Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants

Cell, Journal Year: 2022, Volume and Issue: 186(2), P. 279 - 286.e8

Published: Dec. 14, 2022

The BQ and XBB subvariants of SARS-CoV-2 Omicron are now rapidly expanding, possibly due to altered antibody evasion properties deriving from their additional spike mutations. Here, we report that neutralization BQ.1, BQ.1.1, XBB, XBB.1 by sera vaccinees infected persons was markedly impaired, including individuals boosted with a WA1/BA.5 bivalent mRNA vaccine. Titers against were lower 13- 81-fold 66- 155-fold, respectively, far beyond what had been observed date. Monoclonal antibodies capable neutralizing the original variant largely inactive these new subvariants, responsible individual mutations identified. These found have similar ACE2-binding affinities as predecessors. Together, our findings indicate present serious threats current COVID-19 vaccines, render all authorized antibodies, may gained dominance in population because advantage evading antibodies.

Language: Английский

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Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution

Nature, Journal Year: 2022, Volume and Issue: unknown

Published: Dec. 19, 2022

Abstract Continuous evolution of Omicron has led to a rapid and simultaneous emergence numerous variants that display growth advantages over BA.5 (ref. 1 ). Despite their divergent evolutionary courses, mutations on receptor-binding domain (RBD) converge several hotspots. The driving force destination such sudden convergent its effect humoral immunity remain unclear. Here we demonstrate these can cause evasion neutralizing antibody drugs convalescent plasma, including those from breakthrough infection, while maintaining sufficient ACE2-binding capability. BQ.1.1.10 (BQ.1.1 + Y144del), BA.4.6.3, XBB CH.1.1 are the most antibody-evasive strains tested. To delineate origin evolution, determined escape mutation profiles neutralization activity monoclonal antibodies isolated individuals who had BA.2 infections 2,3 . Owing immune imprinting, especially infection reduced diversity binding sites increased proportions non-neutralizing clones, which, in turn, focused pressure promoted RBD. Moreover, show RBD could be accurately inferred by deep mutational scanning 4,5 , trends BA.2.75 subvariants well foreseen through constructed pseudovirus mutants. These results suggest current herd vaccine boosters may not efficiently prevent variants.

Language: Английский

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Fast evolution of SARS-CoV-2 BA.2.86 to JN.1 under heavy immune pressure

The Lancet Infectious Diseases, Journal Year: 2023, Volume and Issue: 24(2), P. e70 - e72

