Molnupiravir increases SARS‐CoV‐2 genome diversity and complexity: A case‐control cohort study

Author:

Gruber Cesare Ernesto Maria1ORCID,Tucci Fabio Giovanni2,Giombini Emanuela1,Mazzotta Valentina3ORCID,Spezia Pietro Giorgio1,Rueca Martina1ORCID,Mastrorosa Ilaria3,Fabeni Lavinia1,Berno Giulia1,Butera Ornella4,Rosati Silvia3,Specchiarello Eliana1,Carletti Fabrizio1,Focosi Daniele5ORCID,Nicastri Emanuele3,Girardi Enrico6,Antinori Andrea3,Maggi Fabrizio1

Affiliation:

1. Laboratory of Virology National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS Rome Italy

2. Department of Biology University of Rome Tor Vergata Rome Italy

3. Clinical and Research Infectious Diseases Department National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS Rome Italy

4. Laboratory of Microbiology National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS Rome Italy

5. North‐Western Tuscany Blood Bank Pisa University Hospital Pisa Italy

6. Scientific Direction National Institute for Infectious Diseases “L. Spallanzani”—IRCCS Rome Italy

Abstract

AbstractMolnupiravir, an oral direct‐acting antiviral effective in vitro against SARS‐CoV‐2, has been largely employed during the COVID‐19 pandemic, since December 2021. After marketing and widespread usage, a progressive increase in SARS‐CoV‐2 lineages characterized by a higher transition/transversion ratio, a characteristic signature of molnupiravir action, appeared in the Global Initiative on Sharing All Influenza Data (GISAID) and International Nucleotide Sequence Database Collaboration (INSDC) databases. Here, we assessed the drug effects by SARS‐CoV‐2 whole‐genome sequencing on 38 molnupiravir‐treated persistently positive COVID‐19 outpatients tested before and after treatment. Seventeen tixagevimab/cilgavimab‐treated outpatients served as controls. Mutational analyses confirmed that SARS‐CoV‐2 exhibits an increased transition/transversion ratio seven days after initiation of molnupiravir. Moreover we observed an increased G‐>A ratio compared to controls, which was not related to apolipoprotein B mRNAediting enzyme, catalytic polypeptide‐like (APOBEC) activity. In addition, we demonstrated for the first time an increased diversity and complexity of the viral quasispecies.

Funder

European Commission

Ministero della Salute

Publisher

Wiley

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3. EMA Assessment Report. Use of molnupiravir for the treatment of COVID‐19. Accessed January 12 2024.https://www.ema.europa.eu/en/documents/referral/lagevrio-also-known-molnupiravir-or-mk-4482-covid-19-article-53-procedure-assessment-report_en.pdf

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5. TianF TongB SunL et al. Mutation N501Y in RBD of spike protein strengthens the interaction between COVID‐19 and its receptor ACE2.bioRxiv. Preprint posted online February 18 2021.doi:10.1101/2021.02.14.431117

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