Sotrovimab: A Review of Its Efficacy against SARS-CoV-2 Variants

Viruses, Год журнала: 2024, Номер 16(2), С. 217 - 217

Опубликована: Янв. 31, 2024

Among the anti-Spike monoclonal antibodies (mAbs), S-309 derivative sotrovimab was most successful in having longest temporal window of clinical use, showing a high degree resiliency to SARS-CoV-2 evolution interrupted only by appearance BA.2.86* variant interest (VOI). This success undoubtedly reflects rational selection target highly conserved epitope coronavirus Spike proteins. We review here efficacy against different variants outpatients and inpatients, discussing both randomized controlled trials real-world evidence. Although it could not be anticipated at time its development introduction, sotrovimab's use immunocompromised individuals who harbor large populations viruses created conditions for eventual demise, as antibody viral led withdrawal due inefficacy later lineages. Despite this, based on observational data, some authorities have continued promote sotrovimab, but lack binding newer strongly argues futility use. The story highlights power modern biomedical science generate novel therapeutics while also providing cautionary tale need devise strategies minimize emergence resistance antibody-based therapeutics.

Язык: Английский

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

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Ноя. 16, 2023

Abstract While the BA.2.86 variant demonstrated significant antigenic drift and enhanced ACE2 binding affinity, its ability to evade humoral immunity was relatively moderate compared dominant strains like EG.5 HK.3. However, emergence of a new subvariant, JN.1 (BA.2.86.1.1), which possesses an additional spike mutation, L455S, BA.2.86, showed markedly increased prevalence in Europe North America, especially France. Here, we found that L455S significantly enhances immune evasion capabilities at expense reduced affinity. This mutation enables effectively Class 1 neutralizing antibodies, offsetting BA.2.86’s susceptibility thus allowing it outcompete both precursor prevailing variants HV.1 (XBB.1.5+L452R+F456L) JD.1.1 (XBB.1.5+L455F+F456L+A475V) terms evasion. The rapid evolution from JN.1, similar earlier transition BA.2.75 CH.1.1, highlights importance closely monitoring with high affinity distinct antigenicity, despite their temporarily unremarkable capabilities. Such could survive transmit low levels, since large distance allow them target populations accumulate immune-evasive mutations rapidly, often cost receptor

Язык: Английский

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AlphaFold2 Modeling and Molecular Dynamics Simulations of the Conformational Ensembles for the SARS-CoV-2 Spike Omicron JN.1, KP.2 and KP.3 Variants: Mutational Profiling of Binding Energetics Reveals Epistatic Drivers of the ACE2 Affinity and Escape Hotspots of Antibody Resistance

Viruses, Год журнала: 2024, Номер 16(9), С. 1458 - 1458

Опубликована: Сен. 13, 2024

The most recent wave of SARS-CoV-2 Omicron variants descending from BA.2 and BA.2.86 exhibited improved viral growth fitness due to convergent evolution functional hotspots. These hotspots operate in tandem optimize both receptor binding for effective infection immune evasion efficiency, thereby maintaining overall fitness. lack molecular details on structure, dynamics energetics the latest FLiRT FLuQE with ACE2 antibodies provides a considerable challenge that is explored this study. We combined AlphaFold2-based atomistic predictions structures conformational ensembles spike complexes host dominant JN.1, KP.1, KP.2 KP.3 examine mechanisms underlying role balancing antibody evasion. Using ensemble-based mutational scanning protein residues computations affinities, we identified energy characterized basis epistatic couplings between results suggested existence interactions sites at L455, F456, Q493 positions protect restore ACE2-binding affinity while conferring beneficial escape. To escape mechanisms, performed structure-based profiling several classes displayed impaired neutralization against BA.2.86, KP.3. confirmed experimental data harboring L455S F456L mutations can significantly impair neutralizing activity class 1 monoclonal antibodies, effects mediated by facilitate subsequent convergence Q493E changes rescue binding. Structural energetic analysis provided rationale showing BD55-5840 BD55-5514 bind different epitopes retain efficacy all examined support notion may favor emergence lineages combinations involving mediators control balance high

Язык: Английский

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Full-spike deep mutational scanning helps predict the evolutionary success of SARS-CoV-2 clades

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Ноя. 14, 2023

SARS-CoV-2 variants acquire mutations in spike that promote immune evasion and impact other properties contribute to viral fitness such as ACE2 receptor binding cell entry. Knowledge of how affect these phenotypes can provide insight into the current potential future evolution virus. Here we use pseudovirus deep mutational scanning measure >9,000 across full XBB.1.5 BA.2 spikes binding, entry, or escape from human sera. We find outside receptor-binding domain (RBD) have meaningfully impacted during evolution. also neutralization by serum individuals who recently had infections. The strongest are RBD at sites 357, 420, 440, 456, 473-however, antigenic impacts vary individuals. identify strong RBD; however many them decrease suggesting they act modulating conformation. Notably, growth rates clades be explained substantial part measured effects on phenotypes, our data could enable better prediction

Язык: Английский

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The Era of the FLips: How Spike Mutations L455F and F456L (and A475V) Are Shaping SARS-CoV-2 Evolution

Viruses, Год журнала: 2023, Номер 16(1), С. 3 - 3

Опубликована: Дек. 19, 2023

Convergent evolution of the SARS-CoV-2 Spike protein has been mostly driven by immune escape, in particular escape to viral infection-neutralizing antibodies (nAbs) elicited previous infections and/or vaccinations [...]

