Abstract
The reduced susceptibility of mRNA vaccines and diminished neutralizing activity of therapeutic monoclonal antibodies against Omicron variants, including BQ.1.1, XBB, and their descendants, highlight the importance of antiviral therapies. Here, we assessed the efficacy of two antivirals, molnupiravir, targeting a viral RNA-dependent RNA polymerase, and nirmatrelvir, targeting a main protease, against BQ.1.1 in hamsters. We found that prophylactic or therapeutic treatment with either drug significantly reduced the viral load in the lungs of infected hamsters. We also evaluated the risk of emergence of drug-resistant viruses in immunocompromised hamsters. Although 13 days of drug treatment reduced viral titers, the immunocompromised hosts could not completely clear the virus. Viruses isolated from drug-treated immunocompromised hamsters did not show reduced susceptibility to the drugs. Molnupiravir and nirmatrelvir remain effective in vivo against variants with reduced susceptibility to monoclonal antibodies and mRNA vaccine-induced antibodies, with limited emergence of drug-resistant variants under the conditions tested.