Published: Dec. 15, 2023

The SARS-CoV-2 saltation variant BA.2.86, which was quickly designated as a under monitoring after its emergence, has garnered global attention. Although BA.2.86 did not show substantial humoral immune escape and growth advantage compared with current dominant variants, such EG.5.1 HK.3, it showed remarkably high ACE2 binding affinity.1Yang S Yu Y Jian F et al.Antigenicity infectivity characterisation of BA.2.86.Lancet Infect Dis. 2023; 23: e457-e459Summary Full Text PDF PubMed Scopus (36) Google Scholar, 2Wannigama DL Amarasiri M Phattharapornjaroen P al.Tracing the new in community through wastewater surveillance Bangkok, Thailand.Lancet e464-e466Summary (11) 3Wang Q Guo Liu L receptor affinity spike.Nature. (published online Oct 23.)https://doi.org/10.1038/s41586-023-06750-wGoogle 4Uriu K Ito J Kosugi al.Transmissibility, infectivity, evasion variant.Lancet e460-e461Summary (29) 5Sheward DJ Yang Westerberg al.Sensitivity to prevailing neutralising antibody responses.Lancet e462-e463Summary (22) Scholar This increased affinity, coupled distinct antigenicity, could enable accumulate immune-evasive mutations during low-level populational transmission, akin previous evolution from BA.2.75 CH.1.1 XBB.6Cao Song W Wang al.Characterization enhanced Omicron BA.2.75.Cell Host Microbe. 2022; 30: 1527-1539Summary (74) 7Cao al.Imprinted immunity induces convergent RBD domain evolution.Nature. 614: 521-529PubMed 8Yue C al.ACE2 transmissibility XBB.1.5.Lancet 278-280Summary (108) 9Wang Li Z al.Evolving sublineage SARS-CoV-2.iScience. 26108254 Summary (3) With just one additional mutation (L455S) predecessor JN.1 rapidly became predominant France (figure A; appendix 1 p 12), surpassing both so-called FLip (L455F+F456L) strains. A thorough investigation into capability JN.1, particularly given few mutations, is imperative.FigureJN.1 shows profound decreased affinityShow full caption(A) Sequence percentages prevalent variants since August, 2023, including BA.2·86 (the original subvariants, except JN.1), HV.1, FLip+A475V, HK.3. advantages relative HK.3 past two months these strains are denoted legend within parentheses. Data collected covSPECTRUM. (B) 50% titer (NT50) convalescent plasma against measured individuals who received three CoronaVac doses had breakthrough infection BA.5 or BF.7 followed by XBB reinfection (n=54). Labels for geometric mean titers (GMT) located above each group, fold changes statistical significances indicated GMT labels. Below dashed line labels specifying numbers negative samples related limit detection (NT50=20). Two-tailed Wilcoxon signed-rank tests paired were used. *p<0·05, **p<0·01, ***p<0·001, ****p<0·0001. (C) human (angiotensin-converting enzyme 2) affinities (XBB.1.5+L455F+F456L), HV.1 (XBB.1.5+L452R+F456L), EG.5 (XBB.1.5+F456L), JD.1.1 (XBB.1.5+L455F+F456L+A475V), (BA.2.86+L455S) determined surface plasmon resonance sensorgrams. KD values (nM) displayed bars, all replicates represented points. (D) Class Nabs resistance pseudovirus XBB.1.5, EG.5, JD.1.1, IC50 (n=8). when D614G other labelled. (μg per mL) approved candidate monoclonal drugs targeting spike assessed pseudovirus. IC50=50% inhibitory concentration; KD=equilibrium dissociation constant; NAbs=neutralising antibodies; nM=nanomolarView Large Image Figure ViewerDownload Hi-res image Download (PPT) (A) nM=nanomolar We first study using pseudovirus-based neutralisation assays recovering infection. These individuals, having inactivated vaccines, subsequently contracted (XBB subvariants S486P substitution) infections. Our included cohorts, 27 participants post-vaccination infections another patients reinfected (appendix 2). significantly B). finding evidenced 2·1-fold decrease among post-BA.5 1·1-fold NT50 B; 13). Additionally, JN.1's surpassed that competitive (EG.5+L452R) (FLip+A475V). also lower their parental acquiring L452R A475V respectively, explaining advantages. As L455 on interface between 14),10Nutalai R Zhou D Tuekprakhon al.Potent cross-reactive antibodies following vaccinees.Cell. 185 (31.e18): 2116Summary (76) L455S change JN.1. By resonance, we found notable reduction domain, indicating capabilities come at expense reduced C). carried (XBB.1.5+FLip+A475V) resulted enhancing (XBB.1.5+FLip). However, affect affinity. Considering predominantly epitope antibodies, earlier research, our further examined response eight XBB.1·5-neutralising class antibodies.7Cao Pseudovirus addition ability evade D). effectively compensated BA.2.86's susceptibility this group Similarly, FLip+A475V (JD.1.1) (HK.3), offering insights trend variants. In terms therapeutic SA55 retained efficacy E). Together, findings suggest greatly compensation weakness antibodies. summary, inheriting antigenic diversity acquisition L455S, achieved extensive across 1, 2, 3 antibodies,1Yang higher resistant like JD.1·1, binding. evolutionary pattern, similar transition XBB,2Wannigama highlights importance closely BA.2.75, despite unremarkable capabilities. Such survive transmit low levels difference would allow them target populations have potential highly cost publication been corrected. corrected version appeared thelancet.com/infection January 3, 2024 YC inventor provisional patent applications BD series includes BD55–5514 (SA55). founder Singlomics Biopharmaceuticals. All authors declare no competing interests. .pdf (3.2 MB) Help pdf files Supplementary .xls (.02 xls 2 Correction Lancet Dis published Dec 15. https://doi.org/10.1016/S1473-3099(23)00744-2Yang S, Y, Xu al. Fast heavy pressure. https://doi.org/10.1016/S1473-3099(23)00744-2—In Correspondence, author's name should printed Yunlong Cao. corresponding email address read [email protected]. corrections made Jan 2024. Full-Text

