Immune evasion, infectivity, and membrane fusion of SARS-CoV-2 variants LP.8.1.1, XEC.25.1, XFG, and NB.1.8.1

Emerging SARS-CoV-2 variants, with potentially enhanced immune evasion and transmissibility, pose a serious challenge to public health. This study provides a systematic characterization of the virological features of JN.1 descendant subvariants, including LP.8.1.1, KP.3, XEC.25.1, XFG, and NB.1.8.1, focusing on their infectivity, receptor binding, membrane fusion, and immune evasion capacity. Multiple JN.1 descendant variants exhibited reduced infectivity across various human cell lines, whereas XEC.25.1 and NB.1.8.1 demonstrated significantly enhanced cellular infectivity. JN.1 descendant variants retained the capability to infect cells expressing ACE2 orthologs from diverse mammalian species, indicating their persistent risk of zoonotic transmission. Notably, NB.1.8.1 exhibited the highest ACE2-binding affinity among all tested variants, while XEC.25.1 shows superior membrane fusion activity, particularly in cells expressing TMPRSS2. Serum neutralization assays revealed that LP.8.1.1, KP.3, XEC.25.1, XFG, and NB.1.8.1 exhibited enhanced immune evasion capabilities compared to the JN.1 strain, which was closely associated with their rapid transmission. These findings reveal that emerging JN.1 subvariants accelerate viral transmission by altering receptor-binding affinity, optimizing cellular entry efficiency, and enhancing immune evasion. Therefore, it is necessary to update vaccines and improve antiviral treatment strategies to meet the public health challenges posed by these variants.

IMPORTANCE

SARS-CoV-2 JN.1 has continuously evolved during the epidemic, giving rise to multiple descendant variants. Currently, JN.1 sublineages NB.1.8.1, XFG, XEC.25.1, and LP.8.1.1 have emerged as the predominant circulating variants globally. The cellular infectivity, cross-species transmission potential, and immune evasion capacity of these emerging variants remain poorly characterized. This study employed a VSV pseudovirus system to characterize the virological features of JN.1 descendant subvariants. We found that the cellular infectivity of JN.1 descendant variants was significantly altered, which may be attributed to changes in receptor-binding affinity or membrane fusion activity. The emerging JN.1 subvariants retained the ability to infect cells expressing ACE2 orthologs from diverse species. Furthermore, the emerging variants LP.8.1.1, KP.3, XEC.25.1, XFG, and NB.1.8.1 exhibited enhanced immune evasion capabilities compared to the JN.1 strain. Our study underscores the importance of surveillance and virological research for emerging JN.1 descendant variants.