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

---

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

---

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

---

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

---

Lineage-specific pathogenicity, immune evasion, and virological features of SARS-CoV-2 BA.2.86/JN.1 and EG.5.1/HK.3

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Окт. 9, 2024

SARS-CoV-2 JN.1 with an additional L455S mutation on spike when compared its parental variant BA.2.86 has outcompeted all earlier variants to become the dominant circulating variant. Recent studies investigated immune resistance of but factors are speculated contribute global dominance, which remain elusive until today. Here, we find that a higher infectivity than in differentiated primary human nasal epithelial cells (hNECs). Mechanistically, demonstrate gained over associates increased entry efficiency conferred by and better cleavage hNECs. Structurally, S455 altered mode binding protein ACE2 at

Язык: Английский

---

Antigenicity assessment of SARS-CoV-2 saltation variant BA.2.87.1

Emerging Microbes & Infections, Год журнала: 2024, Номер 13(1)

Опубликована: Апрель 15, 2024

The recent emergence of a SARS-CoV-2 saltation variant, BA.2.87.1, which features 65 spike mutations relative to BA.2, has attracted worldwide attention. In this study, we elucidate the antigenic characteristics and immune evasion capability BA.2.87.1. Our findings reveal that BA.2.87.1 is more susceptible XBB-induced humoral immunity compared JN.1. Notably, lacks critical escaping in receptor binding domain (RBD) thus allowing various classes neutralizing antibodies (NAbs) were escaped by XBB or BA.2.86 subvariants neutralize although deletions N-terminal (NTD), specifically 15-23del 136-146del, compensate for resistance immunity. Interestingly, several antibody drugs have been found restore their efficacy against including SA58, REGN-10933 COV2-2196. Hence, our results suggest may not become widespread until it acquires multiple RBD achieve sufficient comparable

Язык: Английский

---

Recurrent SARS-CoV-2 spike mutations confer growth advantages to select JN.1 sublineages

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

Опубликована: Май 29, 2024

Abstract The recently dominant SARS-CoV-2 Omicron JN.1 has evolved into multiple sublineages, with recurrent spike mutations R346T, F456L, and T572I, some of which exhibit growth advantages, such as KP.2. We investigated these in JN.1, examining their individual combined effects on immune evasion, ACE2 receptor affinity, vitro infectivity. F456L increased resistance to neutralization by human sera, including those after breakthrough infections, RBD class-1 monoclonal antibodies, significantly altering antigenicity. R346T enhanced ACE2-binding without a discernible effect serum neutralization. Individually, T572I modestly infectivity each pseudovirus. Importantly, expanding sublineages KP.2 containing V1104L, showed similar suggesting V1104L does not appreciably affect antibody evasion. Our findings illustrate how certain confer advantages the population could inform design next COVID-19 vaccine booster.

Язык: Английский

---

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

---

Potent and broadly neutralizing antibodies against sarbecoviruses elicited by single ancestral SARS-CoV-2 infection

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

Опубликована: Июнь 7, 2024

Abstract Monoclonal antibody (mAb) therapeutics hold promise for both preventing and treating infectious diseases, especially among vulnerable populations. However, the emergence of various variants severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents challenges current mAb treatments, emphasizing need more potent broadly neutralizing antibodies. In this study, we employed an unbiased screening approach to discover antibodies successfully isolated two mAbs from individuals with only exposure ancestral SARS-CoV-2. One these antibodies, CYFN1006-1, exhibited robust cross-neutralization against a spectrum SARS-CoV-2 variants, including latest JN.1 KP.2 consistent IC 50 values ranging ∼1 5 ng/mL. Notably, it also displayed broad neutralization activity SARS-CoV related sarbecoviruses, such as WIV1, SHC014, RaTG13, GD-Pangolin. Structural analysis revealed that target shared hotspot but mutation-resistant epitopes, their Fabs locking RBD in “down” conformation through interactions adjacent RBDs, cross-linking Spike trimers into di-trimers block viral infection. vivo studies conducted JN.1-infected hamster model validated protective efficacy its therapeutic potential. These findings suggest that, meticulous approaches, rare activities sarbecoviruses can be identified exclusively virus exposure.

Язык: Английский

---

JN.1 and the ongoing battle: unpacking the characteristics of a new dominant COVID-19 variant

Pathogens and Global Health, Год журнала: 2024, Номер 118(6), С. 453 - 458

Опубликована: Июнь 17, 2024

In the fourth year of COVID-19 occurrence, a new variant, JN.1, has emerged and spread globally become dominant strain in several regions. It some specific mutations its spike proteins, empowering it with higher transmissibility. Regarding significance issue, understanding clinical immunological traits JN.1 is critical for enhancing health strategies vaccination efforts globally, ultimate goal bolstering our collective response to pandemic. this study, we take look at latest findings characteristics as well consequences on bypassing immune system. We demonstrate importance continual surveillance strategic adaptation within healthcare frameworks along wastewater sampling rapid identification emerging SARS-CoV-2 variants.

Язык: Английский

---