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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Antibody Neutralization of Emerging SARS-CoV-2: EG.5.1 and XBC.1.6

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

Published: Aug. 22, 2023

Abstract SARS-CoV-2 variants EG.5.1 and XBC.1.6 have recently emerged, attracting increased attention due to their rapid expansion globally in Australia, respectively. evolved from Omicron subvariant XBB.1.9, harboring additional Q52H F456L spike substitutions. The mutation is located within the epitopes of many class-1 monoclonal antibodies (mAbs) directed receptor-binding domain (RBD), raising concerns about further antibody evasion. XBC.1.6, a descendant Delta-BA.2 recombinant, carries 15 mutations. extent which evasion contributes growth advantage Australia remains be determined. To assess properties emergent variants, we conducted pseudovirus neutralization assays using sera individuals who received three doses COVID-19 mRNA monovalent vaccines plus one dose BA.5 bivalent vaccine, as well patients with BQ or XBB breakthrough infection. were also performed panel 14 mAbs that retained neutralizing activity against prior subvariants. Our data suggested was slightly but significantly more resistant (< 2-fold) by than XBB.1.16, known antigenically similar XBB.1.5. Moreover, conferred heightened resistance certain RBD mAbs. In contrast, sensitive Notably, only weak summary, exhibited distinct properties. recent global might attributable, part, its enhanced resistance. That infections did not elicit robust response subvariants indicative immunological imprinting. high prevalence

Language: Английский

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Fitness models provide accurate short-term forecasts of SARS-CoV-2 variant frequency

PLoS Computational Biology, Journal Year: 2024, Volume and Issue: 20(9), P. e1012443 - e1012443

Published: Sept. 6, 2024

Genomic surveillance of pathogen evolution is essential for public health response, treatment strategies, and vaccine development. In the context SARS-COV-2, multiple models have been developed including Multinomial Logistic Regression (MLR) describing variant frequency growth as well Fixed Growth Advantage (FGA), Random Walk (GARW) Piantham parameterizations Rt. These provide estimates fitness can be used to forecast changes in frequency. We introduce a framework evaluating real-time forecasts frequencies, apply this SARS-CoV-2 during 2022 which new viral variants emerged rapidly spread through population. compare across representative countries with different intensities genomic surveillance. Retrospective assessment model accuracy highlights that most perform are able produce reasonable forecasts. find simple MLR provides ∼0.6% median absolute error ∼6% mean when forecasting 30 days out robust investigate impacts sequence quantity quality on conduct systematic downsampling identify 1000 sequences per week fully sufficient accurate short-term conclude represent useful prognostic tool evolutionary forecasting.

Language: Английский

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Contributions of Hyperactive Mutations in M^pro from SARS-CoV-2 to Drug Resistance

ACS Infectious Diseases, Journal Year: 2024, Volume and Issue: 10(4), P. 1174 - 1184

Published: March 12, 2024

The appearance and spread of mutations that cause drug resistance in rapidly evolving diseases, including infections by the SARS-CoV-2 virus, are major concerns for human health. Many drugs target enzymes, resistance-conferring impact inhibitor binding or enzyme activity. Nirmatrelvir, most widely used currently to treat infections, targets main protease (Mpro) preventing it from processing viral polyprotein into active subunits. Our previous work systematically analyzed Mpro reduce inhibitors; here, we investigate affect function. Hyperactive increase activity can contribute but have not been thoroughly studied. To explore how hyperactive resistance, comprehensively assessed all possible individual function using a mutational scanning approach with fluorescence resonance energy transfer (FRET)-based yeast readout. We identified hundreds significantly increased occurred both proximal distal site, consistent protein stability and/or dynamics impacting were observed 3 times more than which reduced apparent nirmatrelvir recent studies laboratory-grown viruses selected resistance. also about three prevalent sequenced isolates circulating SARS-CoV-2. findings indicate likely natural evolution provide comprehensive list future surveillance efforts.

