A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes

Theo Sanderson (), Ryan Hisner, I’ah Donovan-Banfield, Hassan Hartman, Alessandra Løchen, Thomas P. Peacock and Christopher Ruis ()
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Theo Sanderson: Francis Crick Institute
Ryan Hisner: University of Cape Town
I’ah Donovan-Banfield: University of Liverpool
Hassan Hartman: UK Health Security Agency
Alessandra Løchen: UK Health Security Agency
Thomas P. Peacock: Imperial College London
Christopher Ruis: University of Cambridge Department of Medicine, Medical Research Council-Laboratory of Molecular Biology

Nature, 2023, vol. 623, issue 7987, 594-600

Abstract: Abstract Molnupiravir, an antiviral medication widely used against severe acute respiratory syndrome coronavirus 2 (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; thus, molnupiravir-induced elevated mutation rates reduce viral load1,2. However, if some patients treated with molnupiravir do not fully clear the SARS-CoV-2 infections, there could be the potential for onward transmission of molnupiravir-mutated viruses. Here we show that SARS-CoV-2 sequencing databases contain extensive evidence of molnupiravir mutagenesis. Using a systematic approach, we find that a specific class of long phylogenetic branches, distinguished by a high proportion of G-to-A and C-to-T mutations, are found almost exclusively in sequences from 2022, after the introduction of molnupiravir treatment, and in countries and age groups with widespread use of the drug. We identify a mutational spectrum, with preferred nucleotide contexts, from viruses in patients known to have been treated with molnupiravir and show that its signature matches that seen in these long branches, in some cases with onward transmission of molnupiravir-derived lineages. Finally, we analyse treatment records to confirm a direct association between these high G-to-A branches and the use of molnupiravir.

Date: 2023
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DOI: 10.1038/s41586-023-06649-6

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