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The emergence of novel severe acute respiratory syndrome coronavirus 2 variants continues to pose challenges for global public health, particularly in the context of immune evasion and viral stability. This study identifies a key N-terminal domain (NTD) mutation, DelS31, in JN.1-derived subvariants that enhances neutralizing antibody escape while reducing infectivity and cell-cell fusion. The DelS31 mutation stabilizes the spike protein conformation, limits S1 shedding, and increases thermal resistance, which possibly contribute to prolonged viral persistence. Structural analyses reveal that DelS31 enhances NTD-receptor-binding domain interactions by introducing glycan shielding, thus decreasing antibody and ACE2 accessibility. These findings emphasize the critical role of NTD mutations in shaping viral evolution and immune evasion, underscoring the urgent need for updated coronavirus disease 2019 vaccines that account for these adaptive changes.

The updated JN.1 monovalent vaccine (MoV) for the 2024–2025 season elicits strong cross-neutralizing activity against subsequently circulating SARS-CoV-2 variants in 2025, including the recently emerging NB.1.8.1, with titer increases comparable to those against the vaccine strain JN.1. The immune response induced by the JN.1 MoV was markedly stronger than that induced by XBB.1.5 MoV in the previous season, both against the vaccine strain and post-vaccine variant (all P < 0.001). These results likely reflect improved background immunity to circulating variants and support the use of catch-up booster vaccination during the summer surge, particularly for high-risk groups.

SARS-CoV-2 undergoes continuous mutations during transmission, resulting in a variety of Omicron subvariants. Currently, SARS-CoV-2 BA.2.86 and its descendants JN.1, KP.2, KP.1.1 have been identified as the primary variants spreading globally. These emerging Omicron variants have increased transmissibility, potentially elevating the risk of viral reinfection in the population. However, the biological characteristics of newly-emerged Omicron subvariants in infecting host cells remain unclear. In this study, we assessed the neutralization effect of BA.2.86 and its descendant JN.1, as well as D614G, BA.2, BA.4/5, XBB.1.5, EG.5.1, HV.1, HK.3, JD.1.1 and JG.3 on convalescent sera obtained from individuals infected with BA.5 or XBB.1.5 strain. We evaluated the biological characteristics of variants spike proteins by measuring viral infectivity, affinity for receptors, and membrane fusion. Compared to XBB-related subvariants, BA.2.86 exhibited a diminished immune escape response, but JN.1 displayed a markedly augmented immune escape capability, which was closely related to its rapid transmission. BA.2.86 was less infectious in susceptible cells, while the JN.1 variant exhibited relatively high infectivity. Notably, BA.2.86 and JN.1 exhibited low fusion activity in 293 T-ACE2 cells, but relatively high fusogenicity in transmembrane protease serine 2 (TMPRSS2) overexpression cells. This study explored the evolutionary characteristics of emerging Omicron subvariants in host adaptation, and provided new strategies for the prevention and treatment of coronavirus disease 2019 (COVID-19).

Most of vaccinees and COVID-19 convalescents can build effective anti-SARS-CoV-2 humoral immunity, which helps preventing infection and alleviating symptoms. However, breakthrough viral infections caused by emerging SARS-CoV-2 variants, especially Omicron subvariants, still pose a serious threat to global health. By monitoring the viral infections and the sera neutralization ability of a long-tracked cohort, we found out that the immune evasion of emerging Omicron subvariants and the decreasing neutralization led to the mini-wave of SARS-CoV-2 breakthrough infections. Meanwhile, no significant difference had been found in the infectivity of tested SARS-CoV-2 variants, even though the affinity between human angiotensin-converting enzyme 2 (hACE2) and receptor-binding domain (RBDs) of tested variants showed an increasing trend. Notably, the immune imprinting of inactivated COVID-19 vaccine can be relieved by infections of BA.5.2 and XBB.1.5 variants sequentially. Our data reveal the rising reinfection risk of immune evasion variants like Omicron JN.1 in China, suggesting the importance of booster with updated vaccines.