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

Cell, Год журнала: 2022, Номер 186(2), С. 279 - 286.e8

Опубликована: Дек. 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.

Язык: Английский

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

Nature, Год журнала: 2022, Номер unknown

Опубликована: Дек. 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.

Язык: Английский

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

The Lancet Infectious Diseases, Год журнала: 2023, Номер 23(3), С. 278 - 280

Опубликована: Фев. 3, 2023

Язык: Английский

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Characterization of the enhanced infectivity and antibody evasion of Omicron BA.2.75

Cell Host & Microbe, Год журнала: 2022, Номер 30(11), С. 1527 - 1539.e5

Опубликована: Окт. 4, 2022

Recently emerged SARS-CoV-2 Omicron subvariant, BA.2.75, displayed a growth advantage over circulating BA.2.38, BA.2.76, and BA.5 in India. However, the underlying mechanisms for enhanced infectivity, especially compared with BA.5, remain unclear. Here, we show that BA.2.75 exhibits substantially higher affinity host receptor angiotensin-converting enzyme 2 (ACE2) than other variants. Structural analyses of spike shows its decreased thermostability increased frequency binding domain (RBD) "up" conformation under acidic conditions, suggesting low-pH-endosomal cell entry. Relative to BA.4/BA.5, reduced evasion humoral immunity from BA.1/BA.2 breakthrough-infection convalescent plasma but greater Delta plasma. also weaker neutralization against mainly due BA.2.75's distinct neutralizing antibody (NAb) escape pattern. Antibody therapeutics Evusheld Bebtelovimab effective BA.2.75. These results suggest may prevail after receptor-binding capability could support further immune-evasive mutations.

Язык: Английский

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

Nature, Год журнала: 2023, Номер 625(7993), С. 148 - 156

Опубликована: Ноя. 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.

Язык: Английский

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A pseudovirus system enables deep mutational scanning of the full SARS-CoV-2 spike

Cell, Год журнала: 2023, Номер 186(6), С. 1263 - 1278.e20

Опубликована: Фев. 13, 2023

A major challenge in understanding SARS-CoV-2 evolution is interpreting the antigenic and functional effects of emerging mutations viral spike protein. Here, we describe a deep mutational scanning platform based on non-replicative pseudotyped lentiviruses that directly quantifies how large numbers impact antibody neutralization pseudovirus infection. We apply this to produce libraries Omicron BA.1 Delta spikes. These each contain ∼7,000 distinct amino acid context up ∼135,000 unique mutation combinations. use these map escape from neutralizing antibodies targeting receptor-binding domain, N-terminal S2 subunit spike. Overall, work establishes high-throughput safe approach measure ∼10

Язык: Английский

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Neutralization, effector function and immune imprinting of Omicron variants

Nature, Год журнала: 2023, Номер 621(7979), С. 592 - 601

Опубликована: Авг. 30, 2023

Abstract Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain 1 (RBD) of spike protein. The effects these on viral infection and transmission efficacy vaccines therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 XBB.1.5 bind host ACE2 with high affinity promote membrane fusion more efficiently than earlier Omicron variants. Structures BQ.1.1, XBB.1 BN.1 RBDs bound to fragment antigen-binding region S309 antibody (the parent for sotrovimab) human explain preservation binding through conformational selection, altered recognition immune evasion. We show sotrovimab binds avidly all variants, promotes Fc-dependent effector functions protects mice challenged hamsters XBB.1.5. Vaccine-elicited plasma antibodies cross-react trigger against current despite a reduced neutralizing activity, suggesting mechanism protection disease, exemplified by S309. Cross-reactive RBD-directed memory B cells remained dominant even after two exposures spikes, underscoring role persistent imprinting.

Язык: Английский

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Rational identification of potent and broad sarbecovirus-neutralizing antibody cocktails from SARS convalescents

Cell Reports, Год журнала: 2022, Номер 41(12), С. 111845 - 111845

Опубликована: Дек. 1, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages have escaped most receptor-binding domain (RBD)-targeting therapeutic neutralizing antibodies (NAbs), which proves that previous NAb drug screening strategies are deficient against the fast-evolving SARS-CoV-2. Better broad candidate selection methods needed. Here, we describe a rational approach for identifying RBD-targeting SARS-CoV-2 cocktails. Based on high-throughput epitope determination, propose drugs should target non-immunodominant RBD epitopes to avoid herd-immunity-directed escape mutations. Also, their interacting antigen residues focus sarbecovirus conserved sites and associate with critical viral functions, making antibody-escaping mutations less likely appear. Following these criteria, featured non-competing antibody cocktail, SA55+SA58, is identified from large collection of NAbs isolated SARS-CoV-2-vaccinated SARS convalescents. SA55+SA58 potently neutralizes ACE2-utilizing sarbecoviruses, including circulating variants, could serve as prophylactics offer long-term protection, especially individuals who immunocompromised or high-risk comorbidities.

Язык: Английский

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SARS-CoV-2 evolution in the Omicron era

Nature Microbiology, Год журнала: 2023, Номер 8(11), С. 1952 - 1959

Опубликована: Окт. 16, 2023

Язык: Английский

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Fitness effects of mutations to SARS-CoV-2 proteins

Virus Evolution, Год журнала: 2023, Номер 9(2)

Опубликована: Июль 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.

Язык: Английский

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