Neutralization escape, infectivity, and membrane fusion of JN.1-derived SARS-CoV-2 SLip, FLiRT, and KP.2 variants

Cell Reports, Год журнала: 2024, Номер 43(8), С. 114520 - 114520

Опубликована: Июль 17, 2024

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

Язык: Английский

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Evolving antibody response to SARS-CoV-2 antigenic shift from XBB to JN.1

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

Опубликована: Апрель 22, 2024

Abstract The continuous evolution of SARS-CoV-2, particularly the emergence BA.2.86/JN.1 lineage replacing XBB lineages, necessitates re-evaluation current vaccine compositions. Here, we provide a comprehensive analysis humoral immune response to and JN.1 human exposures, emphasizing need for JN.1-lineage-based boosters. We demonstrate antigenic distinctiveness lineages in SARS-CoV-2-naive individuals but not those with prior vaccinations or infections, infection elicits superior plasma neutralization titers against its subvariants. highlight strong evasion receptor binding capability KP.3, supporting foreseeable prevalence. Extensive BCR repertoire, isolating ∼2000 RBD-specific monoclonal antibodies (mAbs) their targeting epitopes characterized by deep mutational scanning (DMS), underscores systematic superiority JN.1-elicited memory B cells (MBCs). Notably, Class 1 IGHV3-53/3-66-derived neutralizing (NAbs) contribute majorly within wildtype (WT)-reactive NAbs JN.1. However, KP.2 KP.3 evade substantial subset them, even induced JN.1, advocating booster updates optimized enrichment. JN.1-induced Omicron-specific also high potency across all Omicron lineages. Escape hotspots these have mainly been mutated RBD, resulting higher barrier escape, considering probable recovery previously escaped NAbs. Additionally, prevalence broadly reactive IGHV3-53/3-66- encoding MBCs, competing suggests inhibitory role on de novo activation naive cells, potentially explaining heavy imprinting mRNA-vaccinated individuals. These findings delineate evolving antibody shift from importance developing lineage, especially KP.3-based boosters, enhance immunity future SARS-CoV-2 variants.

Язык: Английский

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Characteristics of JN.1-derived SARS-CoV-2 subvariants SLip, FLiRT, and KP.2 in neutralization escape, infectivity and membrane fusion

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

Опубликована: Май 21, 2024

SARS-CoV-2 variants derived from the immune evasive JN.1 are on rise worldwide. Here, we investigated JN.1-derived subvariants SLip, FLiRT, and KP.2 for their ability to be neutralized by antibodies in bivalent-vaccinated human sera, XBB.1.5 monovalent-vaccinated hamster sera people infected during BA.2.86/JN.1 wave, class III monoclonal antibody (Mab) S309. We found that compared parental JN.1, SLip KP.2, especially exhibit increased resistance COVID-19 BA.2.86/JN.1-wave convalescent sera. Interestingly, monovalent vaccinated robustly FLiRT but had reduced efficiency SLip. These were resistant neutralization Mab In addition, aspects of spike protein biology including infectivity, cell-cell fusion processing, these subvariants, a decreased infectivity membrane relative correlating with processing. Homology modeling revealed L455S F456L mutations local hydrophobicity hence its binding ACE2. contrast, additional R346T mutation strengthened conformational support receptor-binding motif, thus counteracting effects F456L. three mutations, alongside D339H, which is present all sublineages, alter epitopes targeted therapeutic Mabs, I S309, explaining sensitivity Together, our findings provide insight into newly emerged suggest future vaccine formulations should consider as immunogen, although current could still offer adequate protection.

Язык: Английский

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Sotrovimab: A Review of Its Efficacy against SARS-CoV-2 Variants

Viruses, Год журнала: 2024, Номер 16(2), С. 217 - 217

Опубликована: Янв. 31, 2024

Among the anti-Spike monoclonal antibodies (mAbs), S-309 derivative sotrovimab was most successful in having longest temporal window of clinical use, showing a high degree resiliency to SARS-CoV-2 evolution interrupted only by appearance BA.2.86* variant interest (VOI). This success undoubtedly reflects rational selection target highly conserved epitope coronavirus Spike proteins. We review here efficacy against different variants outpatients and inpatients, discussing both randomized controlled trials real-world evidence. Although it could not be anticipated at time its development introduction, sotrovimab's use immunocompromised individuals who harbor large populations viruses created conditions for eventual demise, as antibody viral led withdrawal due inefficacy later lineages. Despite this, based on observational data, some authorities have continued promote sotrovimab, but lack binding newer strongly argues futility use. The story highlights power modern biomedical science generate novel therapeutics while also providing cautionary tale need devise strategies minimize emergence resistance antibody-based therapeutics.

