Study identifies current mechanism of action behind reduced severity of Omicron variant COVID-19 infection

New research shows evidence that the Omicron variant is less severe compared to the Delta variant. Findings showed that eight current or promising coronavirus disease 2019 (COVID-19) treatments, ranging from remdesivir, molnupiravir, and the active compound found in Pfizer’s oral antiviral COVID-19 drug, were effective against the Omicron variant.

Since its identification in November 2021, the Omicron variant has caused a surge of coronavirus cases across the world. In the United States, scientists expect Omicron to supersede Delta as the dominant variant. While there are increases in COVID-19 cases, there has not been quite an uptick in hospitalizations and deaths.

The weaker disease severity may come from Omicron’s reduced ability to antagonize the host cell interferon response. Deceased effectiveness in inhibiting interferon responses suggests that one’s innate immune system should be better able to detect and target the new variant.

The researchers write:

Taken together, these data show that Omicron viruses are less effective than Delta viruses in antagonizing the interferon response in human cells, which may contribute to the lower pathogenicity of the Omicron variant observed in patients.”

From a medical standpoint, some individuals who are immunocompromised have less vaccine effectiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Having antiviral therapies would be helpful in protecting people at high risk of developing severe COVID-19 complications. Additionally, having mild to moderate COVID-19 cases suggest there may be less of a need for hospitalization or admittance to the ICU.

The new study was recently published without yet undergoing peer review on the bioRxiv* preprint server.

Sensitivity of cells to Omicron and Delta

The researchers exposed Calu-3 and Caco-2 cell cultures to two different Omicron isolates or an isolate from the Delta variant.

Results showed fewer infections when cells were exposed to Omicron versus with Delta. Although, there were similar viral infection patterns.

To study viral replication, Vero cell cultures were engineered to have a defective interferon response. Fewer infections in Vero cells as well suggest Omicron may be less capable of blocking cellular interferon signals compared to the Delta variant.

Omicron, but not Delta, activated interferon signaling by activating the interferon response factor promoter in a separate culture of A549 cells.

The Omicron variant stands out from other variants of concern because it has an abundance of mutations on the spike protein. Compared to Delta, Omicron has double the number of mutations.

Researchers have theorized that Omicron’s spike protein mutations help with increased infectiousness and immune escape. However, the study found that some of Omicron’s mutations are in SARS-CoV-2 proteins — S, NSP3, NSP6, NSP14, nucleocapsid protein, and membrane protein — involved in inhibiting the host cell interferon response.

Antiviral COVID-19 treatments are effective against Omicron

The researchers studied the sensitivity of Omicron and Delta to several antiviral treatments with different mechanisms of action. These included EIDD-1931, PF-07321332, remdesivir, favipravir, ribavirin, nafamostat, camostat, and aprotinin.

Omicron and Delta showed similar sensitivities to the antiviral drugs. The findings suggest mutations in the Omicron variant do not affect the drug sensitivity of current treatments.

Additionally, a mutation on RNA-dependent RNA polymerase Nsp12 — also found in Alpha, Beta, and Gamma variant of concerns — did not impact antiviral drugs that target RNA-dependent RNA polymerase and viral replication of the genome.

The nsp14 substitution on the exonuclease is another variant-defining mutation that causes an I42V change near the interface site with nsp10. The researchers observed that one of the two small hydrophobic side chains on the mutation makes contact with V40 and N41, which makes direct contact with nsp10. Nevertheless, the team believes the substitution will have a minimal effect on the interaction with nsp10 or antiviral treatment effectiveness.

Overall, the findings show that a broad range of antiviral COVID-19 treatments affects the SARS-CoV-2 Omicron virus. Omicron’s reduced disease severity compared to other variants of concern likely stems from a reduced ability to antagonize the host cell interferon response.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Jocelyn Solis-Moreira

Jocelyn Solis-Moreira graduated with a Bachelor's in Integrative Neuroscience, where she then pursued graduate research looking at the long-term effects of adolescent binge drinking on the brain's neurochemistry in adulthood.