.1 spike protein to ACE2 when compared to BA.2.86 spike at ACE2H34, and modified the internal structure of JN.1 spike protein by increasing the number of hydrogen bonds with neighboring residues. These findings indicate that a single mutation (L455S) enhances virus entry in hNECs and increases immune evasiveness, which contribute to the robust transmissibility of SARS-CoV-2 JN.1. We further evaluate the in vitro and in vivo virological characteristics between SARS-CoV-2 BA.2.86/JN.1 and EG.5.1/HK.3, and identify key lineage-specific features of the two Omicron sublineages that contribute to our understanding on Omicron antigenicity, transmissibility, and pathogenicity.

Date: 2024
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DOI: 10.1038/s41467-024-53033-7

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