BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection

Nature, Journal Year: 2022, Volume and Issue: 608(7923), P. 593 - 602

Published: June 17, 2022

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility than the BA.2 lineage 1 . The receptor binding immune-evasion capability of these recently emerged variants require immediate investigation. Here, coupled with structural comparisons spike proteins, we show that (BA.4 are hereafter referred collectively to as BA.4/BA.5) similar affinities for angiotensin-converting enzyme (ACE2) receptor. Of note, BA.2.12.1 BA.4/BA.5 display increased evasion neutralizing antibodies compared against plasma from triple-vaccinated individuals or who developed a BA.1 infection after vaccination. To delineate underlying antibody-evasion mechanism, determined escape mutation profiles , epitope distribution 3 Omicron-neutralization efficiency 1,640 directed receptor-binding domain viral protein, including 614 isolated people had recovered infection. vaccination predominantly recalls humoral immune memory ancestral (hereafter wild-type (WT)) SARS-CoV-2 protein. resulting elicited could neutralize both WT enriched on epitopes do not bind ACE2. However, most cross-reactive evaded by mutants L452Q, L452R F486V. can also induce new clones BA.1-specific potently BA.1. Nevertheless, largely owing D405N F486V mutations, react weakly pre-Omicron variants, exhibiting narrow neutralization breadths. therapeutic bebtelovimab 4 cilgavimab 5 effectively BA.4/BA.5, whereas S371F, R408S mutations undermine broadly sarbecovirus-neutralizing antibodies. Together, our results indicate may evolve evade immunity infection, suggesting BA.1-derived vaccine boosters achieve broad-spectrum protection variants.

Language: Английский

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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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Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4 and BA.5

Nature, Journal Year: 2022, Volume and Issue: 608(7923), P. 603 - 608

Published: July 5, 2022

Abstract SARS-CoV-2 Omicron subvariants BA.2.12.1 and BA.4/5 have surged notably to become dominant in the United States South Africa, respectively 1,2 . These new carrying further mutations their spike proteins raise concerns that they may evade neutralizing antibodies, thereby compromising efficacy of COVID-19 vaccines therapeutic monoclonals. We now report findings from a systematic antigenic analysis these surging subvariants. is only modestly (1.8-fold) more resistant sera vaccinated boosted individuals than BA.2. However, substantially (4.2-fold) thus likely lead vaccine breakthrough infections. Mutation at residue L452 found both facilitates escape some antibodies directed so-called class 2 3 regions receptor-binding domain The F486V mutation certain 1 but compromises affinity for viral receptor. R493Q reversion mutation, however, restores receptor consequently fitness BA.4/5. Among authorized clinical use, bebtelovimab retains full potency against lineage continues evolve, successively yielding are not transmissible also evasive antibodies.

Language: Английский

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Intramuscular AZD7442 (Tixagevimab–Cilgavimab) for Prevention of Covid-19

New England Journal of Medicine, Journal Year: 2022, Volume and Issue: 386(23), P. 2188 - 2200

Published: April 20, 2022

The monoclonal-antibody combination AZD7442 is composed of tixagevimab and cilgavimab, two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that have an extended half-life been shown to prophylactic therapeutic effects in animal models. Pharmacokinetic data humans indicate has approximately 90 days.In ongoing phase 3 trial, we enrolled adults (≥18 years age) who had increased risk inadequate response vaccination disease 2019 (Covid-19), exposure SARS-CoV-2, or both. Participants were randomly assigned a 2:1 ratio receive single dose (two consecutive intramuscular injections, one containing the other cilgavimab) either 300 mg saline placebo, they followed for up 183 days primary analysis. safety end point was incidence adverse events after AZD7442. efficacy symptomatic Covid-19 (SARS-CoV-2 infection confirmed by means reverse-transcriptase-polymerase-chain-reaction assay) occurring administration placebo on before day 183.A total 5197 participants underwent randomization received (3460 group 1737 group). analysis conducted 30% become aware their randomized assignment. In total, 1221 3461 (35.3%) 593 1736 (34.2%) reported having at least event, most which mild moderate severity. Symptomatic occurred 8 3441 (0.2%) 17 1731 (1.0%) (relative reduction, 76.7%; 95% confidence interval [CI], 46.0 90.0; P<0.001); follow-up median 6 months showed relative reduction 82.8% (95% CI, 65.8 91.4). Five cases critical Covid-19-related deaths occurred, all group.A prevention Covid-19, without evident concerns. (Funded AstraZeneca U.S. government; PROVENT ClinicalTrials.gov number, NCT04625725.).

