In vitro and in vivo characterization of SARS-CoV-2 strains resistant to nirmatrelvir

Maki Kiso, Yuri Furusawa, Ryuta Uraki, Masaki Imai, Seiya Yamayoshi () and Yoshihiro Kawaoka ()
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Maki Kiso: University of Tokyo
Yuri Furusawa: University of Tokyo
Ryuta Uraki: University of Tokyo
Masaki Imai: University of Tokyo
Seiya Yamayoshi: University of Tokyo
Yoshihiro Kawaoka: University of Tokyo

Nature Communications, 2023, vol. 14, issue 1, 1-8

Abstract: Abstract Nirmatrelvir, an oral antiviral agent that targets a SARS-CoV-2 main protease (3CLpro), is clinically useful against infection with SARS-CoV-2 including its omicron variants. Since most omicron subvariants have reduced sensitivity to many monoclonal antibody therapies, potential SARS-CoV-2 resistance to nirmatrelvir is a major public health concern. Several amino acid substitutions have been identified as being responsible for reduced susceptibility to nirmatrelvir. Among them, we selected L50F/E166V and L50F/E166A/L167F in the 3CLpro because these combinations of substitutions are unlikely to affect virus fitness. We prepared and characterized delta variants possessing Nsp5-L50F/E166V and Nsp5-L50F/E166A/L167F. Both mutant viruses showed decreased susceptibility to nirmatrelvir and their growth in VeroE6/TMPRSS2 cells was delayed. Both mutant viruses showed attenuated phenotypes in a male hamster infection model, maintained airborne transmissibility, and were outcompeted by wild-type virus in co-infection experiments in the absence of nirmatrelvir, but less so in the presence of the drug. These results suggest that viruses possessing Nsp5-L50F/E166V and Nsp5-L50F/E166A/L167F do not become dominant in nature. However, it is important to closely monitor the emergence of nirmatrelvir-resistant SARS-CoV-2 variants because resistant viruses with additional compensatory mutations could emerge, outcompete the wild-type virus, and become dominant.

Date: 2023
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DOI: 10.1038/s41467-023-39704-x

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