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Basic Characteristics of Mutations
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Mutation Site
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G22894T |
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Mutation Site Sentence
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11 showed a de novo S:K444N mutation (due to G22894T) at day 7 (53% prevalence of the quasispecies) associated with an increase in the RT-PCR cycle threshold from 16 to 22. |
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Mutation Level
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Nucleotide level |
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Mutation Type
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Nonsynonymous substitution |
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Gene/Protein/Region
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S |
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Standardized Encoding Gene
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S
|
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Genotype/Subtype
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BA.4.*;BA.5.* |
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Viral Reference
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-
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Functional Impact and Mechanisms
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Disease
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COVID-19
|
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Immune
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- |
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Target Gene
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-
|
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Clinical and Epidemiological Correlations
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Clinical Information
|
Y |
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Treatment
|
cilgavimab |
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Location
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Italy |
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Literature Information
|
|
PMID
|
37892220
|
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Title
|
Treatment-Emergent Cilgavimab Resistance Was Uncommon in Vaccinated Omicron BA.4/5 Outpatients
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Author
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Gruber CEM,Tucci FG,Rueca M,Mazzotta V,Gramigna G,Vergori A,Fabeni L,Berno G,Giombini E,Butera O,Focosi D,Prandi IG,Chillemi G,Nicastri E,Vaia F,Girardi E,Antinori A,Maggi F
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Journal
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Biomolecules
|
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Journal Info
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2023 Oct 18;13(10):1538
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Abstract
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Mutations in the SARS-CoV-2 Spike glycoprotein can affect monoclonal antibody efficacy. Recent findings report the occurrence of resistant mutations in immunocompromised patients after tixagevimab/cilgavimab treatment. More recently, the Food and Drug Agency revoked the authorization for tixagevimab/cilgavimab, while this monoclonal antibody cocktail is currently recommended by the European Medical Agency. We retrospectively reviewed 22 immunocompetent patients at high risk for disease progression who received intramuscular tixagevimab/cilgavimab as early COVID-19 treatment and presented a prolonged high viral load. Complete SARS-CoV-2 genome sequences were obtained for a deep investigation of mutation frequencies in Spike protein before and during treatment. At seven days, only one patient showed evidence of treatment-emergent cilgavimab resistance. Quasispecies analysis revealed two different deletions on the Spike protein (S:del138-144 or S:del141-145) in combination with the resistance S:K444N mutation. The structural and dynamic impact of the two quasispecies was characterized by using molecular dynamics simulations, showing the conservation of the principal functional movements in the mutated systems and their capabilities to alter the structure and dynamics of the RBD, responsible for the interaction with the ACE2 human receptor. Our study underlines the importance of prompting an early virological investigation to prevent drug resistance or clinical failures in immunocompetent patients.
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Sequence Data
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-
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