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

Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial
Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial
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.
Antiviral Agents/pharmacology, COVID-19/drug therapy, Genomics, Humans, SARS-CoV-2/genetics
2041-1723
Donovan-Banfield, I'ah
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Penrice-Randal, Rebekah
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Goldswain, Hannah
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Rzeszutek, Aleksandra M
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Pilgrim, Jack
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Bullock, Katie
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Saunders, Geoffrey
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Northey, Josh
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Dong, Xiaofeng
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Ryan, Yan
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Reynolds, Helen
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Tetlow, Michelle
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Walker, Lauren E
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FitzGerald, Richard
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Hale, Colin
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Lyon, Rebecca
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Woods, Christie
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Ahmad, Shazaad
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Hadjiyiannakis, Dennis
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Periselneris, Jimstan
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Knox, Emma
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Middleton, Calley
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Lavelle-Langham, Lara
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Shaw, Victoria
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Greenhalf, William
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Edwards, Thomas
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Lalloo, David G
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Edwards, Christopher J
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Darby, Alistair C
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Carroll, Miles W
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Griffiths, Gareth
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Khoo, Saye H
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Hiscox, Julian A
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Fletcher, Thomas
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Donovan-Banfield, I'ah
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Penrice-Randal, Rebekah
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Goldswain, Hannah
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Rzeszutek, Aleksandra M
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Pilgrim, Jack
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Bullock, Katie
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Saunders, Geoffrey
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Northey, Josh
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Dong, Xiaofeng
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Ryan, Yan
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Reynolds, Helen
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Tetlow, Michelle
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Walker, Lauren E
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FitzGerald, Richard
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Hale, Colin
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Lyon, Rebecca
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Woods, Christie
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Ahmad, Shazaad
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Hadjiyiannakis, Dennis
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Periselneris, Jimstan
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Knox, Emma
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Middleton, Calley
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Lavelle-Langham, Lara
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Shaw, Victoria
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Greenhalf, William
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Edwards, Thomas
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Lalloo, David G
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Edwards, Christopher J
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Darby, Alistair C
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Carroll, Miles W
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Griffiths, Gareth
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Khoo, Saye H
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Hiscox, Julian A
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Fletcher, Thomas
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Donovan-Banfield, I'ah, Penrice-Randal, Rebekah, Goldswain, Hannah, Rzeszutek, Aleksandra M, Pilgrim, Jack, Bullock, Katie, Saunders, Geoffrey, Northey, Josh, Dong, Xiaofeng, Ryan, Yan, 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, Thomas, Lalloo, David G, Edwards, Christopher J, Darby, Alistair C, Carroll, Miles W, Griffiths, Gareth, Khoo, Saye H, Hiscox, Julian A 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]. (doi:10.1038/s41467-022-34839-9).

Record type: Article

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.

Text
s41467-022-34839-9
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More information

Accepted/In Press date: 9 November 2022
Published date: 26 November 2022
Additional Information: © 2022. The Author(s).
Keywords: Antiviral Agents/pharmacology, COVID-19/drug therapy, Genomics, Humans, SARS-CoV-2/genetics

Identifiers

Local EPrints ID: 472895
URI: http://eprints.soton.ac.uk/id/eprint/472895
ISSN: 2041-1723
PURE UUID: 51651432-a621-4bab-8538-f914adb1555b
ORCID for Gareth Griffiths: ORCID iD orcid.org/0000-0002-9579-8021

Catalogue record

Date deposited: 05 Jan 2023 17:54
Last modified: 06 Jun 2024 01:53

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Contributors

Author: I'ah Donovan-Banfield
Author: Rebekah Penrice-Randal
Author: Hannah Goldswain
Author: Aleksandra M Rzeszutek
Author: Jack Pilgrim
Author: Katie Bullock
Author: Geoffrey Saunders
Author: Josh Northey
Author: Xiaofeng Dong
Author: Yan Ryan
Author: Helen Reynolds
Author: Michelle Tetlow
Author: Lauren E Walker
Author: Richard FitzGerald
Author: Colin Hale
Author: Rebecca Lyon
Author: Christie Woods
Author: Shazaad Ahmad
Author: Dennis Hadjiyiannakis
Author: Jimstan Periselneris
Author: Emma Knox
Author: Calley Middleton
Author: Lara Lavelle-Langham
Author: Victoria Shaw
Author: William Greenhalf
Author: Thomas Edwards
Author: David G Lalloo
Author: Christopher J Edwards
Author: Alistair C Darby
Author: Miles W Carroll
Author: Saye H Khoo
Author: Julian A Hiscox
Author: Thomas Fletcher

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