The Fitness of Molnupiravir-Signed SARS-CoV-2 Variants: Imputation Analysis Based on Prescription Counts and Global Initiative on Sharing All Influenza Data Analyses by Country

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 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 sequences deposited in GISAID in individual countries. Conclusions: Molnupiravir can generate fit SARS-CoV-2 variants that transmit in the general population.