Recombinant XBB.1.5 boosters induce robust neutralization against KP.2- and KP.3-included JN.1 sublineages

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Янв. 27, 2025

Abstract The newly emerged variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) demonstrate resistance to present therapeutic antibodies as well the capability evade vaccination-elicited antibodies. JN.1 sublineages were demonstrated one most immune-evasive variants, showing higher neutralization compared XBB.1.5. In this study, serum samples collected from adult participants including those who had gone through BA.5/BF.7, EG.5/HK.3 and XBB/JN.1 infection waves, characterized by different vaccination histories. We evaluated in these against pseudoviruses Omicron lineages. further investigated humoral immune response recombinant XBB vaccines estimated sublineages, KP.2 KP.3. Our results showed that sera previous circulating subvariant breakthrough infections exhibited low GMTs 50% all tested significantly elevated individuals received WSK-V102C or WSK-V102D boosters. Importantly, 4 months after a booster XBB.1.5, JN.1, JN.1.13, KP.3 3479, 1684, 1397, 1247 1298, with 9.86-, 9.79-, 8.73-, 8.66- 8.16-fold increase without booster, respectively, indicating boosting XBB.1.5 subunit still induced strong antibody responses sublineages. However, KP.3, revealed more than 2-fold decreases neutralizing titers suggesting enhanced evasion necessity boosters based on

Язык: Английский

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Neutralization and Stability of JN.1-derived LB.1, KP.2.3, KP.3 and KP.3.1.1 Subvariants

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 5, 2024

SUMMARY During the summer of 2024, COVID-19 cases surged globally, driven by variants derived from JN.1 subvariants SARS-CoV-2 that feature new mutations, particularly in N-terminal domain (NTD) spike protein. In this study, we report on neutralizing antibody (nAb) escape, infectivity, fusion, and stability these subvariants—LB.1, KP.2.3, KP.3, KP.3.1.1. Our findings demonstrate all are highly evasive nAbs elicited bivalent mRNA vaccine, XBB.1.5 monovalent mumps virus-based or infections during BA.2.86/JN.1 wave. This reduction nAb titers is primarily a single serine deletion (DelS31) NTD spike, leading to distinct antigenic profile compared parental other variants. We also found DelS31 mutation decreases pseudovirus infectivity CaLu-3 cells, which correlates with impaired cell-cell fusion. Additionally, protein appears more conformationally stable, as indicated reduced S1 shedding both without stimulation soluble ACE2, increased resistance elevated temperatures. Molecular modeling suggests induces conformational change stabilizes strengthens NTD-Receptor-Binding Domain (RBD) interaction, thus favoring down conformation RBD reducing accessibility ACE2 receptor certain nAbs. introduces an N-linked glycan modification at N30, shields underlying region recognition. data highlight critical role mutations for evasion, stability, viral suggest consideration updating vaccines antigens containing DelS31.

Язык: Английский

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AlphaFold2 Modeling and Molecular Dynamics Simulations of the Conformational Ensembles for the SARS-CoV-2 Spike Omicron JN.1, KP.2 and KP.3 Variants: Mutational Profiling of Binding Energetics Reveals Epistatic Drivers of the ACE2 Affinity and Escape Hotspots of Antibody Resistance

Viruses, Год журнала: 2024, Номер 16(9), С. 1458 - 1458

Опубликована: Сен. 13, 2024

The most recent wave of SARS-CoV-2 Omicron variants descending from BA.2 and BA.2.86 exhibited improved viral growth fitness due to convergent evolution functional hotspots. These hotspots operate in tandem optimize both receptor binding for effective infection immune evasion efficiency, thereby maintaining overall fitness. lack molecular details on structure, dynamics energetics the latest FLiRT FLuQE with ACE2 antibodies provides a considerable challenge that is explored this study. We combined AlphaFold2-based atomistic predictions structures conformational ensembles spike complexes host dominant JN.1, KP.1, KP.2 KP.3 examine mechanisms underlying role balancing antibody evasion. Using ensemble-based mutational scanning protein residues computations affinities, we identified energy characterized basis epistatic couplings between results suggested existence interactions sites at L455, F456, Q493 positions protect restore ACE2-binding affinity while conferring beneficial escape. To escape mechanisms, performed structure-based profiling several classes displayed impaired neutralization against BA.2.86, KP.3. confirmed experimental data harboring L455S F456L mutations can significantly impair neutralizing activity class 1 monoclonal antibodies, effects mediated by facilitate subsequent convergence Q493E changes rescue binding. Structural energetic analysis provided rationale showing BD55-5840 BD55-5514 bind different epitopes retain efficacy all examined support notion may favor emergence lineages combinations involving mediators control balance high

