Abstract: Article
https://doi.org/10.1038/s41467-024-45641-0
Randomized controlled trial of molnupiravir
SARS-CoV-2 viral and antibody response in
at-risk adult outpatients
Received: 4 August 2023
A list of authors and their affiliations appears at the end of the paper
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Accepted: 26 January 2024
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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
Treatment of SARS-CoV-2 with the nucleoside analogue molnupiravir
(MK4482, EIDD2801) was reported to reduce viral load, hospitalisation
and mortality in unvaccinated participants with early COVID-19 in the
MOVeOUT trial1,2. Based on these data, molnupiravir received emergency use authorisation in the UK in November 2021 for early treatment of SARS-CoV-2 in individuals deemed to be at higher risk of
complications due to age or underlying comorbidities.
Molnupiravir is metabolised intracellularly to NHC-triphosphate,
which competes with natural cytidine and uridine for incorporation by
the viral RNA-dependent RNA polymerase (RdRp) into the nascent viral
RNA. This leads to abnormal, non-Watson-Crick pairing with guanosine
and uridine in further rounds of replication, increasing the substitution
of adenosine for guanosine and cytosine for uridine, so-called transition mutations, within the SARS-CoV-2 genome. Lethal mutagenesis
resulting from treatment with RdRp inhibitors eventually leads to viral
extinction3,4. A distinctive pattern of transition mutagenesis is evident
in viral genomes recovered from animals and humans who have
received molnupiravir3–5. The risk that, following molnupiravir treatment, some highly mutated viruses might remain viable and capable of
onward transmission has been postulated6,7.
To measure the impact of molnupiravir in a largely vaccinated
population, the Platform Adaptive trial of NOvel antiviRals for eArly
treatMent of covid-19 In the Community (PANORAMIC) was established. The first drug tested in PANORAMIC was molnupiravir, and
amongst 25,783 mostly vaccinated individuals, found that molnupiravir did not reduce hospitalisation or death8 (primary endpoint). Secondary outcomes showed those receiving molnupiravir experienced
significantly reduced viral load during treatment and reported faster
symptom recovery and fewer general..
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'abstract': '<jats:title>Abstract</jats:title><jats:p>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\u2009'
'=\u2009253) or Usual Care (n\u2009=\u2009324) 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</jats:p>',
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'title': 'Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk '
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{ 'value': 'J.F.S. has participated on a data safety monitoring board for GlaxoSmithKline '
'(Sotrovimab) with fees paid to his institution. JSN-V-T was seconded to the '
'Department of Health and Social Care, England (DHSC) from October 2017–March '
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'Research (NIHR), received a grant from AstraZeneca (paid to their institution) '
'to support a trial of Evusheld for the prevention of COVID-19 in high-risk '
'individuals (RAPID-Protection), and was an independent member of the '
'independent data monitoring committee for the OCTAVE-DUO trial of vaccines in '
'individuals at high risk of COVID-19. D.M.L. has received grants or contracts '
'from LifeArc, the UK Medical Research Council, Bristol Myers Squibb, '
'GlaxoSmithKline, the British Society for Antimicrobial Chemotherapy, and Blood '
'Cancer UK, personal fees or honoraria from Biotest UK, Gilead, and Merck, '
'consulting fees from GlaxoSmithKline (paid to their institution), and '
'conference support from Octapharma. DBR has received consulting fees from OMASS '
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'in the Heal-COVID trial TMG. M.L. is a member of the data monitoring and ethics '
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'grants from GlaxoSmithKline, ViiV, Ridgeback Biotherapeutics, Vir, Merck, the '
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'institution), speaker’s honoraria from ViiV, and donations of drugs for '
'clinical studies from ViiV Healthcare, Toyama, and GlaxoSmithKline. M.A. has '
'received grants from the Blood and Transplant Research Unit, Janssen, Pfizer, '
'Prenetics, Dunhill Medical Trust, the BMA Trust (Kathleen Harper Fund), and '
'Antibiotic Research UK (all of which were paid to their institution), and '
'consultancy fees from Prenetics and OxDx. M.A. reports a planned patent for '
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'trial, and has an unpaid leadership or fiduciary role in the British Society of '
'Antimicrobial Chemotherapy. J.B. has received consulting fees from '
'GlaxoSmithKline (paid to her institution). All other authors declare no '
'competing interests.',
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