Molnupiravir Inhibits Replication of the Emerging SARS-CoV-2 Variants of Concern in a Hamster Infection Model

Abstract

The emergence of SARS-CoV-2 variants of concern (VoCs) has exacerbated the COVID-19 pandemic. Currently available monoclonal antibodies and vaccines appear to have reduced efficacy against some of these VoCs. Antivirals targeting conserved proteins of SARS-CoV-2 are unlikely to be affected by mutations arising in VoCs and should therefore be effective against emerging variants. We here investigate the efficacy of molnupiravir, currently in phase 2 clinical trials, in hamsters infected with Wuhan strain or B.1.1.7 and B.1.351 variants. Molnupiravir proved to be effective against infections with each of the variants and therefore may have potential combating current and future emerging VoCs.

Keywords: B.1.351; SARS-CoV-2; VoC; antivirals; coronavirus; hamsters; molnupiravir.

Figure 1.

Molnupiravir (EIDD-2801) reduced viral loads in Syrian hamsters infected with different SARS-CoV-2 variants. A, Set-up of the study. B, Viral RNA levels in the lungs of control (vehicle-treated, twice a day) and EIDD-2801–treated (200 mg/kg, twice a day) hamsters infected with 10⁵ TCID₅₀ B.1-G, B.1.1.7, or B.1.351 SARS-CoV-2 variants at day 4 postinfection expressed as log₁₀ SARS-CoV-2 RNA genome copies per mg lung tissue. Individual data and median values are presented. C, Infectious viral loads in the lungs of control (vehicle-treated) and EIDD-2801–treated hamsters infected with the different SARS-CoV-2 variants at day 4 postinfection expressed as log₁₀ TCID₅₀ per mg lung tissue. Individual data and median values are presented. D, Weight change at day 4 postinfection in percentage, normalized to the body weight at the time of infection (day 0). Bars represent means ± SD. E, Cumulative severity score from H&E-stained slides of lungs from control (vehicle-treated) and EIDD-2801–treated SARS-CoV-2–infected hamsters. Individual data and median values are presented, and the dotted line represents the median score of untreated noninfected hamsters. All data were analyzed with the Mann-Whitney U test. *P < .05, **P < .01, ***P < .001, ****P < .0001. Data are from 2 independent experiments. The number of animals were 12 and 10 per vehicle and EIDD-2801–treated groups, respectively. Abbreviations: NS, not significant; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TCID₅₀, 50% tissue culture infectious dose.

Figure 2.

Molnupiravir improved histopathology of lungs of Syrian hamsters infected with different SARS-CoV-2 variants. Representative H&E images of lungs of control (vehicle-treated) and EIDD-2801–treated (200 mg/kg, twice a day) hamsters infected with 105 TCID₅₀ B.1-G, B.1.1.7, or B.1.351 SARS-CoV-2 variants at day 4 postinfection. Left panel, the lungs of the vehicle-treated hamsters infected with B.1-G, B.1.1.7, or B.1.351 SARS-CoV-2 variants showing extensive bronchopneumonia (alveoli filled with neutrophils and histiocytes), perivascular oedema (black arrows), and perivascular cuff of inflammatory cells (arrows with white heads). Right panel, the lungs of EIDD-2801–treated groups showed no or very focal bronchopneumonia (green triangles), no or focal perivascular inflammation (arrows with white heads), and no perivascular oedema. Asterisks indicate blood vessels. Scale bar, 100 µM. Abbreviations: H&E, hematoxylin and eosin; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TCID₅₀, 50% tissue culture infectious dose.