Язык: Английский

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Rapid spread of the SARS-CoV-2 JN.1 lineage is associated with increased neutralization evasion

iScience, Год журнала: 2024, Номер 27(6), С. 109904 - 109904

Опубликована: Май 3, 2024

In July/August 2023, the highly mutated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) BA.2.86 lineage emerged and its descendant JN.1 is on track to become dominant SARS-CoV-2 globally. Compared spike (S) protein of parental lineage, S contains one mutation, L455S, which may affect receptor binding antibody evasion. Here, we performed a virological assessment employing pseudovirus particles bearing diverse proteins. Using this strategy, it was found that mutation L455S confers increased neutralization resistance but reduces ACE2 capacity protein-driven cell entry efficiency. Altogether, these data suggest benefit evasion outweighs reduced further enabled effectively spread in human population.

Язык: Английский

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Monitoring SARS-CoV-2 variants with complementary surveillance systems: risk evaluation of the Omicron JN.1 variant in France, August 2023 to January 2024

Eurosurveillance, Год журнала: 2025, Номер 30(1)

Опубликована: Янв. 9, 2025

Background Early detection and characterisation of SARS-CoV-2 variants have been continue to be essential for assessing their public health impact. In August 2023, Santé publique France implemented enhanced surveillance BA.2.86 sub-lineage JN.1 because genetic divergence from other increased prevalence. Aim To detail how combining epidemiological laboratory data sources, targeted investigations modelling enabled comprehensive JN.1. Methods Data were collected using a standardised questionnaire routine novel (RELAB network) systems. cases compared with infected previously circulating variants, such as EG.5, BA.4/BA.5 sub-lineages. The growth rate doubling time estimated. Results was first detected in September 2023 the Île-de-France region, France, spread widely across country. By late November, estimated 8.6 26.4 days depending on region. For all by showed similar demographics, rates hospitalisation RT-PCR cycle threshold values those previous variants. also had older median age (54 years; 40–71 vs 47 30–59), more frequent reports feverish feeling less cough or nausea cases. significantly higher frequency anosmia Conclusion Combining different sources played key role detecting emerging variant JN.1, which no evidence impact found despite its divergence.

Язык: Английский

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An update on the anti-spike monoclonal antibody pipeline for SARS-CoV-2

Clinical Microbiology and Infection, Год журнала: 2024, Номер 30(8), С. 999 - 1006

Опубликована: Апрель 24, 2024

Язык: Английский

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Neutralizing antibody response to XBB.1.5, BA.2.86, FL.1.5.1, and JN.1 six months after the BNT162b2 bivalent booster

International Journal of Infectious Diseases, Год журнала: 2024, Номер 143, С. 107028 - 107028

Опубликована: Апрель 5, 2024

IntroductionAn increase evasion of the SARS-CoV-2 virus towards vaccination strategies and natural immunity has been rapidly described notably due to mutations in spike receptor binding domain N-terminal domain.Material methodsParticipants CRO-VAX HCP study who received bivalent booster were followed at 6 months. A pseudovirus‐neutralization test was used assess neutralization potency antibodies against D614G, Delta, BA.1, BA.5, XBB.1.5, BA.2.86, FL.1.5.1, JN-1.ResultsThe neutralizing capacity Omicron variant or subvariants significantly reduced compared D614G Delta (p<0.0001). The lowest response that observed with JN-1 (GMT=22.1) also lower XBB.1.5 (GMT=29.5, p<0.0001), BA.2.86 (GMT=29.6, FL.1.5.1 (GMT=25.2, p<0.0001). Participants contracted a breakthrough infection had higher all variants uninfected participants, especially subvariants.ConclusionOur results confirm JN.1 is one most immune evading date subvariant did not show an increased escape XBB.1.5. stronger BKI supports need use vaccine antigens target circulating variants.

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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Effectiveness of Updated 2023–2024 (Monovalent XBB.1.5) COVID-19 Vaccination Against SARS-CoV-2 Omicron XBB and BA.2.86/JN.1 Lineage Hospitalization and a Comparison of Clinical Severity—IVY Network, 26 Hospitals, October 18, 2023–March 9, 2024

Clinical Infectious Diseases, Год журнала: 2024, Номер unknown

Опубликована: Авг. 6, 2024

Assessing variant-specific COVID-19 vaccine effectiveness (VE) and severity can inform public health risk assessments decisions about composition. BA.2.86 its descendants, including JN.1 (referred to collectively as "JN lineages"), emerged in late 2023 exhibited substantial divergence from co-circulating XBB lineages.

Язык: Английский

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