Identification of a molnupiravir-associated mutational signature in SARS-CoV-2 sequencing databases
Sanderson et al.
, Identification of a molnupiravir-associated mutational signature in SARS-CoV-2 sequencing databases
, medRxiv, doi:10.1101/2023.01.26.23284998 (Preprint)
Identification of SARS-CoV-2 variants likely to have been created by molnupiravir treatment. Authors find a class of long phylogenetic branches almost exclusively matching the time period, location, and age groups of widespread molnupiravir treatment.Concerns have been raised that the mutagenic mechanism of action may create dangerous variants or cause cancer [Hadj Hassine, Swanstrom]. See [Fountain-Jones, Sanderson, ] for analysis of variants potentially created by molnupiravir.
Sanderson et al., 27 Jan 2023, preprint, 5 authors.
email@example.com (corresponding author), firstname.lastname@example.org.
Abstract: medRxiv preprint doi: https://doi.org/10.1101/2023.01.26.23284998; this version posted January 27, 2023. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
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Identification of a molnupiravir-associated
mutational signature in SARS-CoV-2 sequencing
, Ryan Hisner
, I’ah Donovan-Banfield
, Thomas Peacock
, and Christopher Ruis
Francis Crick Institute, London, UK; 2 Independent researcher, USA; 3 Department of Infection Biology and Microbiomes, Institute of Infection, Veterinary and
Ecological Sciences, University of Liverpool, Liverpool, UK; 4 NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, Liverpool, UK; 5 Department
of Infectious Disease, Imperial College London, London, UK; 6 Molecular Immunity Unit, University of Cambridge Department of Medicine, MRC-Laboratory of
Molecular Biology, Cambridge, UK; 7 Department of Veterinary Medicine, University of Cambridge, Cambridge, UK; 8 Cambridge Centre for AI in Medicine, University
of Cambridge, Cambridge, UK
Molnupiravir, an antiviral medication that has been
widely used against SARS-CoV-2, acts by inducing
mutations in the virus genome during replication.
Most random mutations are likely to be deleterious
to the virus, and many will be lethal. Molnupiravirinduced elevated mutation rates have been shown
to decrease viral load in animal models. However, it is possible that some patients treated
with molnupiravir might not fully clear SARS-CoV2 infections, with the potential for onward transmission of molnupiravir-mutated viruses. We set
out to systematically investigate global sequencing databases for a signature of molnupiravir mutagenesis. We find that a specific class of long
phylogenetic branches appear almost exclusively
in sequences from 2022, after the introduction of
molnupiravir treatment, and in countries and agegroups with widespread usage of the drug. We
calculate a mutational spectrum from the AGILE
placebo-controlled clinical trial of molnupiravir and
show that its signature, with elevated G-to-A and
C-to-T rates, largely corresponds to the mutational
spectrum seen in these long branches. Our data
suggest a signature of molnupiravir mutagenesis
can be seen in global sequencing databases, in
some cases with onwards transmission.
Correspondence: email@example.com firstname.lastname@example.org
cation in 24 hours by 880-fold in vitro, and to reduce
viral load in animal models (Rosenke et al., 2021). Molnupiravir initially showed some limited efficacy as a
treatment for COVID-19 (Jayk Bernal et al., 2022; Extance, 2022), but subsequent larger clinical trials found
that molnupiravir did not reduce hospitalisation or death
rates in high risk groups (Butler, 2022). As one of the
first orally bioavailable antivirals on the market, molnupiravir has been widely adopted by many countries,
most recently China (Reuters, 2022). However, recent
trial results and the approval of more efficacious antivirals have since led to several countries recommending
against molnupiravir usage on the basis of limited effectiveness (NICE Guidance ; NC19CET, 2022).
MTP appears to be incorporated into nascent RNA primarily by acting as an analogue of cytosine (C), pairing
opposite guanine (G) bases (Fig. 1). However, once
incorporated, the molnupiravir..
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