Combinatorial Regimens Augment Drug Monotherapy for SARS-CoV-2 Clearance in Mice

Direct acting antivirals (DAAs) represent critical tools for combating SARS-CoV-2 variants of concern (VOCs) that have escaped vaccine-elicited spike-based immunity and future coronaviruses with pandemic potential. Here, we used bioluminescence imaging to evaluate therapeutic efficacy of DAAs that target SARS-CoV-2 RNA-dependent RNA polymerase (favipiravir, molnupiravir) or Main protease (nirmatrelvir) against Delta or Omicron VOCs in K18hACE2 mice. Nirmatrelvir displayed the best efficacy followed by molnupiravir and favipiravir in suppressing viral loads in the lung. While DAA monotherapy at the administered dose did not eliminate SARS-CoV-2 in mice, targeting two viral enzymes by combining molnupiravir with nirmatrelvir resulted in superior efficacy and virus clearance. Furthermore, combining molnupiravir with Caspase-1/4 inhibitor mitigated inflammation and lung pathology whereas combining molnupiravir with COVID-19 convalescent plasma yielded rapid virus clearance and 100% survival. Thus, our study provides insights into treatment efficacies of DAAs and other effective 
combinations to bolster COVID-19 therapeutic arsenal.