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

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Sept. 16, 2022

Abstract Continuous evolution of Omicron has led to a rapid and simultaneous emergence numerous variants that display growth advantages over BA. 5. Despite their divergent evolutionary courses, mutations on receptor-binding domain (RBD) converge several hotspots. The driving force destination such convergent its impact humoral immunity remain unclear. Here, we demonstrate these can cause striking evasion neutralizing antibody (NAb) drugs convalescent plasma, including those from BA.5 breakthrough infection, while maintaining sufficient ACE2 binding capability. BQ.1.1.10, BA.4.6.3, XBB, CH. 1.1 are the most antibody-evasive strain tested, even exceeding SARS-CoV-1 level. To delineate origin evolution, determined escape mutation profiles neutralization activity monoclonal antibodies (mAbs) isolated BA.2 breakthrough-infection convalescents. Importantly, due immune imprinting, especially infection caused significant reductions in epitope diversity NAbs increased proportion non-neutralizing mAbs, which turn concentrated pressure promoted evolution. Moreover, showed RBD could be accurately inferred by integrated deep mutational scanning (DMS) profiles, trends BA.2.75/BA.5 subvariants well-simulated through constructed pseudovirus mutants. Together, our results suggest current herd vaccine boosters may not provide good protection against infection. Broad-spectrum SARS-CoV-2 vaccines NAb development should highly prioritized, mutants help examine effectiveness advance.

Language: Английский

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Omicron spike function and neutralizing activity elicited by a comprehensive panel of vaccines

Science, Journal Year: 2022, Volume and Issue: 377(6608), P. 890 - 894

Published: July 19, 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern comprises several sublineages, with BA.2 and BA.2.12.1 having replaced the previously dominant BA.1 BA.4 BA.5 increasing in prevalence worldwide. We show that large number sublineage spike mutations leads to enhanced angiotensin-converting enzyme (ACE2) binding, reduced fusogenicity, dampening plasma neutralizing activity elicited by infection or seven clinical vaccines relative ancestral virus. Administration a homologous heterologous booster based on Wuhan-Hu-1 sequence markedly increased antibody titers breadth against BA.1, BA.2, BA.2.12.1, BA.4, across all evaluated. Our data suggest although sublineages evade polyclonal responses primary vaccine series, boosters may provide sufficient protection Omicron-induced disease.

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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Compensatory epistasis maintains ACE2 affinity in SARS-CoV-2 Omicron BA.1

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Nov. 16, 2022

The Omicron BA.1 variant emerged in late 2021 and quickly spread across the world. Compared to earlier SARS-CoV-2 variants, has many mutations, some of which are known enable antibody escape. Many these antibody-escape mutations individually decrease spike receptor-binding domain (RBD) affinity for ACE2, but still binds ACE2 with high affinity. fitness evolution lineage is therefore driven by combined effects numerous mutations. Here, we systematically map epistatic interactions between 15 RBD relative Wuhan Hu-1 strain. Specifically, measure all possible combinations (2

Language: Английский

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Molecular fate-mapping of serum antibody responses to repeat immunization

Nature, Journal Year: 2023, Volume and Issue: 615(7952), P. 482 - 489

Published: Jan. 16, 2023

Language: Английский

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Selection Analysis Identifies Clusters of Unusual Mutational Changes in Omicron Lineage BA.1 That Likely Impact Spike Function

Molecular Biology and Evolution, Journal Year: 2022, Volume and Issue: 39(4)

Published: March 16, 2022

Among the 30 nonsynonymous nucleotide substitutions in Omicron S-gene are 13 that have only rarely been seen other SARS-CoV-2 sequences. These mutations cluster within three functionally important regions of at sites will likely impact (1) interactions between subunits Spike trimer and predisposition to shift from down up configurations, (2) with ACE2 receptors, (3) priming for membrane fusion. We show here that, based on both rarity these intrapatient sequencing reads patterns selection codon where occur related sarbecoviruses, prior emergence would predicted decrease fitness any virus which they occurred. further propose each clusters therefore cooperatively interact mitigate their individual costs, and, combination mutations, adaptively alter function Spike. Given evident epidemic growth advantages overall previously known lineages, it is crucial determine how such complex highly adaptive mutation constellations were assembled S-gene, why, despite unprecedented global genomic surveillance efforts, early stages this assembly process went completely undetected.

Language: Английский

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Deep mutational learning predicts ACE2 binding and antibody escape to combinatorial mutations in the SARS-CoV-2 receptor-binding domain

Cell, Journal Year: 2022, Volume and Issue: 185(21), P. 4008 - 4022.e14

Published: Aug. 31, 2022

The continual evolution of SARS-CoV-2 and the emergence variants that show resistance to vaccines neutralizing antibodies threaten prolong COVID-19 pandemic. Selection are driven in part by mutations within viral spike protein particular ACE2 receptor-binding domain (RBD), a primary target site for antibodies. Here, we develop deep mutational learning (DML), machine-learning-guided engineering technology, which is used investigate massive sequence space combinatorial mutations, representing billions RBD variants, accurately predicting their impact on binding antibody escape. A highly diverse landscape possible identified could emerge from multitude evolutionary trajectories. DML may be predictive profiling current prospective including mutated such as Omicron, thus guiding development therapeutic treatments COVID-19.

Language: Английский

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