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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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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T cell immune evasion by SARS-CoV-2 JN.1 escapees targeting two cytotoxic T cell epitope hotspots

Nature Immunology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 28, 2025

Язык: Английский

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Enhanced potency of an IgM-like nanobody targeting conserved epitope in SARS-CoV-2 spike N-terminal domain

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Май 13, 2024

Abstract Almost all the neutralizing antibodies targeting receptor-binding domain (RBD) of spike (S) protein show weakened or lost efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged emerging variants, such as Omicron and its sub-variants. This suggests that highly conserved epitopes are crucial for development antibodies. Here, we present one nanobody, N235, displaying broad neutralization SARS-CoV-2 prototype multiple including newly Cryo-electron microscopy demonstrates N235 binds a novel, conserved, cryptic epitope in N-terminal (NTD) S protein, which interferes with RBD neighboring protein. The mechanism interpreted via flow cytometry Western blot shows appears to induce S1 subunit shedding from trimeric complex. Furthermore, nano-IgM construct (MN235), engineered by fusing human IgM Fc region, displays prevention inducing cross-linking virus particles. Compared MN235 exhibits varied enhancement pseudotyped authentic viruses vitro. intranasal administration low doses can effectively prevent infection sub-variant BA.1 XBB vivo, suggesting it be developed promising prophylactic antibody cope ongoing future infection.

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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Fortifying defenses: Tactical safety protocols for COVID-19 sub-variant JN.1 in healthcare and laboratory settings

Journal of Family Medicine and Primary Care, Год журнала: 2025, Номер 14(1), С. 78 - 84

Опубликована: Янв. 1, 2025

A BSTRACT Introduction: Primary care physicians are crucial in fighting COVID-19, especially with the emergence of new JN.1 sub-variant. Measures to Reduce Risk: Given your direct exposure infected patients, it is imperative establish a protocol for triaging patients respiratory symptoms and uphold minimum distance 2 meters between primary physicians. Patients suspected or diagnosed sub-variant should be advised wear surgical masks their protection others protection. must also use personal protective equipment (PPE) maintain strict hand hygiene practices when dealing these patients. Patient samples treated as high risk contamination, laboratory procedures meticulously evaluated potential hazards. PPE tailored procedure. Conclusion: To protect health well-being physicians, who play critical role addressing challenges, essential strictly adhere infection control measures.

Язык: Английский

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A Hidden Guardian: The Stability and Spectrum of Antibody-Dependent Cell-Mediated Cytotoxicity in COVID-19 Response in Chinese Adults

Vaccines, Год журнала: 2025, Номер 13(3), С. 262 - 262

Опубликована: Фев. 28, 2025

Objectives: Identifying immune-protective biomarkers is crucial for the effective management and mitigation of current future COVID-19 outbreaks, particularly in preventing or counteracting immune evasion exhibited by Omicron variants. The emergence SARS-CoV-2 variants, especially those within lineage, has highlighted their capacity to evade neutralizing antibodies, emphasizing need understand role antibody-dependent cell-mediated cytotoxicity (ADCC) combating these infections. Methods: This study, conducted Qichun City, Hubei province, from December 2021 March 2023, involved 50 healthy Chinese adults who had received two doses inactivated vaccines subsequently experienced mild infections with BA.5 variant. Blood samples were collected at six distinct time points: baseline 1st, 3rd, 6th, 9th months following third dose vaccine, as well 3 post-breakthrough infection. Their sera analyzed assess ADCC neutralization effects. Results: results indicated that antibodies elicited vaccine targeted spike protein, exhibiting both pre-existing activities against variants XBB.1.5. Notably, activity demonstrated greater stability compared effects, persisting least 15 post-vaccination, could be augmented additional breakthrough effect associated hybrid immunity effectively targets a spectrum prospective including BA.2.86, CH.1.1, EG.5.1, JN.1. Conclusions: In light its broad-spectrum efficacy, we recommend use biomarker assessing protective guiding development monoclonal antibodies.

Язык: Английский

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SARS-CoV-2 serotyping based on spike antigenicity and its implications for host immune evasion

EBioMedicine, Год журнала: 2025, Номер 114, С. 105634 - 105634

Опубликована: Март 12, 2025

Язык: Английский

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Beyond the Pandemic Era: Recent Advances and Efficacy of SARS-CoV-2 Vaccines Against Emerging Variants of Concern

Vaccines, Год журнала: 2025, Номер 13(4), С. 424 - 424

Опубликована: Апрель 17, 2025

Vaccination has been instrumental in curbing the transmission of SARS-CoV-2 and mitigating severity clinical manifestations associated with COVID-19. Numerous COVID-19 vaccines have developed to this effect, including BioNTech-Pfizer Moderna’s mRNA vaccines, as well adenovirus vector-based such Oxford–AstraZeneca. However, emergence new variants subvariants SARS-CoV-2, characterized by enhanced transmissibility immune evasion, poses significant challenges efficacy current vaccination strategies. In review, we aim comprehensively outline landscape emerging concern (VOCs) sub-lineages that recently surfaced post-pandemic years. We assess effectiveness existing their booster doses, against these subvariants, BA.2-derived sub-lineages, XBB BA.2.86 (Pirola). Furthermore, discuss latest advancements vaccine technology, multivalent pan-coronavirus approaches, along development several next-generation coronavirus exosome-based, virus-like particle (VLP), mucosal, nanomaterial-based vaccines. Finally, highlight key critical areas for future research address evolving threat develop strategies combating viral threats, thereby improving preparedness pandemics.

Язык: Английский

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Protective RBD-dimer vaccines against SARS-CoV-2 and its variants produced in glycoengineered Pichia pastoris

PLoS Pathogens, Год журнала: 2024, Номер 20(8), С. e1012487 - e1012487

Опубликована: Авг. 30, 2024

Protective vaccines are crucial for preventing and controlling coronavirus disease 2019 (COVID-19). Updated needed to confront the continuously evolving circulating severe acute respiratory syndrome 2 (SARS-CoV-2) variants. These should be safe, effective, amenable easily scalable production, affordable. Previously, we developed receptor binding domain (RBD) dimer-based protein subunit (ZF2001 updated vaccines) in mammalian cells. In this study, explored a strategy producing RBD-dimer immunogens Pichia pastoris. We found that wild-type P. pastoris produced hyperglycosylated containing four N-glycosylation sites Therefore, engineered wild type (GS strain) into GSΔOCH1pAO by deleting OCH1 gene (encoding α-1,6-mannosyltransferase enzyme) decrease glycosylation, as well overexpressing HIS4 histidine dehydrogenase) increase synthesis better growth. addition, was truncated remove R328/F329 cleavage Several homogeneous proteins were strain, demonstrating feasibility of using expression system. further resolved cryo-EM structure prototype-Beta complexed with neutralizing antibody CB6 reveal completely exposed immune epitopes RBDs. murine model, demonstrated yeast-produced induces robust protective responses, which is suitable boosting immunization. This study yeast system SARS-CoV-2 immunogens, providing promising platform pipeline future continuous updating production vaccines.

Язык: Английский

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