Neutralization Escape, Infectivity, and Membrane Fusion of JN.1-Derived SARS-CoV-2 SLip, FLiRT, and KP.2 Variants

Authors

Pei Li
Julia N Faraone
Cheng Chih Hsu
Michelle Chamblee
Yi-Min Zheng
Claire Carlin
Joseph S Bednash
Jeffrey C Horowitz
Rama K Mallampalli
Linda J Saif
Eugene M Oltz
Daniel Jones
Jianrong Li
Richard J Gumina
Kai Xu
Shan-Lu Liu

Publication Date

8-27-2024

Journal

Cell Reports

Abstract

We investigate JN.1-derived subvariants SLip, FLiRT, and KP.2 for neutralization by antibodies in vaccinated individuals, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients, or class III monoclonal antibody S309. Compared to JN.1, SLip, KP.2, and especially FLiRT exhibit increased resistance to bivalent-vaccinated and BA.2.86/JN.1-wave convalescent human sera. XBB.1.5 monovalent-vaccinated hamster sera robustly neutralize FLiRT and KP.2 but have reduced efficiency for SLip. All subvariants are resistant to S309 and show decreased infectivity, cell-cell fusion, and spike processing relative to JN.1. Modeling reveals that L455S and F456L in SLip reduce spike binding for ACE2, while R346T in FLiRT and KP.2 strengthens it. These three mutations, alongside D339H, alter key epitopes in spike, likely explaining the reduced sensitivity of these subvariants to neutralization. Our findings highlight the increased neutralization resistance of JN.1 subvariants and suggest that future vaccine formulations should consider the JN.1 spike as an immunogen, although the current XBB.1.5 monovalent vaccine could still offer adequate protection.

Keywords

SARS-CoV-2, Animals, Humans, Antibodies, Neutralizing, COVID-19, Spike Glycoprotein, Coronavirus, Cricetinae, Antibodies, Viral, Membrane Fusion, Antibodies, Monoclonal, Mutation, Chlorocebus aethiops, Angiotensin-Converting Enzyme 2, Epitopes, Vero Cells, Neutralization Tests, COVID-19 Vaccines

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Associated Data

PMID: 39024099