Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial

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Donovan-Banfield, I'ah ORCID: 0000-0002-5124-2427, Penrice-Randal, Rebekah ORCID: 0000-0002-0653-2097, Goldswain, Hannah ORCID: 0000-0003-4194-8714, Rzeszutek, Aleksandra M, Pilgrim, Jack ORCID: 0000-0002-2941-1482, Bullock, Katie ORCID: 0000-0002-5758-0179, Saunders, Geoffrey, Northey, Josh, Dong, Xiaofeng, Ryan, Yan et al (show 24 more authors) , Reynolds, Helen ORCID: 0000-0001-7443-4520, Tetlow, Michelle, Walker, Lauren E ORCID: 0000-0002-3827-4387, FitzGerald, Richard, Hale, Colin, Lyon, Rebecca, Woods, Christie, Ahmad, Shazaad, Hadjiyiannakis, Dennis, Periselneris, Jimstan, Knox, Emma, Middleton, Calley, Lavelle-Langham, Lara, Shaw, Victoria ORCID: 0000-0002-0429-0186, Greenhalf, William ORCID: 0000-0002-1865-3195, Edwards, Thomas, Lalloo, David G, Edwards, Christopher J, Darby, Alistair C ORCID: 0000-0002-3786-6209, Carroll, Miles W, Griffiths, Gareth, Khoo, Saye H ORCID: 0000-0002-2769-0967, Hiscox, Julian A ORCID: 0000-0002-6582-0275 and Fletcher, Thomas (2022) Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial NATURE COMMUNICATIONS, 13 (1). 7284-. ISSN 2041-1723, 2041-1723

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Abstract

Molnupiravir 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.

Item Type:	Article
Uncontrolled Keywords:	Humans, Hydroxylamines, Cytidine, Antiviral Agents, Genomics, SARS-CoV-2, COVID-19 Drug Treatment
Divisions:	Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Infection, Vet & Ecological Sciences Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	30 Nov 2022 12:20
Last Modified:	16 Jun 2026 08:54
DOI:	10.1038/s41467-022-34839-9
Open Access URL:	https://doi.org/10.1038/s41467-022-34839-9
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3166454
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