The fitness of molnupiravir-signed SARS-CoV-2 variants: imputation analysis based on prescription counts and GISAID analyses by country.
Daniele Focosi, Dave Mcnally, Fabrizio Maggi
Intervirology, doi:10.1159/000540282
Introduction : Molnupiravir is one of the oral direct-acting antivirals against SARS-CoV-2, largely deployed during the COVID-19 pandemic since the 2022 Omicron wave. While efficacy has been questioned in post-marketing clinical trials (leading to the EMA withdrawing its authorization), growing concerns have mounted regarding its possible mutagenic effects on the virus. While it has been assumed that either all the host viral load was cleared by the drug or that drug-generated variants were not fit enough to survive, several lineages with a high transition/transversion ratio (a signature of molnupiravir action) have been recently reported from GISAID. Methods : We report here a systematic analysis of the GISAID database for sequences showing a molnupiravir signature, exposing a public web-based interface ( https://ukcovid.xyz/molnupiravir/ ), and performing an imputation analysis based on per-country prescription (corrected by sequencing). Results: Our analysis confirms a direct correlation between the number of molnupiravir courses and the number of mutationally signed deposited in GISAID in individual countries. Conclusions: Molnupiravir can generate fit SARS-CoV-2 variants that transmit in the general population.
Ethics statement: An ethics statement is not applicable because this study is based exclusively on published literature. Author contributions: D.M. analyzed the GISAID database, created the public web repository, and revised the manuscript; D.F. retrieved prescription counts by country and wrote the first draft; F.M. revised the manuscript. Conflict of interest disclosure: We declare that we have no conflict of interests related to this manuscript.
References
Alteri, Fox, Scutari, Burastero, Volpi et al., A proof-of-concept study on the genomic evolution of Sars-Cov-2 in molnupiravir-treated, paxlovid-treated and drug-naïve patients, Commun Biol
Alteri, Fox, Scutari, Burastero, Volpi et al., A proof-of-concept study on the genomic evolution of Sars-Cov-2 in molnupiravir-treated, paxlovid-treated and drug-naïve patients, Commun Biol
Bernal, Da Silva, Musungaie, Kovalchuk, Gonzalez et al., Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients, N Engl J Med
Bloom, Beichman, Neher, Harris, Evolution of the SARS-CoV-2 mutational spectrum, Molecular biology and evolution
Chen, Azman, Chen, Zou, Tian et al., Global landscape of SARS-CoV-2 genomic surveillance and data sharing, Nature genetics
Donovan-Banfield, Penrice-Randal, Goldswain, Rzeszutek, Pilgrim et al., Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial, Nat Commun
El-Haddad, Adhikari, Tu, Cheng, Leng et al., Intra-host mutation rate of acute SARS-CoV-2 infection during the initial pandemic wave, Virus genes
Fischer, Eron, Holman, Cohen, Fang et al., A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus
Fletcher, Ia, Penrice-Randal, Characterisation of SARS-CoV-2 genomic variations in response to molnupiravir treatment in the AGILE Phase IIa clinical trial,
doi:10.21203/rs.3.rs-1835695/v1Focosi, Molnupiravir: From Hope to Epic Fail
Fountain-Jones, Vanhaeften, Williamson, Maskell, Chua et al., Antiviral treatments lead to the rapid accrual of hundreds of SARS-CoV-2 mutations in immunocompromised patients
Gold, Kelleher, Magid, Jackson, Pennini et al., Dispensing of Oral Antiviral Drugs for Treatment of COVID-19 by Zip Code-Level Social Vulnerability -United States, December 23, 2021
Hisner, LongDesertTrain) tweet
Illingworth, Guerra-Assuncao, Gregg, Charles, Pang et al., Genetic consequences of effective and suboptimal dosing with mutagenic drugs in a hamster model of SARS-CoV-2 infection
Khare, Gurry, Freitas, Schultz, Bach et al., GISAID's Role in Pandemic Response, China CDC Wkly
Kimata, Watanabe, Yanagida, Kinoshita, Maekawa, Safety and Effectiveness of Molnupiravir (LAGEVRIO(®)) Capsules in Japanese Patients with COVID-19: Interim Report of Post-marketing Surveillance in Japan, Infectious diseases and therapy
Neher, SARS-CoV-2 variant rates
Penrice-Randal, Bentley, Sharma, Kirby, Ia et al., The effect of molnupiravir and nirmatrelvir on SARS-CoV-2 genome diversity in infected and immune suppressed mice, bioRxiv
Plata, The black market for covid-19 antiviral drugs
Robert F Service, A prominent virologist warns COVID-19 pill could unleash dangerous mutants. Others see little cause for alarm
Sanderson, Hisner, Ia, Peacock, Ruis, A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes, Nature
Sheahan, Sims, Zhou, Graham, Pruijssers et al., An orally bioavailable broadspectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice, Science translational medicine
Sheahan, Stevens, Narowski, Krajewski, Lee et al., The Antiviral Mechanism of Action of Molnupiravir in Humans with COVID-19, medRxiv
Sonnleitner, Prelog, Sonnleitner, Hinterbichler, Halbfurter et al., Cumulative SARS-CoV-2 mutations and corresponding changes in immunity in an immunocompromised patient indicate viral evolution within the host, Nat Commun
Sublineage, 2 with 8 additional spike mutations (9 seq, Australia), PANGO
Swanstrom, Schinazi, Lethal mutagenesis as an antiviral strategy, Science
Tibble, Mueller, Proud, Hall, Kurdi et al., Uptake of monoclonal antibodies and antiviral therapies for COVID-19 in Scotland, Lancet
William, Haseltine, Supercharging New Viral Variants: The Dangers Of Molnupiravir (Part 1)
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