Author Correction: Development of a model-inference system for estimating epidemiological characteristics of SARS-CoV-2 variants of concern.
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ABSTRACT:
SUBMITTER: Yang W
PROVIDER: S-EPMC8675117 | biostudies-literature | 2021 Dec
REPOSITORIES: biostudies-literature
Publications
Author Correction: Development of a model-inference system for estimating epidemiological characteristics of SARS-CoV-2 variants of concern.
Nature communications 20211216 1
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Project description:To support COVID-19 pandemic planning, we develop a model-inference system to estimate epidemiological properties of new SARS-CoV-2 variants of concern using case and mortality data while accounting for under-ascertainment, disease seasonality, non-pharmaceutical interventions, and mass-vaccination. Applying this system to study three variants of concern, we estimate that B.1.1.7 has a 46.6% (95% CI: 32.3-54.6%) transmissibility increase but nominal immune escape from protection induced by prior wild-type infection; B.1.351 has a 32.4% (95% CI: 14.6-48.0%) transmissibility increase and 61.3% (95% CI: 42.6-85.8%) immune escape; and P.1 has a 43.3% (95% CI: 30.3-65.3%) transmissibility increase and 52.5% (95% CI: 0-75.8%) immune escape. Model simulations indicate that B.1.351 and P.1 could outcompete B.1.1.7 and lead to increased infections. Our findings highlight the importance of preventing the spread of variants of concern, via continued preventive measures, prompt mass-vaccination, continued vaccine efficacy monitoring, and possible updating of vaccine formulations to ensure high efficacy.
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Project description:The ongoing COVID-19 pandemic represents an unprecedented global health crisis. Here, we report the identification of a synthetic nanobody (sybody) pair, Sb#15 and Sb#68, that can bind simultaneously to the SARS-CoV-2 spike-RBD and efficiently neutralize pseudotyped and live-viruses by interfering with ACE2 interaction. Cryo-EM confirms that Sb#15 and Sb#68 engage two spatially-discrete epitopes, influencing rational design of bispecific and tri-bispecific fusion constructs that exhibit up to 100- and 1000-fold increase in neutralization potency, respectively. Cryo-EM of the sybody-spike complex additionally reveals a novel up-out RBD conformation. While resistant viruses emerge rapidly in the presence of single binders, no escape variants are observed in presence of the bispecific sybody. The multivalent bispecific constructs further increase the neutralization potency against globally-circulating SARS-CoV-2 variants of concern. Our study illustrates the power of multivalency and biparatopic nanobody fusions for the potential development of therapeutic strategies that mitigate the emergence of new SARS-CoV-2 escape mutants.
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Project description:The spread of the current Sars-Cov-2 pandemics leads to the development of mutations that are constantly monitored because they could affect the efficacy of vaccines. Three recently identified mutated strains, known as variants of concern, are rapidly spreading worldwide. Here, we study possible effects of these mutations on the immune response to Sars-Cov-2 infection using NetTepi a computational method based on artificial neural networks that considers binding and stability of peptides obtained by proteasome degradation for widely represented HLA class I alleles present in human populations as well as the T-cell propensity of viral peptides that measures their immune response. Our results show variations in the number of potential highly ranked peptides ranging between 0 and 20% depending on the specific HLA allele. The results can be useful to design more specific vaccines.
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Project description:A key feature of RNA viruses, including SARS-CoV-2, is their high mutation rate, which allows them to develop resistance to vaccines and antiviral drugs targeting viral proteins. To overcome this downside, a strategy would be to target host factors, i.e. cell proteins required by the virus for its replication. However, it is still unclear whether cell responses induced by different SARS-CoV-2 variants are conserved and if the same core of host factors is exploited by different variants. We compared 3 variants of concern (VOC) that emerged during the first year of the pandemic and observed that the host transcriptional response was mostly conserved, differing only in the kinetics and magnitude. By CRISPR screening we identified the host genes required for infection by each VOC. These genes were associated with interferon and JAK/STAT pathway, autophagy, mTOR pathway, mitochondrial organisation and activity. Crucially, we failed to identify genes required by only one variant. We further validated our candidates with small molecules and repurposed FDA-approved drugs, which were effective against a novel variant emerged during the course of the study. We observed that SARS-CoV-2 infection induces a rapid spike in Reactive Oxygen Species (ROS) production, which can be targeted to block viral propagation. Our study identifies a core of host genes required for infection, and lays the foundation for general therapeutic strategies aimed at minimising emergence of novel resistant variants.
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Project description:The global spread of SARS-CoV-2 lead to the most challenging pandemic in this century, posing major economic and health challenges worldwide. Revealing host genes essential for infection by multiple variants of SARS-CoV-2 can provide insights into the virus pathogenesis, and facilitates the development of novel broad-spectrum host-directed therapeutics. Here, employing genome-scale CRISPR screens, we provide a comprehensive data-set of cellular factors that are exploited by WT-SARS-CoV-2 as well as two additional recently emerged variants of concerns (VOCs), Alpha and Beta. These screens identified known and novel host factors critical for SARS-CoV-2 infection, including various components belonging to the Clathrin-dependent transport pathway, ubiquitination and Heparan sulfate biogenesis. In addition, the host phosphatidylglycerol biosynthesis processes appeared to have major anti-viral functions. Comparative analysis of the different VOCs revealed the host factors KREMEN2 and SETDB1 as potential unique candidates required only to the Alpha variant, providing a possible explanation for the increased infectivity of this variant. Furthermore, the analysis identified GATA6, a zinc finger transcription factor, as an essential pro-viral gene for all variants inspected. We revealed that GATA6 directly regulates ACE2 transcription and accordingly, is critical for SARS-CoV-2 cell entry. Analysis of clinical samples collected from SARS-CoV-2 infected individuals showed an elevated level of GATA6, indicating the important role GATA6 may be playing in COVID-19 pathogenesis. Finally, pharmacological inhibition of GATA6 resulted in down-modulation of ACE2 and consequently to inhibition of the viral infectivity. Overall, we show GATA6 represents a target for the development of anti-SARS-CoV-2 therapeutic strategies and reaffirm the value of the CRISPR loss-of-function screens in providing a list of potential new targets for therapeutic interventions.
2022-03-27 | GSE197962 | GEO
Project description:An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Project description:Viral reproduction of SARS-CoV-2 provides opportunities for the acquisition of advantageous mutations, altering viral transmissibility, disease severity, and/or allowing escape from natural or vaccine-derived immunity. We use three mathematical models: a parsimonious deterministic model with homogeneous mixing; an age-structured model; and a stochastic importation model to investigate the effect of potential variants of concern (VOCs). Calibrating to the situation in England in May 2021, we find epidemiological trajectories for putative VOCs are wide-ranging and dependent on their transmissibility, immune escape capability, and the introduction timing of a postulated VOC-targeted vaccine. We demonstrate that a VOC with a substantial transmission advantage over resident variants, or with immune escape properties, can generate a wave of infections and hospitalisations comparable to the winter 2020-2021 wave. Moreover, a variant that is less transmissible, but shows partial immune-escape could provoke a wave of infection that would not be revealed until control measures are further relaxed.
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