Are COVID-19 treatments holding up against variants?

With the appearance of more virulent and more transmissible COVID variants, such as Delta and Omicron, the biggest concern has been that these variants would escape vaccine-induced immunity. We’ve discovered that immunity is somewhat reduced against both Delta and Omicron, but vaccines can still protect us from becoming severely ill and dying.

Besides vaccines, many therapeutics have helped reduce severe disease and death. But how well do anti-COVID drugs work against variants?

At the end of January, the US Food and Drug Administration announced the withdrawal of two monoclonal antibodies because they seem to lose effectiveness against Omicron.

Monoclonal antibodies are used early in the infection to avoid mild or moderate symptoms progressing to severe disease. They act by binding to the virus’ spike protein, which is highly mutable.

The large array of mutations on the Omicron’s spike protein, which helps the variant evade pre-existing immunity, also diminishes the ability of monoclonal antibodies to bind and neutralise the virus.

“Monoclonal antibodies that target the SARS-CoV-2 spike protein may no longer block the virus,” says Professor Gilda Tachedjian, a virologist at the Burnet Institute.

Another fundamental drug class is antivirals, such as remdesivir, molnupiravir and nirmatrelvir plus ritonavir. These drugs sabotage the viral RNA polymerase and viral protease – enzymes critical for virus replication.

Those two enzymes don’t mutate as much as spike proteins. However, Tachedjian says, there is still a risk that the virus mutates enough to decrease the ability of antivirals to block the virus replication process – a possibility that has been observed with HIV antivirals in the past.

Then there are glucocorticoid medications. These drugs are usually used to treat rheumatic diseases – chronic autoimmune and inflammatory diseases that cause the immune system to attack joints, muscles, bones and organs.

Among these, Dexamethasone has been shown to reduce deaths by around one-third in COVID-19 patients on ventilators and by one-fifth among those on oxygen.

“Dexamethasone is completely different,” says Professor Anthony Cunningham, an infectious diseases physician and clinical virologist at the University of Sydney. It’s given to patients with mild symptoms progressing to severe disease.

The glucocorticoid doesn’t target the virus. Instead, it suppresses the immune system overreaction, which causes severe inflammation in the lungs.

“During a severe COVID-19 infection, the immune system goes haywire producing inflammatory molecules,” says Cunningham. “Dexamethasone suppresses that inflammatory response.”

Other immunomodulating drugs are the monoclonal antibodies tocilizumab and siltuximab. These act by binding to IL-6 (interleukin 6) – cytokines the immune system produces in response to the infection, preventing them from binding to IL-6 receptors, thus regulating inflammation.

Overall, antibody-based therapies targeting the COVID-19 spike protein are most at risk of losing effectiveness against variants, because this part of the virus is more likely to mutate. Antivirals that target more stable viral proteins will likely hold up better, while immunomodulating drugs should continue to work against COVID-19 as long as the immune response to infection remains similar, and are least likely to be impacted by viral mutation or evolution.

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