Language: Английский

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ACE2 binding and antibody evasion in enhanced transmissibility of XBB.1.5

The Lancet Infectious Diseases, Journal Year: 2023, Volume and Issue: 23(3), P. 278 - 280

Published: Feb. 3, 2023

Language: Английский

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Virological characteristics of the SARS-CoV-2 XBB variant derived from recombination of two Omicron subvariants

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: May 16, 2023

In late 2022, SARS-CoV-2 Omicron subvariants have become highly diversified, and XBB is spreading rapidly around the world. Our phylogenetic analyses suggested that emerged through recombination of two cocirculating BA.2 lineages, BJ.1 BM.1.1.1 (a progeny BA.2.75), during summer 2022. XBB.1 variant most profoundly resistant to BA.2/5 breakthrough infection sera date more fusogenic than BA.2.75. The breakpoint located in receptor-binding domain spike, each region recombinant spike confers immune evasion increases fusogenicity. We further provide structural basis for interaction between human ACE2. Finally, intrinsic pathogenicity male hamsters comparable or even lower multiscale investigation provides evidence suggesting first observed increase its fitness rather substitutions.

Language: Английский

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Enhanced neutralization resistance of SARS-CoV-2 Omicron subvariants BQ.1, BQ.1.1, BA.4.6, BF.7, and BA.2.75.2

Cell Host & Microbe, Journal Year: 2022, Volume and Issue: 31(1), P. 9 - 17.e3

Published: Nov. 22, 2022

Language: Английский

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Resistance of Omicron subvariants BA.2.75.2, BA.4.6, and BQ.1.1 to neutralizing antibodies

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 14, 2023

Abstract Convergent evolution of SARS-CoV-2 Omicron BA.2, BA.4, and BA.5 lineages has led to the emergence several new subvariants, including BA.2.75.2, BA.4.6. BQ.1.1. The subvariant BQ.1.1 became predominant in many countries December 2022. subvariants carry an additional often redundant set mutations spike, likely responsible for increased transmissibility immune evasion. Here, we established a viral amplification procedure easily isolate strains. We examined their sensitivity 6 therapeutic monoclonal antibodies (mAbs) 72 sera from Pfizer BNT162b2-vaccinated individuals, with or without BA.1/BA.2 breakthrough infection. Ronapreve (Casirivimab Imdevimab) Evusheld (Cilgavimab Tixagevimab) lose antiviral efficacy against BA.2.75.2 BQ.1.1, whereas Xevudy (Sotrovimab) remaine weakly active. is also resistant Bebtelovimab. Neutralizing titers triply vaccinated individuals are low undetectable 4 months after boosting. A infection increases these titers, which remains about 18-fold lower than BA.1. Reciprocally, more efficiently neutralization BA.2.75.2. Thus, trajectory novel facilitates spread immunized populations raises concerns most available mAbs.

