Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients

Joseph F Standing; Laura Buggiotti; Jose Afonso Guerra-Assuncao; Maximillian Woodall; Samuel Ellis; Akosua A Agyeman; Charles Miller; Mercy Okechukwu; Emily Kirkpatrick; Amy I Jacobs; Charlotte A Williams; Sunando Roy; Luz M Martin-Bernal; Rachel Williams; Claire M Smith; Theo Sanderson; Fiona B Ashford; Beena Emmanuel; Zaheer M Afzal; Adrian Shields; Alex G Richter; Jienchi Dorward; Oghenekome Gbinigie; Oliver Van Hecke; Mark Lown; Nick Francis; Bhautesh Jani; Duncan B Richards; Najib M Rahman; Ly-Mee Yu; Nicholas P B Thomas; Nigel D Hart; Philip Evans; Monique Andersson; Gail Hayward; Kerenza Hood; Jonathan S Nguyen-Van-Tam; Paul Little; F D Richard Hobbs; Saye Khoo; Christopher Butler; David M Lowe; Judith Breuer; PANORAMIC Virology Group

doi:10.1038/s41467-024-45641-0

Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients

Nat Commun. 2024 Feb 23;15(1):1652. doi: 10.1038/s41467-024-45641-0.

Authors

Joseph F Standing^{1

2}, Laura Buggiotti³, Jose Afonso Guerra-Assuncao³, Maximillian Woodall³, Samuel Ellis³, Akosua A Agyeman³, Charles Miller⁴, Mercy Okechukwu³, Emily Kirkpatrick³, Amy I Jacobs³, Charlotte A Williams⁵, Sunando Roy⁵, Luz M Martin-Bernal⁵, Rachel Williams⁵, Claire M Smith³, Theo Sanderson⁶, Fiona B Ashford⁷, Beena Emmanuel⁷, Zaheer M Afzal⁷, Adrian Shields⁷, Alex G Richter⁷, Jienchi Dorward^{8

9}, Oghenekome Gbinigie⁸, Oliver Van Hecke⁸, Mark Lown¹⁰, Nick Francis¹⁰, Bhautesh Jani¹¹, Duncan B Richards¹², Najib M Rahman¹³, Ly-Mee Yu⁸, Nicholas P B Thomas¹⁴, Nigel D Hart¹⁵, Philip Evans^{16

17}, Monique Andersson¹⁸, Gail Hayward⁸, Kerenza Hood¹⁹, Jonathan S Nguyen-Van-Tam²⁰, Paul Little¹⁰, F D Richard Hobbs⁸, Saye Khoo²¹, Christopher Butler⁸, David M Lowe^#^{22

23}, Judith Breuer^#^{3

4}; PANORAMIC Virology Group

Collaborators

PANORAMIC Virology Group:
Julie Allen, Nadua Bayzid, Julianne Brown, Doug Burns, Elizabeth Hadley, Jim Hatcher, Tim McHugh, Chris Thalasselis, Mia Tomlinson, Francis Yongblah

Affiliations

¹ Infection, Immunity and Inflammation, Great Ormond Street Institute of Child Health, University College London, London, UK. j.standing@ucl.ac.uk.
² Great Ormond Street Hospital for Children NHS Trust, London, UK. j.standing@ucl.ac.uk.
³ Infection, Immunity and Inflammation, Great Ormond Street Institute of Child Health, University College London, London, UK.
⁴ Great Ormond Street Hospital for Children NHS Trust, London, UK.
⁵ Genetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London, UK.
⁶ Francis Crick Institute, London, UK.
⁷ Clinical Immunology Service, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
⁸ Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
⁹ Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.
¹⁰ Primary Care Research Centre, University of Southampton, Southampton, UK.
¹¹ School of Health and Wellbeing, University of Glasgow, Glasgow, UK.
¹² Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
¹³ Respiratory Trials Unit and Oxford NIHR Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹⁴ Windrush Medical Practice, Witney, UK.
¹⁵ School of Medicine, Dentistry and Biomedical Sciences. Queen's University Belfast, Belfast, UK.
¹⁶ APEx (Exeter Collaboration for Academic Primary Care), University of Exeter Medical School, Exeter, UK.
¹⁷ National Institute of Health and Care Research, Clinical Research Network, University of Leeds, Leeds, UK.
¹⁸ Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
¹⁹ Centre for Trials Research, Cardiff University, Wales, UK.
²⁰ Lifespan and Population Health, University of Nottingham School of Medicine, Nottingham, UK.
²¹ Department of Pharmacology, University of Liverpool and Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.
²² Department of Clinical Immunology, Royal Free London NHS Foundation Trust, London, UK.
²³ Institute of Immunity and Transplantation, University College London, London, UK.

^# Contributed equally.

Abstract

Viral clearance, antibody response and the mutagenic effect of molnupiravir has not been elucidated in at-risk populations. Non-hospitalised participants within 5 days of SARS-CoV-2 symptoms randomised to receive molnupiravir (n = 253) or Usual Care (n = 324) were recruited to study viral and antibody dynamics and the effect of molnupiravir on viral whole genome sequence from 1437 viral genomes. Molnupiravir accelerates viral load decline, but virus is detectable by Day 5 in most cases. At Day 14 (9 days post-treatment), molnupiravir is associated with significantly higher viral persistence and significantly lower anti-SARS-CoV-2 spike antibody titres compared to Usual Care. Serial sequencing reveals increased mutagenesis with molnupiravir treatment. Persistence of detectable viral RNA at Day 14 in the molnupiravir group is associated with higher transition mutations following treatment cessation. Viral viability at Day 14 is similar in both groups with post-molnupiravir treated samples cultured up to 9 days post cessation of treatment. The current 5-day molnupiravir course is too short. Longer courses should be tested to reduce the risk of potentially transmissible molnupiravir-mutated variants being generated. Trial registration: ISRCTN30448031.

Publication types

Randomized Controlled Trial

MeSH terms

Adult
Antibodies, Viral
Antibody Formation
Antiviral Agents / therapeutic use
COVID-19*
Cytidine / analogs & derivatives*
Humans
Hydroxylamines*
Outpatients
SARS-CoV-2* / genetics

Substances

molnupiravir
Antibodies, Viral
Antiviral Agents
Cytidine
Hydroxylamines

Abstract

Publication types

MeSH terms

Substances

Grants and funding