Evolving antibody response to SARS-CoV-2 antigenic shift from XBB to JN.1

Fanchong Jian, Jing Wang, Ayijiang Yisimayi, Weiliang Song, Yanli Xu, Xiaosu Chen, Xiao Niu, Sijie Yang, Yuanling Yu, Peng Wang, Haiyan Sun, Lingling Yu, Jing Wang, Yao Wang, Ran An, Wenjing Wang, Miaomiao Ma, Tianhe Xiao, Qingqing Gu, Fei Shao, Youchun Wang, Zhongyang Shen, Ronghua Jin and Yunlong Cao ()
Additional contact information
Fanchong Jian: Peking University
Jing Wang: Peking University
Ayijiang Yisimayi: Peking University
Weiliang Song: Peking University
Yanli Xu: Capital Medical University
Xiaosu Chen: Nankai University
Xiao Niu: Peking University
Sijie Yang: Peking University
Yuanling Yu: Changping Laboratory
Peng Wang: Changping Laboratory
Haiyan Sun: Changping Laboratory
Lingling Yu: Changping Laboratory
Jing Wang: Changping Laboratory
Yao Wang: Changping Laboratory
Ran An: Changping Laboratory
Wenjing Wang: Changping Laboratory
Miaomiao Ma: Changping Laboratory
Tianhe Xiao: Peking University
Qingqing Gu: Changping Laboratory
Fei Shao: Changping Laboratory
Youchun Wang: Changping Laboratory
Zhongyang Shen: Nankai University
Ronghua Jin: Capital Medical University
Yunlong Cao: Peking University

Nature, 2025, vol. 637, issue 8047, 921-929

Abstract: Abstract The continuous evolution of SARS-CoV-2, particularly the emergence of the BA.2.86/JN.1 lineage replacing XBB, necessitates re-evaluation of vaccine compositions1–3. Here, we provide a comprehensive analysis of the humoral immune response to XBB and JN.1 human exposure. We demonstrate the antigenic distinctiveness of XBB and JN.1 lineages in SARS-CoV-2-naive individuals and show that infection with JN.1 elicits superior plasma neutralization against its subvariants. We highlight the strong immune evasion and receptor-binding capability of KP.3, supporting its foreseeable prevalence. Extensive analysis of the B cell receptor repertoire, in which we isolate approximately 2,000 receptor-binding-domain-specific antibodies, with targeting epitopes characterized by deep mutational scanning, underscores the superiority of JN.1-elicited memory B cells4,5. Class 1 IGHV3-53/3-66-derived neutralizing antibodies (NAbs) are important contributors to the wild-type reactivity of NAbs against JN.1. However, KP.2 and KP.3 evade a substantial subset of these antibodies, even those induced by JN.1, supporting a need for booster updates. JN.1-induced Omicron-specific antibodies also demonstrate high potency across Omicron. Escape hotspots for these NAbs have already been mutated, resulting in a higher immune barrier to escape and indicating probable recovery of escaped NAbs. In addition, the prevalence of IGHV3-53/3-66-derived antibodies and their ability to compete with all Omicron-specific NAbs suggests that they have an inhibitory effect on the activation of Omicron-specific naive B cells, potentially explaining the heavy immune imprinting in mRNA-vaccinated individuals6–8. These findings delineate the evolving antibody response to the antigenic shift of Omicron from XBB to JN.1 and highlight the importance of developing the JN.1 lineage, especially KP.2- and KP.3-based vaccine boosters.

Date: 2025
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DOI: 10.1038/s41586-024-08315-x

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