- The genome of the Omicron variant has a large number of mutations, including more than 30 in the spike protein.
- This has raised concerns about the efficacy of monoclonal antibody treatments that target the spike protein.
- A new study has found that most antibody treatments were less effective against the Omicron variant than against earlier variants.
- Antiviral drugs remdesivir and molnupiravir maintained their effectiveness against the Omicron variant, as did an intravenous (IV) candidate drug that Pfizer is trialling.
The large number of mutations that the Omicron variant carries raises concerns about the effectiveness of antiviral drugs and antibody treatments.
A new laboratorystudy found that most antibody treatments are less effective against the Omicron variant than against the previous variants. These results support earlier studies that reached similar conclusions.
Notably, the three antiviral drugs, all of which the Food and Drug Administration (FDA) has authorized, retained their effectiveness against Omicron.
The results of this study appear as correspondence in The New England Journal of Medicine.
Monoclonal antibody treatments
Monoclonal antibodies are synthesized in the laboratory and mimic antibodies that the immune system makes. Similar to the antibodies produced by the immune system, monoclonal antibodies bind to the virus and prevent it from infecting human cells.
Monoclonal antibody treatment during the early stages of SARS-CoV-2 infection can significantly reduce the risk of hospitalization and death and has been an invaluable tool in the treatment of people at high risk of COVID-19.
Monoclonal antibodies for the treatment of COVID-19 tend to target the SARS-CoV-2 spike protein, which plays a vital role in mediating the entry of the virus into human cells.
Mutations in the gene encoding the spike protein can lead to a change in the structure of the protein. Such mutations can subsequently alter the ability of monoclonal antibodies to bind to the spike protein and neutralize the virus.
The Omicron variant has at least 33 mutations in the spike protein. For this reason, scientists were worried about whether antibody treatments would retain their efficacy against the new variant.
To assess the effectiveness of monoclonal antibodies against Omicron, the scientists used a laboratory assay to compare the ability of various antibody treatments to neutralize Omicron and earlier SARS-CoV-2 variants.
Effectiveness of monoclonal antibodies
The researchers evaluated how well a live virus infects laboratory cultured cells in the presence of a particular monoclonal antibody.
They assessed the neutralizing ability of seven different monoclonal antibodies against the Alpha, Beta, Gamma, Delta, and Omicron variants.
For each monoclonal antibody, the researchers determined the concentration of antibodies necessary to reduce the ability of a particular variant to infect the cells by half.
Although most antibodies were effective against the earlier variants, all monoclonal antibodies tested in the study showed a reduced ability to neutralize Omicron.
For instance, the Regeneron monoclonal antibody casirivimab effectively neutralized Gamma and Beta, but to neutralize Omicron, 18–75 times higher concentrations of the antibody were necessary.
The GlaxoSmithKline antibody sotrovimab was superior to other antibodies at neutralizing Omicron, with lower concentrations needed to inhibit it. Still, the concentrations of the drug that were able to neutralize the Omicron variant were three times higher than those for the Delta or Beta variants.
Medical News Today spoke with Dr. Stuart Turville, a virologist at the University of New South Wales, Sydney. He explained why sotrovimab may have faired better than casirivimab:
“Whilst many developed antibodies have great potency towards previous variants, the changes in the spike glycoprotein rendered them ineffective. Sotrovimab binds to a conserved site that persists in Omicron, so its activity is largely retained.”
Similar to monoclonal antibody treatments, the currently authorized COVID-19 vaccines were also designed to elicit an immune response against the wild-type SARS-CoV-2 spike protein.
Consistent with the results of the present study, other studies have shown a decline in the levels of neutralizing antibodies against Omicron in individuals who have received two doses of mRNA vaccine.
These antibodies are important to prevent SARS-CoV-2 infection and at least partially explain the higher number of breakthrough infections with the Omicron variant.
In addition to the use of individual monoclonal antibodies, doctors have used cocktails of two or more antibodies to treat COVID-19. In the present study, the researchers examined the efficacy of three such antibody combinations.
Of the three, the AstraZeneca antibody combination Evusheld was most effective at inhibiting the ability of Omicron to infect cultured cells. Yet, the concentrations of the antibody combination that could neutralize the Omicron variant were as many as 24–142 times higher than those for the previous variants.
The other two antibody combinations failed to neutralize Omicron.
Incidentally, the reduced effectiveness of these two antibody combinations — produced by Eli Lilly and Regeneron Pharmaceuticals — has led the FDA to discontinue the use of these drugs for COVID-19 caused by Omicron.
Next, the researchers evaluated whether the high number of genetic mutations dampened the effectiveness of currently used antiviral drugs against Omicron.
These antivirals included remdesivir and molnupiravir, both of which inhibit the key enzyme required for making copies of the SARS-CoV-2 genome. The researchers also tested an IV version of a Pfizer candidate drug, which inhibits a SARS-CoV-2 enzyme required for the cleavage of viral proteins during replication.
Using IV drugs is a method of administering medication into a vein and directly into the bloodstream.
The study authors tested these drugs, because Omicron has a single mutation in each of the two enzymes that these antivirals target.
They found that all three drugs were as effective against Omicron as they were against the earlier variants. The researchers caution, however, that these results from laboratory experiments need verifying in clinical studies.
MNT spoke with Dr. Rajesh Gandhi, an infectious disease physician at Massachusetts General Hospital and a professor of medicine at Harvard Medical School in Boston. Dr. Gandhi, who was not involved in the study, said:
“These data are consistent with results from several other studies. The laboratory studies show that the activity of several anti-SARS-CoV-2 monoclonal antibodies (casirivimab/imdevimab, bamlanivimab/etesevimab) is markedly reduced against Omicron. By contrast, in these lab studies, sotrovimab, another authorized anti-SARS-CoV-2 monoclonal antibody, continues to be active against Omicron.”
“In addition, the two oral [COVID-19] medications — Paxlovid and molnupiravir — and the [IV] medication remdesivir are active in these lab studies against Omicron.”
“The results of this study,” Dr. Gandhi concluded, “support the recommendations to use one of the following four medications for non-hospitalized patients with COVID-19 who are at high risk [of] progression: Paxlovid, sotrovimab, remdesivir, and, if those are not available, molnupiravir.”
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