Language: Английский

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Neutralization Escape by SARS-CoV-2 Omicron Subvariants BA.2.12.1, BA.4, and BA.5

New England Journal of Medicine, Journal Year: 2022, Volume and Issue: 387(1), P. 86 - 88

Published: June 22, 2022

To the Editor: In recent months, multiple lineages of omicron (B.1.1.529)variant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged, 1 with subvariants BA.1 and BA.2 showing substantial escape from neutralizing antibodies. 2-5Subvariant BA.2.12.1 is now dominant strain in United States, BA.4 BA.5 are South Africa (Fig. 1A).Subvariants identical sequences spike protein.We evaluated antibody titers against reference WA1/2020 isolate SARS-CoV-2 along BA.1, BA.2, BA.2.12.1, or 27 participants who had been vaccinated boosted messenger RNA vaccine BNT162b2 (Pfizer-BioNTech) infected subvariant a median 29 days earlier (range, to 113) (Tables S1 andS2 Supplementary Appendix, available full text this letter at NEJM.org).In cohort, were excluded if they history infection posi-The New England Journal Medicine Downloaded nejm.

Language: Английский

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SARS-CoV-2 Omicron variant: recent progress and future perspectives

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: April 28, 2022

Abstract Since the outbreak of coronavirus disease 2019 (COVID-19) pandemic, there have been a few variants severe acute respiratory syndrome 2 (SARS-CoV-2), one which is Omicron variant (B.1.1.529). The most mutated SARS-CoV-2 variant, and its high transmissibility immune evasion ability raised global concerns. Owing to enhanced transmissibility, has rapidly replaced Delta as dominant in several regions. However, recent studies shown that exhibits reduced pathogenicity due altered cell tropism. In addition, significant resistance neutralizing activity vaccines, convalescent serum, antibody therapies. present review, advances molecular clinical characteristics infectivity, pathogenicity, was summarized, potential therapeutic applications response infection were discussed. Furthermore, we highlighted future waves strategies end pandemic.

Language: Английский

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Evolution of the SARS‐CoV‐2 omicron variants BA.1 to BA.5: Implications for immune escape and transmission

Reviews in Medical Virology, Journal Year: 2022, Volume and Issue: 32(5)

Published: July 20, 2022

Abstract The first dominant SARS‐CoV‐2 Omicron variant BA.1 harbours 35 mutations in its Spike protein from the original that emerged late 2019. Soon after discovery, rapidly to become worldwide and has since evolved into several variants. is of major public health concern owing high infectivity antibody evasion. This review article examines theories have been proposed on evolution including zoonotic spillage, infection immunocompromised individuals cryptic spread community without being diagnosed. Added complexity Omicron's are multiple reports recombination events occurring between co‐circulating variants with Delta other such as XE. Current literature suggests combination novel resulted having higher than Wuhan‐Hu‐1 variant. However, severity believed be less reduced syncytia formation lower multiplication human lung tissue. Perhaps most challenging studies indicate efficacy available vaccines against (8–127 times reduction) compared administration booster vaccine, however, compensates reduction improves by 12–35 fold. Concerningly though, broadly neutralising monoclonal antibodies, those approved FDA for therapeutic use previous variants, mostly ineffective exception Sotrovimab recent suggest BA.2 also resistant Sotrovimab. Currently two new BA.4 BA.5 emerging reported more transmissible immunity generated antibodies. As will likely continue emerge it important evolution, biological consequences mutations, existing well understood.

