Treatment-Emergent Cilgavimab Resistance Is Uncommon In Vaccinated Omicron BA.4/5 Outpatients

Mutations in the SARS-CoV-2 Spike glycoprotein can affect monoclonal antibody efficacy. Even if the emergence of resistant mutations during treatment has been observed in vitro, acquired resistance has rarely been described in vivo. We retrospectively reviewed 22 immunocompetent patients at high risk for disease progression who received intramuscular tixagevimab/cilgavimab as early COVID-19 treatment and presented a prolonged high viral load. Complete SARS-CoV-2 genome sequences were obtained for a deep investigation of mutation frequencies in Spike protein before and during treatment. After seven days after the start of drug administration, our patient cohort showed a collection of both innate and acquired mutations, known to be associated with tixagevimab/cilgavimab resistance. The structural and dynamic impact of two quasispecies with two different deletions on the Spike protein (S:Delta138-144 or S:Delta141-145), in combination with the S:K444N mutation, was characterized by molecular dynamics simulations. Our study underlines the importance of prompting an early virological investigation to prevent drug resistance or clinical failures in immunocompetent patients.