Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial
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Published:2022-11-26
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Donovan-Banfield I’ahORCID, Penrice-Randal RebekahORCID, Goldswain HannahORCID, Rzeszutek Aleksandra M., Pilgrim Jack, Bullock Katie, Saunders Geoffrey, Northey Josh, Dong Xiaofeng, Ryan YanORCID, Reynolds Helen, Tetlow Michelle, Walker Lauren E., FitzGerald Richard, Hale Colin, Lyon Rebecca, Woods Christie, Ahmad Shazaad, Hadjiyiannakis Dennis, Periselneris Jimstan, Knox Emma, Middleton Calley, Lavelle-Langham Lara, Shaw Victoria, Greenhalf William, Edwards ThomasORCID, Lalloo David G.ORCID, Edwards Christopher J., Darby Alistair C., Carroll Miles W., Griffiths Gareth, Khoo Saye H., Hiscox Julian A.ORCID, Fletcher Thomas
Abstract
AbstractMolnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that induces lethal error catastrophe in SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. To investigate this, we used samples from the AGILE Candidate Specific Trial (CST)−2 (clinical trial number NCT04746183). The primary outcomes of AGILE CST-2 were to measure the drug safety and antiviral efficacy of molnupiravir in humans (180 participants randomised 1:1 with placebo). Here, we describe the pre-specified exploratory virological endpoint of CST-2, which was to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment. We use high-throughput amplicon sequencing and minor variant analysis to characterise viral genomics in each participant whose longitudinal samples (days 1, 3 and 5 post-randomisation) pass the viral genomic quality criteria (n = 59 for molnupiravir and n = 65 for placebo). Over the course of treatment, no specific mutations were associated with molnupiravir treatment. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatment-emergent adaptations.
Funder
Cancer Research UK U.S. Department of Health & Human Services | U.S. Food and Drug Administration RCUK | Medical Research Council Wellcome Trust DH | National Institute for Health Research
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference18 articles.
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