Language: Английский

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Using big sequencing data to identify chronic SARS-Coronavirus-2 infections

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

Published: July 17, 2023

Abstract The evolution of SARS-Coronavirus-2 (SARS-CoV-2) has been characterized by the periodic emergence highly divergent variants, many which may have arisen during chronic infections immunocompromised individuals. Here, we harness a global phylogeny ∼11.7 million SARS-CoV-2 genomes and search for clades composed sequences with identical metadata (location, age, sex) spanning more than 21 days. We postulate that such represent repeated sampling from same chronically infected individual. A set 271 chronic-like was inferred, displayed signatures an elevated rate adaptive evolution, in line validated infections. More 70% mutations present currently circulating variants are found BA.1 predate months, demonstrating predictive nature clades. find probability observing is approximately 10-20 higher transmission chains. next employ language models to most use them infer hundreds additional absence phylogenetic information. Our proposed approach presents innovative method mining extensive sequencing data providing valuable insights into future evolutionary patterns.

Language: Английский

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

Vaccines, Journal Year: 2024, Volume and Issue: 12(8), P. 887 - 887

Published: Aug. 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.

Language: Английский

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Jointly modeling deep mutational scans identifies shifted mutational effects among SARS-CoV-2 spike homologs

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

Published: Aug. 2, 2023

Deep mutational scanning (DMS) is a high-throughput experimental technique that measures the effects of thousands mutations to protein. These experiments can be performed on multiple homologs protein or same selected under conditions. It often biological interest identify with shifted across However, it challenging determine if observed shifts arise from signal noise. Here, we describe method for jointly inferring DMS while also identifying have in their among experiments. A key aspect our regularize inferred shifts, so they are nonzero only when strongly supported by data. We apply this measure how spike proteins SARS-CoV-2 variants (Delta, Omicron BA.1, and BA.2) affect cell entry. Most conserved between these homologs, but fraction markedly shifted. experimentally validate subset effects, confirm differences > 1,000-fold impact mutation spike-mediated viral infection spikes different variants. Overall, work establishes general approach comparing sets biologically important effects.

Language: Английский

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Clonal Interference and Changing Selective Pressures Shape the Escape of Sars-Cov-2 from Hundreds of Antibodies

Published: Jan. 1, 2025

Language: Английский

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Towards Pandemic-Scale Ancestral Recombination Graphs of SARS-CoV-2

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

Published: June 8, 2023

Abstract Recombination is an ongoing and increasingly important feature of circulating lineages SARS-CoV-2, challenging how we represent the evolutionary history this virus giving rise to new variants potential public health concern by combining transmission immune evasion properties different lineages. Detection recombinant strains challenging, with most methods looking for breaks between sets mutations that characterise distinct In addition, many basic approaches fundamental study viral evolution assume recombination negligible, in a single phylogenetic tree can genetic ancestry strains. Here present initial version sc2ts, method automatically detect recombinants real time cohesively integrate them into genealogy form ancestral graph (ARG), which jointly records mutation, inheritance. We infer two ARGs under sampling strategies, their properties. One contains 1.27 million sequences sampled up June 30, 2021, second more sparsely sampled, consisting 657K 2022. find both are highly consistent known features SARS-CoV-2 evolution, recovering backbone phylogeny, mutational spectra, recapitulating details on majority Using well-established feature-rich tskit library, also be stored concisely processed efficiently using standard Python tools. For example, ARG sequences—encoding inferred reticulate ancestry, variation, extensive metadata—requires 58MB storage, loads less than second. The ability fully effects downstream analyses, quickly recombinants, utilise efficient convenient platform computation based well-engineered technologies makes sc2ts promising approach.

Language: Английский

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A comprehensive study of SARS-CoV-2 mfigain protease (Mpro) inhibitor-resistant mutants selected in a VSV-based system

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(9), P. e1012522 - e1012522

Published: Sept. 11, 2024

Nirmatrelvir was the first protease inhibitor specifically developed against SARS-CoV-2 main (3CLpro/Mpro) and licensed for clinical use. As continues to spread, variants resistant nirmatrelvir other currently available treatments are likely arise. This study aimed identify characterize mutations that confer resistance nirmatrelvir. To safely generate Mpro mutations, we passaged a previously developed, chimeric vesicular stomatitis virus (VSV-Mpro) with increasing, yet suboptimal concentrations of Using Wuhan-1 Omicron variants, selected large set mutants. Some frequently present in GISAID, suggesting their relevance SARS-CoV-2. The phenotype subset characterized clinically inhibitors (nirmatrelvir ensitrelvir) cell-based, biochemical replicon assays. Moreover, showed putative molecular mechanism based on silico modelling. These findings have implications development future generation inhibitors, will help understand mechanisms show specific thereby informing treatment decisions.

Language: Английский

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