A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes.
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.
Acknowledgements: We thank all data contributors, that is, the authors and their originating laboratories responsible for obtaining the specimens, and their submitting laboratories for generating the genetic sequence and metadata and sharing via the GISAID initiative, on which this research is based. We also thank everyone who contributed to the generation of the genomes deposited in the INSDC databases, on which this research is also based. We thank A. Hinrichs and colleagues for access to an UShER mutation-annotated tree built with all available genomic data. We thank NHS England for providing the Blueteq data on treatment records. We thank the UKHSA COVID-19 Therapeutics Programme Team past and present, in particular J. Charlesworth, A. Lackenby, A. Demirjian, M. Chand and C. Brown. We thank J. Bloom, M. Lin, R. Neher, K. Harris and F. Débarre for useful discussions. T.S. was supported by the Wellcome Trust (no. 210918/Z/18/Z) and the Francis Crick Institute, which receives its core funding from Cancer Research UK (no. FC001043), the UK Medical Research Council (MRC) (no. FC001043) and the Wellcome Trust (no. FC001043). This research was funded in whole, or in part, by the Wellcome Trust (nos. 210918/Z/18/Z, FC001043). For the purpose of open access, the authors have applied a CC-BY public copyright licence to any author-accepted manuscript resulting from this article. I.D.-B. is supported by PhD funding from the National Institute for Health and Care Research (NIHR) Health Protection Research Unit in Emerging and Zoonotic Infections at the University of Liverpool in partnership with Public Health England (now UKHSA), in collaboration with the Liverpool School of Tropical Medicine and the University of Oxford (award no. 200907). The views expressed are those of the authors and not necessarily those of the Department of Health and Social Care or NIHR. Neither the funders nor the trial sponsor were involved in study design, data collection, analysis, interpretation or preparation of the manuscript. T.P.P. was funded by the G2P-UK National Virology Consortium, which is funded by the MRC (no. MR/W005611/1). C.R. was supported by a Fondation Botnar Research Award (programme grant no. 6063), the UK Cystic Fibrosis Trust (Innovation Hub Award 001) and funding from the Oxford Martin School.