The Omicron variant of SARS-CoV-2 is the fast-spreading version and contains most mutations compared to the previous variants, with the majority of the mutations located around the receptor-binding domain of the spike protein. This can compromise the efficacy of the existing COVID-19 vaccines. Most of the monoclonal antibodies developed for treating COVID-19 target the spike protein to prevent virus entry into human cells, thus a majority of these antibodies are not effective against the Omicron variant. 

A study evaluated the effectiveness of two clinically available direct-acting antiviral agents on the Omicron variant in relevant experimental models.

Molnupiravir is a prodrug of the nucleoside derivative N-hydroxycytidine (NHC), which has shown a significant clinical benefit in a large phase 3 clinical trial for COVID-19 patients and stands as the first approved oral antiviral agent for treating COVID-19. 

However, the current clinical data utilized the infection of the wild type (WT) or previous variants of SARS-CoV-2. So a study assessed its effectiveness on the Omicron variant by using an isolate, cultured from an infected patient in the Netherlands and observed that Omicron has a reduced capability of propagation in human lung epithelial Calu-3 cells. On treatment with molnupiravir, potent and dose-dependent inhibition of viral replication based on qRT-PCR quantification of intracellular viral genomic RNA was observed. 1 μM molnupiravir decreased Omicron viral RNA by 70.4% ± 12.5% and was completely inhibited at 10 μM and higher concentrations. 

The estimated half-maximal inhibitory concentration (IC50) of molnupiravir was found to be 1.965 μM for WT SARS-CoV-2 and 0.7556 μM for the Omicron variant. 

The dose-response curves suggested Omicron be more sensitive to the treatment than WT, particularly at low concentrations ranging from 0.5 μM to 5 μM, with no cytotoxicity. Furthermore, the potent inhibition of the production of infectious viruses by molnupiravir treatment was confirmed. 

U.S. Food and Drug Administration (FDA) have also authorized the emergency use of PAXLOVID, which contains Nirmatrelvir, as another oral antiviral therapy for treating COVID-19. A large phase 2/3 trial on PAXLOVID has reported an 89% reduction in the risk of hospitalization or death for COVID-19 patients. But to assess the effects of nirmatrelvir on the Omicron variant, a study treated Omicron-infected Calu-3 cells with a series of concentrations of nirmatrelvir and observed Potent and dose-dependent inhibition of intracellular viral genomic RNA.

A low concentration of 0.1 μM showed Omicron viral RNA reduction by 79.9% ± 8.3% and complete inhibition at 2.5 μM and higher concentrations. The dose-response curves showed the IC50 of 0.1765 μM to WT and 0.02462 μM to Omicron SARS-CoV-2, indicating Omicron to be more sensitive to nirmatrelvir in Calu-3 cell model than the parental WT SARS-CoV-2, with no cytotoxicity. Furthermore, the potent inhibition was confirmed. 2.5 μM concentration of nirmatrelvir reduced the infectious titers of Omicron by > 1200-fold. 

On assessing the combination of molnupiravir and nirmatrelvir for treating SARS-CoV-2 infection in Calu-3 cells, the synergistic antiviral activity of the combination against both WT and Omicron SARS-CoV-2 was observed. 

Thus molnupiravir and nirmatrelvir can be used for treating Omicron-infected patients. However, more clinical studies are warranted to evaluate the combination of molnupiravir and nirmatrelvir for treating COVID-19.

Source- Cell Res,2022. https://doi.org/10.1038/s41422-022-00618-w