Язык: Английский

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Ensemble-Based Mutational Profiling and Network Analysis of the SARS-CoV-2 Spike Omicron XBB Lineages for Interactions with the ACE2 Receptor and Antibodies: Cooperation of Binding Hotspots in Mediating Epistatic Couplings Underlies Binding Mechanism and Immune Escape

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(8), С. 4281 - 4281

Опубликована: Апрель 12, 2024

In this study, we performed a computational study of binding mechanisms for the SARS-CoV-2 spike Omicron XBB lineages with host cell receptor ACE2 and panel diverse class one antibodies. The central objective investigation was to examine molecular factors underlying epistatic couplings among convergent evolution hotspots that enable optimal balancing antibody evasion variants BA.1, BA2, BA.3, BA.4/BA.5, BQ.1.1, XBB.1, XBB.1.5, XBB.1.5 + L455F/F456L. By combining evolutionary analysis, dynamics simulations, ensemble-based mutational scanning protein residues in complexes ACE2, identified structural stability affinity are consistent results biochemical studies. agreement deep experiments, our quantitative analysis correctly reproduced strong variant-specific effects BA.2 variants. It shown Y453W F456L mutations can enhance when coupled Q493 while these become destabilized R493 position variant. provided rationale mechanism variants, showing role Q493/R493 hotspot modulating between sites L455F lineages. receptors antibodies provide experimental evidence interactions physically proximal Y501, R498, Q493, L455F, determine binding, F486P instrumental mediating broad resistance. supports which impact on is mediated through small group universal hotspots, effect immune could be more variant-dependent modulated by conformationally adaptable regions.

Язык: Английский

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

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Сен. 4, 2023

Abstract The recently identified SARS-CoV-2 variant, BA.2.86, which carries a substantial number of Spike mutations, has raised global alarm. An immediate assessment its antigenic properties and infectivity is necessary. Here, we reveal the distinct antigenicity BA.2.86 compared with previous variants including XBB.1.5. significantly evades convalescent plasma from XBB breakthrough infection (BTI) reinfections. Key mutations that mediate enhanced resistance include N450D, K356T, L452W, A484K, V483del, V445H on RBD, while BA.2.86’s NTD E554K SD1 also largely contribute. However, found pseudovirus exhibits compromised efficiency infecting HEK293T-hACE2 cells to XBB.1.5 EG.5, may be caused by E554K, could potentially limit transmissibility. In sum, it appears traded for higher immune evasion during long-term host-viral evolution. Close attention should paid monitoring additional improve infectivity.

Язык: Английский

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Subsequent Waves of Convergent Evolution in SARS-CoV-2 Genes and Proteins

Vaccines, Год журнала: 2024, Номер 12(8), С. 887 - 887

Опубликована: Авг. 5, 2024

Beginning in 2022, following widespread infection and vaccination among the global population, SARS-CoV-2 virus mainly evolved to evade immunity derived from vaccines past infections. This review covers convergent evolution of structural, nonstructural, accessory proteins SARS-CoV-2, with a specific look at common mutations found long-lasting infections that hint potentially reverting an enteric sarbecovirus type.

Язык: Английский

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Deep mutational scans of XBB.1.5 and BQ.1.1 reveal ongoing epistatic drift during SARS-CoV-2 evolution

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Сен. 12, 2023

Substitutions that fix between SARS-CoV-2 variants can transform the mutational landscape of future evolution via epistasis. For example, large epistatic shifts in effects caused by N501Y underlied original emergence Omicron variants, but whether such saltations continue to define ongoing remains unclear. We conducted deep scans measure impacts all single amino acid mutations and single-codon deletions spike receptor-binding domain (RBD) on ACE2-binding affinity protein expression recent BQ.1.1 XBB.1.5 we compared patterns earlier viral strains have previously profiled. As with previous RBD scans, find many are tolerated or even enhance binding ACE2 receptor. The tolerance sites deletion largely conforms mutation. Though not yet been seen dominant lineages, observe including at positions exhibit indel variation across broader sarbecovirus emerging interest, most notably well-tolerated Δ483 BA.2.86. substitutions distinguish induced as dramatic perturbations N501Y, identify drift interaction R493Q reversions 453, 455, 456, like F456L newly EG.5 lineage. Our results highlight due epistasis, which may direct into new regions sequence space.

Язык: Английский

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Bayesian phylogenetics on globally emerging SARS-CoV-2 variant BA.2.86 suggest global distribution and rapid evolution

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Сен. 11, 2023

Abstract Using bioinformatic pipelines and Bayseian phylogenetic analyses, we characterized a SARS-CoV-2 variant designated by the World Health Organization as under monitoring in August 2023. Here analyze genomes of this variant, BA.2.86, deposited into GISAID within two weeks its emergence (2023-08-14 first submission to 2023-08-31), including BA.2.86 genome reported from traveler originating Japan. We present bioinformatics methods using publicly available tools help analysts identify lineage-defining 12 nucleotide insertion (S:Ins16MPLF), which is often masked most pipelines. also applied maximum-likelihood Bayesian phylogenetics demonstrate high mutational rate tree branch leading hinting at possible origins, predict that emerged around May 2023 spread globally rapidly. Taken together, these results provide framework for more rigorous approaches teams performing genomic surveillance on viral respiratory pathogens.

Язык: Английский

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