Language: Английский

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Deep mutational scans for ACE2 binding, RBD expression, and antibody escape in the SARS-CoV-2 Omicron BA.1 and BA.2 receptor-binding domains

PLoS Pathogens, Journal Year: 2022, Volume and Issue: 18(11), P. e1010951 - e1010951

Published: Nov. 18, 2022

SARS-CoV-2 continues to acquire mutations in the spike receptor-binding domain (RBD) that impact ACE2 receptor binding, folding stability, and antibody recognition. Deep mutational scanning prospectively characterizes impacts of on these biochemical properties, enabling rapid assessment new seen during viral surveillance. However, effects can change as virus evolves, requiring updated deep scans. We determined all single amino acid Omicron BA.1 BA.2 RBDs ACE2-binding affinity, RBD folding, escape from binding by LY-CoV1404 (bebtelovimab) monoclonal antibody. The some differ those measured ancestral Wuhan-Hu-1 background. These epistatic shifts largely resemble previously Alpha variant due convergent epistatically modifying N501Y substitution. variants show additional lineage-specific shifts, including examples phenomenon entrenchment causes Q498R substitutions present be more favorable background than earlier strains. In contrast, substitution Q493R exhibits no sign entrenchment, with derived state, R493, being unfavorable for Wuhan-Hu-1. Likely this reason, R493Q reversion has occurred sub-variants BA.4/BA.5 BA.2.75, where affinity buffer may potentiate concurrent antigenic change. Consistent prior studies, we find have reduced expression, identify candidate stabilizing ameliorate deficit. Last, our maps highlight a broadening sites compared datasets landscape inform ongoing efforts

Language: Английский

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Virological characteristics of the SARS-CoV-2 Omicron BA.2.75 variant

Cell Host & Microbe, Journal Year: 2022, Volume and Issue: 30(11), P. 1540 - 1555.e15

Published: Oct. 18, 2022

The SARS-CoV-2 Omicron BA.2.75 variant emerged in May 2022. is a BA.2 descendant but phylogenetically distinct from BA.5, the currently predominant descendant. Here, we show that has greater effective reproduction number and different immunogenicity profile than BA.5. We determined sensitivity of to vaccinee convalescent sera as well panel clinically available antiviral drugs antibodies. Antiviral largely retained potency, antibody varied depending on several key BA.2.75-specific substitutions. spike exhibited profoundly higher affinity for its human receptor, ACE2. Additionally, fusogenicity, growth efficiency alveolar epithelial cells, intrinsic pathogenicity hamsters were those BA.2. Our multilevel investigations suggest acquired virological properties independent potential risk global health

Language: Английский

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Repeated Omicron exposures override ancestral SARS-CoV-2 immune imprinting

Nature, Journal Year: 2023, Volume and Issue: 625(7993), P. 148 - 156

Published: Nov. 22, 2023

Abstract The continuing emergence of SARS-CoV-2 variants highlights the need to update COVID-19 vaccine compositions. However, immune imprinting induced by vaccination based on ancestral (hereafter referred as WT) strain would compromise antibody response Omicron-based boosters 1–5 . Vaccination strategies counter are critically needed. Here we investigated degree and dynamics in mouse models human cohorts, especially focusing role repeated Omicron stimulation. In mice, efficacy single boosting is heavily limited when using that antigenically distinct from WT—such XBB variant—and this concerning situation could be mitigated a second booster. Similarly, humans, infections alleviate WT vaccination-induced generate broad neutralization responses both plasma nasal mucosa. Notably, deep mutational scanning-based epitope characterization 781 receptor-binding domain (RBD)-targeting monoclonal antibodies isolated infection revealed double exposure induce large proportion matured Omicron-specific have RBD epitopes WT-induced antibodies. Consequently, was largely mitigated, bias towards non-neutralizing observed exposures restored. On basis scanning profiles, identified evolution hotspots XBB.1.5 demonstrated these mutations further boost immune-evasion capability while maintaining high ACE2-binding affinity. Our findings suggest component should abandoned updating vaccines, individuals without prior receive two updated boosters.

Language: Английский

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