Язык: Английский

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The rising SARS‐CoV‐2 JN.1 variant: evolution, infectivity, immune escape, and response strategies

MedComm, Год журнала: 2024, Номер 5(8)

Опубликована: Июль 29, 2024

The JN.1 variant of COVID-19 has emerged as the dominant strain worldwide since end 2023. As a subclade BA.2.86 variant, harbors unique combination mutations inherited from lineage, notably featuring novel L455S mutation within its receptor-binding motif. This been linked to increased transmissibility and enhanced immune evasion capabilities. During rise JN.1, evidence resistance various monoclonal antibodies reduced cross-neutralization effects XBB.1.5 vaccine have observed. Although public health threat posed by appears relatively low, concerns persist regarding evolutionary trajectory under pressure. review provides comprehensive overview evolving highlighting need for continuous monitoring investigation new variants that could lead widespread infection. It assesses efficacy current vaccines therapeutics against emerging variants, particularly focusing on immunocompromised populations. Additionally, this summarizes potential advancements clinical treatments COVID-19, offering insights optimize prevention treatment strategies. thoroughly evaluates variant's impact implications future therapeutic development, contributing ongoing efforts mitigate risk virus transmission disease severity.

Язык: Английский

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Nonhuman primate antigenic cartography of SARS-CoV-2

Cell Reports, Год журнала: 2025, Номер 44(1), С. 115140 - 115140

Опубликована: Янв. 1, 2025

Язык: Английский

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Neutralization and spike stability of JN.1-derived LB.1, KP.2.3, KP.3, and KP.3.1.1 subvariants

mBio, Год журнала: 2025, Номер unknown

Опубликована: Март 26, 2025

ABSTRACT During the summer of 2024, coronavirus disease 2019 (COVID-19) cases surged globally, driven by variants derived from JN.1 subvariants severe acute respiratory syndrome 2 that feature new mutations, particularly in N-terminal domain (NTD) spike protein. In this study, we report on neutralizing antibody (nAb) escape, infectivity, fusion, and stability these subvariants—LB.1, KP.2.3, KP.3, KP.3.1.1. Our findings demonstrate all are highly evasive nAbs elicited bivalent mRNA vaccine, XBB.1.5 monovalent mumps virus-based or infections during BA.2.86/JN.1 wave. This reduction nAb titers is primarily a single serine deletion (DelS31) NTD spike, leading to distinct antigenic profile compared parental other variants. We also found DelS31 mutation decreases pseudovirus infectivity CaLu-3 cells, which correlates with impaired cell-cell fusion. Additionally, protein appears more conformationally stable, as indicated reduced S1 shedding both without stimulation soluble ACE2 increased resistance elevated temperatures. Molecular modeling suggests enhances NTD-receptor-binding (RBD) interaction, favoring RBD down conformation reducing accessibility specific nAbs. Moreover, introduces an N-linked glycan at N30, shielding recognition. These underscore role mutations immune evasion, stability, viral highlighting need consider DelS31-containing antigens updated COVID-19 vaccines. IMPORTANCE The emergence novel continues pose challenges for global public health, context evasion stability. study identifies key mutation, DelS31, JN.1-derived escape while stabilizes conformation, limits shedding, increases thermal resistance, possibly contribute prolonged persistence. Structural analyses reveal interactions introducing shielding, thus decreasing accessibility. emphasize critical shaping evolution underscoring urgent vaccines account adaptive changes.