Language: Английский

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LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants

Cell Reports, Journal Year: 2022, Volume and Issue: 39(7), P. 110812 - 110812

Published: April 25, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing monoclonal antibodies (mAbs) can reduce the risk of hospitalization from disease 2019 (COVID-19) when administered early. However, SARS-CoV-2 variants concern (VOCs) have negatively affected therapeutic use some authorized mAbs. Using a high-throughput B cell screening pipeline, we isolated LY-CoV1404 (bebtelovimab), highly potent spike glycoprotein receptor binding domain (RBD)-specific antibody. potently neutralizes authentic SARS-CoV-2, B.1.1.7, B.1.351, and B.1.617.2. In pseudovirus neutralization studies, variants, including B.1.617.2, B.1.427/B.1.429, P.1, B.1.526, B.1.1.529, BA.2 subvariant. Structural analysis reveals that contact residues epitope are conserved, except for N439 N501. The neutralizing activity is unaffected by most common mutations at these positions (N439K N501Y). broad relatively conserved suggest has potential to be an effective agent treat all known variants.

Language: Английский

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Covid-19 Vaccines — Immunity, Variants, Boosters

New England Journal of Medicine, Journal Year: 2022, Volume and Issue: 387(11), P. 1011 - 1020

Published: Aug. 31, 2022

T he coronavirus disease 2019 (Covid-19) pandemic has claimed an estimated 15 million lives, including more than 1 lives in the United States alone.The rapid development of multiple Covid-19 vaccines been a triumph biomedical research, and billions vaccine doses have administered worldwide.Challenges facing field include inequitable distribution, hesitancy, waning immunity, emergence highly transmissible viral variants that partially escape antibodies.This review summarizes current state knowledge about immune responses to importance both humoral cellular immunity for durable protection against severe disease. A nti v ir l Immunit yThe system is broadly divided into innate adaptive systems.Innate are first line defense viruses rapidly triggered when pattern-recognition receptors, such as toll-like recognize pathogen-associated molecular patterns.Innate antiviral includes secretion type I interferons, cytokines, certain responses, neutrophils, monocytes macrophages, dendritic cells, natural killer cells. Adaptive second viruses, involve antigen-specific recognition epitopes.Adaptive two complementary branches system: immunity.Humoral acute respiratory syndrome 2 (SARS-CoV-2) antibodies bind SARS-CoV-2 spike protein either neutralize virus or eliminate it through other effector mechanisms. 2,3ellular virus-specific B cells which provide long-term immunologic memory expand on reexposure antigen.B produce antibodies, CD8+ directly virally infected CD4+ help support responses.5][6][7] For variant largely escapes neutralizing may be particularly important longterm

Language: Английский

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Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir

Nature, Journal Year: 2022, Volume and Issue: 613(7944), P. 558 - 564

Published: Nov. 9, 2022

Nirmatrelvir, an oral antiviral targeting the 3CL protease of SARS-CoV-2, has been demonstrated to be clinically useful against COVID-19 (refs. 1,2). However, because SARS-CoV-2 evolved become resistant other therapeutic modalities3-9, there is a concern that same could occur for nirmatrelvir. Here we examined this possibility by in vitro passaging nirmatrelvir using two independent approaches, including one on large scale. Indeed, highly viruses emerged from both and their sequences showed multitude mutations. In experiment peformed with many replicates, 53 viral lineages were selected mutations observed at 23 different residues enzyme. Nevertheless, several common mutational pathways resistance preferred, majority descending T21I, P252L or T304I as precursor Construction analysis 13 recombinant clones these mediated only low-level resistance, whereas greater required accumulation additional E166V mutation conferred strongest (around 100-fold), but resulted loss replicative fitness was restored compensatory changes such L50F T21I. Our findings indicate does readily arise via multiple vitro, specific herein form strong foundation which study mechanism detail inform design next-generation inhibitors.

Language: Английский

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