Enhanced reverse zoonotic potential and immune evasion by omicron JN.1 variant

Jiaxin Hu; Fuwen Zan; Yixin He; Xiuyuan Ou; Xiaolu Tang; Yan Liu; Xing Lu; Pei Li; Zhixia Mu; Siwen Dong; Yahan Chen; Lin Tan; Mengmeng Cao; Pinghuang Liu; Terrence Tsz-Tai Yuen; Jian Lu; Zhaohui Qian

doi:10.1016/j.isci.2025.112824

Enhanced reverse zoonotic potential and immune evasion by omicron JN.1 variant

iScience. 2025 Jun 6;28(7):112824. doi: 10.1016/j.isci.2025.112824. eCollection 2025 Jul 18.

Authors

Jiaxin Hu^{1

2

3}, Fuwen Zan^{1

2}, Yixin He⁴, Xiuyuan Ou^{1

2

3}, Xiaolu Tang⁴, Yan Liu^{1

2}, Xing Lu^{1

2}, Pei Li^{1

2}, Zhixia Mu^{1

2}, Siwen Dong^{1

2}, Yahan Chen^{1

2}, Lin Tan^{1

2}, Mengmeng Cao^{1

2}, Pinghuang Liu⁵, Terrence Tsz-Tai Yuen⁴, Jian Lu⁶, Zhaohui Qian^{1

2

3}

Affiliations

¹ NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
² MOE Key Laboratory of Pathogen Infection Prevention and Control, Peking Union Medical College, Beijing, China.
³ State Key Laboratory of Respiratory Health and Multimorbidity, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
⁴ Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
⁵ Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, China.
⁶ College of Life Sciences, Peking University, Beijing, China.

Abstract

SARS-CoV-2 infects not only humans but also animals, posing reverse zoonotic risks. As SARS-CoV-2 rapidly evolves, JN.1 has become dominant globally. In this study, we determined the susceptibility of XBB.1.16, EG.5.1, BA.2.86, and JN.1 to 27 different animal angiotensin-converting enzyme 2 (ACE2) orthologs using pseudoviruses, and found that JN.1 displayed substantially higher overall reverse zoonotic risk potential compared to other variants except for EG.5.1. Live virus infection experiments further confirmed higher infectivity of JN.1 than BA.2.86. Mechanistic analyses revealed that L455S might be responsible for substantial increase in overall fusogenecity and infectivity by lowering S protein thermostability. Additionally, we also found that L455S mutation enhanced immune evasion of SARS-CoV-2, and XBB breakthrough infection increased levels of neutralization antibodies against JN.1. Together, our findings offer a better mechanistic understanding of CoV entry, host range, evolution, and immunogenicity and highlight the importance of surveillance of susceptible hosts to prevent potential outbreaks.

Keywords: Immunology; Virology.