Язык: Английский

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Immune Evasion, Cell-Cell Fusion, and Spike Stability of the SARS-CoV-2 XEC Variant: Role of Glycosylation Mutations at the N-terminal Domain

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 13, 2024

SARS-CoV-2 continues to evolve, producing new variants that drive global COVID-19 surges. XEC, a recombinant of KS.1.1 and KP.3.3, contains T22N F59S mutations in the spike protein's N-terminal domain (NTD). The mutation, similar DelS31 mutation KP.3.1.1, introduces potential N-linked glycosylation site XEC. In this study, we examined neutralizing antibody (nAb) response effects sera from bivalent-vaccinated healthcare workers, BA.2.86/JN.1 wave-infected patients, XBB.1.5 monovalent-vaccinated hamsters, assessing responses XEC alongside D614G, JN.1, KP.3, KP.3.1.1. demonstrated significantly reduced neutralization titers across all cohorts, largely due mutation. Notably, removal sites KP.3.1.1 substantially restored nAb titers. Antigenic cartography analysis revealed be more antigenically distinct its common ancestral compared with as determining factor. Similar showed cell-cell fusion relative parental change attributed glycosylation. We also observed S1 shedding for which was reversed by ablation mutations, respectively. Molecular modeling suggests alters hydrophobic interactions adjacent protein residues, impacting both conformational stability neutralization. Overall, our findings underscore pivotal role NTD shaping biology immune escape mechanisms.

Язык: Английский

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Neutralization of SARS-CoV-2 KP.1, KP.1.1, KP.2 and KP.3 by human and murine sera

npj Vaccines, Год журнала: 2024, Номер 9(1)

Опубликована: Ноя. 11, 2024

We report SARS-CoV-2 KP.1, KP.1.1, KP.2 and KP.3 neutralizing antibody titers. They displayed increased immune evasion compared to JN.1, especially KP.1 KP.3, for participants who experienced BF.7/BA.5.2 breakthrough infection or received bivalent (delta/BA.5) vaccine boosting. Second XBB sub-variants enhanced the neutralization responses. HK.3-JN.1 RBD-heterodimer induced balanced potent responses against recently-circulating in mice, supporting replace COVID-19 antigen containing JN.1 its sub-variants.

Язык: Английский

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Evolution of Omicron lineage towards increased fitness in the upper respiratory tract in the absence of severe lung pathology

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 11, 2025

Abstract The emergence of the Omicron lineage represented a major genetic drift in SARS-CoV-2 evolution. This was associated with phenotypic changes including evasion pre-existing immunity and decreased disease severity. Continuous evolution within raised concerns potential increased transmissibility and/or To address this, we evaluate fitness pathogenesis contemporary variants XBB.1.5, XBB.1.16, EG.5.1, JN.1 upper (URT) lower respiratory tract (LRT). We compare vivo infection Syrian hamsters primary human nasal lung epithelium cells assess differences transmissibility, antigenicity, innate immune activation. replicate efficiently URT but display limited pathology lungs compared to previous fail organoids. is attenuated both LRT other fails transmit male hamster model. Our data demonstrate that has favored URT.

Язык: Английский

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4D-DIA Proteomics Uncovers New Insights into Host Salivary Response Following SARS-CoV-2 Omicron Infection

Journal of Proteome Research, Год журнала: 2025, Номер 24(2), С. 499 - 514

Опубликована: Янв. 13, 2025

Since late 2021, Omicron variants have dominated the epidemiological scenario as most successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sublineages, driving new and breakthrough infections globally over past two years. In this study, we investigated for first time host salivary response of COVID-19 patients infected with (BA.1, BA.2, BA.4/5) by using an untargeted four-dimensional data-independent acquisition (4D-DIA)-based proteomics approach. We identified 137 proteins whose abundance levels differed between positive negative groups. Salivary signatures were mainly enriched in ribosomal proteins, linked to mRNAviral translation, protein synthesis processing, immune innate, antiapoptotic signaling. The higher 14-3-3 (YWHAG, YWHAQ, YWHAE, SFN) saliva, reported here, may be associated increased infectivity improved viral replicative fitness. also seven (ACTN1, H2AC2, GSN, NDKA, CD109, GGH, PCYOX) that yielded comprehension into infection performed outstandingly screening a hospital setting. This panel presented enhanced anti-COVID-19 anti-inflammatory signature, providing insights disease severity, supported comparisons other proteome data sets. signature provided valuable host's SARS-CoV-2 infection, shedding light on pathophysiology COVID-19, particularly cases mild disease. It underscores potential clinical applications saliva settings. Data are available via ProteomeXchange identifier PXD054133.

Язык: Английский

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