{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T07:02:26Z","timestamp":1772953346573,"version":"3.50.1"},"reference-count":18,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,11,26]],"date-time":"2022-11-26T00:00:00Z","timestamp":1669420800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,11,26]],"date-time":"2022-11-26T00:00:00Z","timestamp":1669420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C18616\/A25153"],"award-info":[{"award-number":["C18616\/A25153"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000038","name":"U.S. Department of Health & Human Services | U.S. Food and Drug Administration","doi-asserted-by":"publisher","award":["75F40120C00085"],"award-info":[{"award-number":["75F40120C00085"]}],"id":[{"id":"10.13039\/100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000038","name":"U.S. Department of Health & Human Services | U.S. Food and Drug Administration","doi-asserted-by":"publisher","award":["75F40120C00085"],"award-info":[{"award-number":["75F40120C00085"]}],"id":[{"id":"10.13039\/100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000038","name":"U.S. Department of Health & Human Services | U.S. Food and Drug Administration","doi-asserted-by":"publisher","award":["75F40120C00085"],"award-info":[{"award-number":["75F40120C00085"]}],"id":[{"id":"10.13039\/100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000038","name":"U.S. Department of Health & Human Services | U.S. Food and Drug Administration","doi-asserted-by":"publisher","award":["75F40120C00085"],"award-info":[{"award-number":["75F40120C00085"]}],"id":[{"id":"10.13039\/100000038","id-type":"DOI","asserted-by":"publisher"}]},{"name":"U.S. Department of Health & Human Services | U.S. Food and Drug Administration"},{"DOI":"10.13039\/501100000265","name":"RCUK | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/V028391\/1"],"award-info":[{"award-number":["MR\/V028391\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"RCUK | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/W005611\/1"],"award-info":[{"award-number":["MR\/W005611\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["221590\/Z\/20\/Z"],"award-info":[{"award-number":["221590\/Z\/20\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"name":"U.S. Department of Health & Human Services | U.S. Food and Drug Administration"},{"DOI":"10.13039\/501100000272","name":"DH | National Institute for Health Research","doi-asserted-by":"publisher","award":["200907"],"award-info":[{"award-number":["200907"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"DH | National Institute for Health Research","doi-asserted-by":"publisher","award":["200907"],"award-info":[{"award-number":["200907"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"name":"U.S. Department of Health & Human Services | U.S. Food and Drug Administration"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    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)\u22122 (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                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200959 for molnupiravir and\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200965 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.\n                  <\/jats:p>","DOI":"10.1038\/s41467-022-34839-9","type":"journal-article","created":{"date-parts":[[2022,11,26]],"date-time":"2022-11-26T20:24:43Z","timestamp":1669494283000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial"],"prefix":"10.1038","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5124-2427","authenticated-orcid":false,"given":"I\u2019ah","family":"Donovan-Banfield","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0653-2097","authenticated-orcid":false,"given":"Rebekah","family":"Penrice-Randal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4194-8714","authenticated-orcid":false,"given":"Hannah","family":"Goldswain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksandra 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Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat. Struct. Mol. Biol. 28, 740\u2013746 (2021).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"34839_CR2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20542-0","volume":"12","author":"G Kokic","year":"2021","unstructured":"Kokic, G. et al. Mechanism of SARS-CoV-2 polymerase stalling by remdesivir. Nat. Commun. 12, 279 (2021).","journal-title":"Nat. Commun."},{"key":"34839_CR3","doi-asserted-by":"crossref","unstructured":"Gordon, C. J., Tchesnokov, E. P., Schinazi, R. F. & G\u00f6tte, M. Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template. J. Biol. Chem. 297, 100770 (2021).","DOI":"10.1016\/j.jbc.2021.100770"},{"key":"34839_CR4","doi-asserted-by":"crossref","unstructured":"Sheahan, T. P. et al. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci. Transl. 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AGILE-ACCORD: a randomized, multicentre, seamless, adaptive phase I\/II platform study to determine the optimal dose, safety and efficacy of multiple candidate agents for the treatment of COVID-19: a structured summary of a study protocol for a randomised platform trial. Trials 21, 544 (2020).","journal-title":"Trials"},{"key":"34839_CR8","doi-asserted-by":"publisher","first-page":"3286","DOI":"10.1093\/jac\/dkab318","volume":"76","author":"SH Khoo","year":"2021","unstructured":"Khoo, S. H. et al. Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study. J. Antimicrob. Chemother. 76, 3286\u20133295 (2021).","journal-title":"J. Antimicrob. Chemother."},{"key":"34839_CR9","doi-asserted-by":"publisher","unstructured":"Khoo, S. H. et al. Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Infect. Dis. S1473-3099(22)00644-2. https:\/\/doi.org\/10.1016\/S1473-3099(22)00644-2. Epub ahead of print. (2022).","DOI":"10.1016\/S1473-3099(22)00644-2"},{"key":"34839_CR10","doi-asserted-by":"publisher","first-page":"e66857","DOI":"10.7554\/eLife.66857","volume":"10","author":"G Tonkin-Hill","year":"2021","unstructured":"Tonkin-Hill, G. et al. Patterns of within-host genetic diversity in SARS-CoV-2. Elife 10, e66857 (2021).","journal-title":"Elife"},{"key":"34839_CR11","first-page":"e01348","volume":"93","author":"L Agostini Maria","year":"2019","unstructured":"Agostini Maria, L. et al. Small-molecule antiviral \u03b2-d-N4-hydroxycytidine inhibits a proofreading-intact coronavirus with a high genetic barrier to resistance. J. Virol. 93, e01348\u201301319 (2019).","journal-title":"J. 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Euro Surveill. 22, 30494 (2017).","DOI":"10.2807\/1560-7917.ES.2017.22.13.30494"},{"key":"34839_CR15","doi-asserted-by":"publisher","first-page":"104993","DOI":"10.1016\/j.jcv.2021.104993","volume":"144","author":"JPM Coolen","year":"2021","unstructured":"Coolen, J. P. M. et al. SARS-CoV-2 whole-genome sequencing using reverse complement PCR: For easy, fast and accurate outbreak and variant analysis. J. Clin. Virol. 144, 104993 (2021).","journal-title":"J. Clin. Virol."},{"key":"34839_CR16","doi-asserted-by":"crossref","unstructured":"O\u2019Toole, \u00c1. et al. Assignment of epidemiological lineages in an emerging pandemic using the pangolin tool. Virus Evol. 7, veab064 (2021).","DOI":"10.1093\/ve\/veab064"},{"key":"34839_CR17","first-page":"e00913","volume":"0","author":"T Prince","year":"2022","unstructured":"Prince, T. et al. Analysis of SARS-CoV-2 in nasopharyngeal samples from patients with COVID-19 illustrates population variation and diverse phenotypes, placing the growth properties of variants of concern in context with other lineages. mSphere\u00a07, e00913\u2013e00921 (2022).","journal-title":"mSphere"},{"key":"34839_CR18","doi-asserted-by":"publisher","unstructured":"Donovan-Banfield, I. et al. Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial. Hiscox-lab\/AGILE-molnupiravir-viral-genomics: manuscript repository (v1.0). Zenodo https:\/\/doi.org\/10.5281\/zenodo.7245793 (2022).","DOI":"10.5281\/zenodo.7245793"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-022-34839-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-022-34839-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-022-34839-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,27]],"date-time":"2022-11-27T06:29:09Z","timestamp":1669530549000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-022-34839-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,26]]},"references-count":18,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["34839"],"URL":"https:\/\/doi.org\/10.1038\/s41467-022-34839-9","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-1835695\/v1","asserted-by":"object"}]},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,26]]},"assertion":[{"value":"26 September 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 November 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 November 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"SHK has received research funding from ViiV Healthcare and Merck for the Liverpool HIV Drug Interactions programme and for unrelated clinical studies. GG has received funding from Janssen-Cilag, AstraZeneca, Novartis, Astex, Roche, Heartflow, Celldex, BMS, BionTech, Cancer Research UK, the NIHR, the British Lung Foundation, Unitaid, and GSK for unrelated academic clinical trials and programme funding. WG has received funding from the Wellcome Trust. JP (Periselneris) has received honoraria for lectures from Gilead and London International Patient Services UK. JAH, ACD, MWC and TF have received research funding from the US Food and Drug Administration. TE has received unrelated research funding from the Medical Research Council, the Wellcome Trust, and Bloomsbury SET and travel grants from the European Society of Clinical Microbiology and Infectious Diseases. All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The study protocol was reviewed and approved by the UK Medicines and Healthcare product Regulatory Agency (MHRA) (EudraCT 2020-001860-27) and West Midlands Edgbaston Research Ethics Committee (20\/WM\/0136).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"All participants provided written informed consent before enrolment.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}],"article-number":"7284"}}