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

I’ah Donovan-Banfield, Rebekah Penrice-Randal, Hannah Goldswain, Aleksandra M. Rzeszutek, Jack Pilgrim, Katie Bullock, Geoffrey Saunders, Josh Northey, Xiaofeng Dong, Yan Ryan, Helen Reynolds, Michelle Tetlow, Lauren E. Walker, Richard FitzGerald, Colin Hale, Rebecca Lyon, Christie Woods, Shazaad Ahmad, Dennis Hadjiyiannakis, Jimstan Periselneris, Emma Knox, Calley Middleton, Lara Lavelle-Langham, Victoria Shaw, William Greenhalf, Thomas Edwards, David G. Lalloo, Christopher J. Edwards, Alistair C. Darby, Miles W. Carroll, Gareth Griffiths, Saye H. Khoo, Julian A. Hiscox () and Thomas Fletcher ()
Additional contact information
I’ah Donovan-Banfield: University of Liverpool
Rebekah Penrice-Randal: University of Liverpool
Hannah Goldswain: University of Liverpool
Aleksandra M. Rzeszutek: University of Liverpool
Jack Pilgrim: University of Liverpool
Katie Bullock: University of Liverpool
Geoffrey Saunders: University of Southampton
Josh Northey: University of Southampton
Xiaofeng Dong: University of Liverpool
Yan Ryan: University of Liverpool
Helen Reynolds: University of Liverpool
Michelle Tetlow: University of Liverpool
Lauren E. Walker: University of Liverpool
Richard FitzGerald: University of Liverpool
Colin Hale: NIHR Royal Liverpool and Broadgreen Clinical Research Facility, Liverpool University Hospitals NHS Foundation Trust
Rebecca Lyon: NIHR Royal Liverpool and Broadgreen Clinical Research Facility, Liverpool University Hospitals NHS Foundation Trust
Christie Woods: NIHR Royal Liverpool and Broadgreen Clinical Research Facility, Liverpool University Hospitals NHS Foundation Trust
Shazaad Ahmad: Manchester University NHS Foundation Trust
Dennis Hadjiyiannakis: Lancashire Teaching Hospitals NHS Foundation Trust
Jimstan Periselneris: King’s College Hospital NHS Foundation Trust
Emma Knox: University of Southampton
Calley Middleton: University of Southampton
Lara Lavelle-Langham: University of Liverpool
Victoria Shaw: University of Liverpool
William Greenhalf: University of Liverpool
Thomas Edwards: Liverpool School of Tropical Medicine
David G. Lalloo: Liverpool School of Tropical Medicine
Christopher J. Edwards: University of Southampton
Alistair C. Darby: University of Liverpool
Miles W. Carroll: NIHR Health Protection Research Unit in Emerging and Zoonotic Infections
Gareth Griffiths: University of Southampton
Saye H. Khoo: University of Liverpool
Julian A. Hiscox: University of Liverpool
Thomas Fletcher: NIHR Health Protection Research Unit in Emerging and Zoonotic Infections

Nature Communications, 2022, vol. 13, issue 1, 1-9

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34839-9

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