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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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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Antigenicity and receptor affinity of SARS-CoV-2 BA.2.86 spike

Nature, Journal Year: 2023, Volume and Issue: 624(7992), P. 639 - 644

Published: Oct. 23, 2023

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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Antigenicity and infectivity characterisation of SARS-CoV-2 BA.2.86

The Lancet Infectious Diseases, Journal Year: 2023, Volume and Issue: 23(11), P. e457 - e459

Published: Sept. 19, 2023

Language: Английский

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Enhanced transmissibility of XBB.1.5 is contributed by both strong ACE2 binding and antibody evasion

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 3, 2023

Abstract SARS-CoV-2 recombinant subvariant XBB.1.5 is growing rapidly in the United States, carrying an additional Ser486Pro substitution compared to XBB.1 and outcompeting BQ.1.1 other XBB sublineages. The underlying mechanism for such high transmissibility remains unclear. Here we show that exhibits a substantially higher hACE2-binding affinity XBB/XBB.1. Convalescent plasma samples from BA.1, BA.5, BF.7 breakthrough infection are significantly evaded by both XBB.1.5, with displaying slightly weaker immune evasion capability than XBB.1. Evusheld Bebtelovimab could not neutralize XBB.1/XBB.1.5, while Sotrovimab weakly reactive notably, SA55 still highly effective. fact showed comparable antibody but distinct suggests enhanced receptor-binding would indeed lead growth advantages. strong hACE2 binding of also enable its tolerance further escape mutations, which should be closely monitored.

Language: Английский

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Fitness effects of mutations to SARS-CoV-2 proteins

Virus Evolution, Journal Year: 2023, Volume and Issue: 9(2)

Published: July 1, 2023

Knowledge of the fitness effects mutations to SARS-CoV-2 can inform assessment new variants, design therapeutics resistant escape, and understanding functions viral proteins. However, experimentally measuring is challenging: we lack tractable lab assays for many proteins, comprehensive deep mutational scanning has been applied only two Here, develop an approach that leverages millions publicly available sequences estimate mutations. We first calculate how independent occurrences each mutation are expected be observed along phylogeny in absence selection. then compare these observations actual effect mutation. These estimates correlate well with measurements. For most genes, synonymous nearly neutral, stop-codon deleterious, amino acid have a range effects. some accessory proteins under little no provide interactive visualizations all (https://jbloomlab.github.io/SARS2-mut-fitness/). The framework describe applicable any virus which number sufficiently large neutral observed.

Language: Английский

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Convergent evolution of SARS-CoV-2 XBB lineages on receptor-binding domain 455–456 synergistically enhances antibody evasion and ACE2 binding

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(12), P. e1011868 - e1011868

Published: Dec. 20, 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) XBB lineages have achieved dominance worldwide and keep on evolving. Convergent evolution of the receptor-binding domain (RBD) L455F F456L is observed, resulting in variants with substantial growth advantages, such as EG.5, FL.1.5.1, XBB.1.5.70, HK.3. Here, we show that neutralizing antibody (NAb) evasion drives convergent F456L, while epistatic shift caused by enables subsequent convergence through ACE2 binding enhancement further immune evasion. evade RBD-targeting Class 1 public NAbs, reducing neutralization efficacy breakthrough infection (BTI) reinfection convalescent plasma. Importantly, single substitution significantly dampens receptor binding; however, combination forms an adjacent residue flipping, which leads to enhanced NAbs resistance affinity. The perturbed mode exceptional NAb evasion, revealed structural analyses. Our results indicate flexibility contributed epistasis cannot be underestimated, potential SARS-CoV-2 RBD remains high.

Language: Английский

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

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: May 2, 2023

Abstract The continuous emergence of highly immune evasive SARS-CoV-2 variants, like XBB.1.5 1,2 and XBB.1.16 3,4 , highlights the need to update COVID-19 vaccine compositions. However, imprinting induced by wildtype (WT)-based vaccination would compromise antibody response Omicron-based boosters 5-9 . Vaccination strategies that can counter are critically needed. In this study, we investigated degree dynamics in mouse models human cohorts, especially focusing on role repeated Omicron stimulation. Our results show mice, efficacy single Omicron-boosting is heavily limited imprinting, when using variants antigenically distinct from WT, XBB, while concerning situation could be largely mitigated a second booster. Similarly, humans, found infections also alleviate WT-vaccination-induced generate high neutralizing titers against both plasma nasal mucosa. By isolating 781 RBD-targeting mAbs infection revealed double exposure alleviates generating large proportion matured potent Omicron-specific antibodies. Importantly, epitope characterization deep mutational scanning (DMS) showed these antibodies target RBD epitopes compared WT-induced antibodies, bias towards non-neutralizing observed exposures due was restored after stimulation, together leading substantial shift. Based DMS profiles, identified evolution hotspots demonstrated combinations mutations further boost XBB.1.5’s immune-evasion capability maintaining ACE2 binding affinity. findings suggest WT component should abandoned updating antigen compositions XBB lineages, those who haven’t been exposed yet receive two updated boosters.

Language: Английский

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Unsupervised evolution of protein and antibody complexes with a structure-informed language model

Science, Journal Year: 2024, Volume and Issue: 385(6704), P. 46 - 53

Published: July 4, 2024

Large language models trained on sequence information alone can learn high-level principles of protein design. However, beyond sequence, the three-dimensional structures proteins determine their specific function, activity, and evolvability. Here, we show that a general model augmented with structure backbone coordinates guide evolution for diverse without need to individual functional tasks. We also demonstrate ESM-IF1, which was only single-chain structures, be extended engineer complexes. Using this approach, screened about 30 variants two therapeutic clinical antibodies used treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. achieved up 25-fold improvement in neutralization 37-fold affinity against antibody-escaped viral concern BQ.1.1 XBB.1.5, respectively. These findings highlight advantage integrating structural identify efficient trajectories requiring any task-specific training data.

Language: Английский

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