SARS-CoV-2 variants reduce the number of treatments for COVID-19 | Coronavirus

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SARS-CoV-2 variants reduce number of treatments for COVID-19 | Coronavirus

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The majority of monoclonal antibody treatments must be administered intravenously and are usually very expensive .

With the proliferation of SARS-CoV-2 variants, the number of drugs available to treat and protect those at risk of severe complications from COVID-19 is diminishing.

In Canada, six treatments have been authorized since the start of the pandemic, namely:

Monoclonal antibodies :

  • Evusheld (cilgavimab/tixagevimab)

  • sotrovimab

  • casirivimab/imdevimab

  • bamlanivimab

< strong>Antiviral agents :

  • Paxlovid (nirmatrelvir/ritonavir)

  • < p class="e-p">Veklury (remdesivir)

Monoclonal antibodies are used to protect against infection or to treat disease. For example, they may help prevent COVID-19 in people with weakened immune systems or in people who cannot receive a vaccine.

On the other hand, the majority of monoclonal antibodies authorized in Canada are no longer effective against the new variants in circulation.

The World Health Organization (WHO) recently indicated that it The use of sotrovimab and casirivimab/imdevimab is no longer recommended, since they are no longer considered effective against the various Omicron subvariants.

Health Canada also specifies that these two monoclonal antibodies present a high risk of therapeutic failure against Omicron.

Alain Lamarre, professor and researcher in immunology and virology at the Institut national de scientific research (INRS), points out that some monoclonal antibodies still work, but only against certain variants.

For example, bamlanivimab is effective only against the Alpha variant (B.1.1. 7).

A preliminary study, which has not yet been peer reviewed, has shown that several monoclonal antibodies, including bamlanivimab, casirivimab and imdevimab, fail to neutralize three subvariants of 'Omicron, namely BA.4, BA.5 and BA.2.75.

This study also shows that if sotrovimab and tixagevimab are less effective against the subvariants BA.4 and BA.5, these monoclonal antibodies still seem effective against BA.2.75.

According to Brian Conway, medical director of the Center for Infectious Diseases in Vancouver, Evusheld is one of the last monoclonal antibodies that still works well against the original strain of the virus and several of its variants.

Currently it is used for prevention in immunocompromised people who are unlikely to mount an adequate immune response after vaccination and in those for whom vaccination is not recommended. Dr. Conway says it's also being considered for use as a treatment, but says Evusheld may one day become resistant too.

“Will Evusheld still work?” Hard to say. If that doesn't work, what do we do? Since the start of the pandemic, as soon as we think we know everything, we realize that we don't know everything.

— Dr. Brian Conway, Center for Infectious Diseases Vancouver

In fact, a preliminary non-peer-reviewed study from China shows that Evusheld appears to be ineffective against BQ.1.1 and BA.2.75.2 variants, two variants tipped to become dominant across the world. over the next few months.

The monoclonal antibodies target the SARS-CoV-2 spike protein, which acts as a receptor and allows the virus to latch onto human cells to trigger an infection.

The Dr. Arturo Casadevall, an infectious disease researcher at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, is not surprised to see that the new variants are becoming increasingly resistant to monoclonal antibodies.

Recall that monoclonal antibodies target the spike protein of the COVID-19 virus and can thus inhibit the ability of the virus to attach to the host cell and infect it.

However, as with the first vaccines, monoclonal antibodies were designed based on ancestral forms of the virus. Lamarre adds that monoclonal antibodies act very specifically against the virus. If the virus mutates enough, the monoclonal antibody will no longer be able to attach to the spike protein and will not be able to neutralize the virus.

Monoclonal antibodies are wonderful therapeutic agents with high efficacy and low toxicity, but they are very vulnerable to antigenic changes, adds Dr. Casadevall.

“SARS-CoV-2 is a rapidly evolving virus, and we have seen that monoclonal antibody therapies only last for a while, until a new variant emerges. »

— Dr. Arturo Casadevall, researcher at the Johns Hopkins Bloomberg School of Public Health

New monoclonal antibodies can take several months to make, adds Dr. Casadevall. So they will always reflect the past, he says, and these treatments are usually very expensive to develop and produce, he says.

Pfizer's Paxlovid antiviral tablets against COVID-19.

If monoclonal antibodies are no longer an effective option to prevent complications from COVID-19, Dr. Conway says the antiviral drugs Paxlovid (nirmatrelvir/ritonavir) and Veklury (remdesivir) remain effective against the different variants.

These treatments are less sensitive to mutations, because they interfere with the replication process of the virus; they don't target a specific location on the virus like monoclonal antibodies do, says Lamarre.

He adds that they must be given within the first five days of infection and that there are many drug contraindications.

Additionally, researchers observed that while Paxlovid reduced hospitalizations in people 65 and older by about 75%, there did not appear to be a measurable benefit in 40 to 65 year olds.

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Among seniors who received Paxlovid, the hospitalization rate was 14.7 cases per 100,000, compared to 58.9 cases per 100,000 among those who did not receive Paxlovid. treatment.

In comparison, among 40-64 year olds, the hospitalization rate was 15.2 hospitalizations per 100,000 among those who received Paxlovid, compared to 15.8 among those who did not.

In the youngest, more people need to be treated to see population benefits. The benefit is less in a younger population, unless you are someone with significant risk factors, says Lamarre.

Finally, note the possibility of viral rebound with Paxlovid – the resurgence of symptoms after resolution of acute illness. There may be cases where Paxlovid will greatly reduce the viral load, but not eliminate the virus. At the end of the treatment, it is possible not to have completely eliminated the virus and that can cause a rebound, says Mr. Lamarre; he adds that this phenomenon is poorly understood, but infrequent.

Despite this, the three experts regret that Paxlovid is not used more.

The public isn't aware it exists, says Dr. Conway. Health professionals are not always informed.

In July, Radio-Canada reported that approximately 60,000 doses had been administered in Canada. On Monday, CBC revealed that approximately 100,000 doses had been administered since January; less than 15% of the doses sent to the provinces.

Finally, there is also molnupiravir, Merck's antiviral pill. This pill is available in many countries, but has not yet been authorized in Canada, a situation that Dr. Conway misunderstands, especially since its effectiveness has been demonstrated.

A vial of the antiviral remdesivir

Yes, monoclonal antibody resistance is a setback in the fight against COVID-19, but the three experts are confident that new treatments will be developed.

One way around the problem is to try using a cocktail of drugs, hitting the virus simultaneously with compounds that target more than one replication mechanism. In fact, treatments for HIV and hepatitis C combine drugs.

That's why Dr. Casadevall thinks that some COVID-19 treatments could be combined to improve their effectiveness. However, he specifies that there is not yet any clinical data authorizing this strategy.

M. Lamarre adds that several treatments, which target the inflammatory response of the disease rather than the spike protein of the virus, are being studied. Researchers are trying to identify regions in the virus spike that are consistent across variants. It has the advantage of being immune to mutations and variants.

Dr. Casadevall also believes that authorities should consider allowing the use of convalescent plasma in immunocompromised people. This treatment consists of transfusing plasma from recovered COVID-19 patients – convalescent plasma – to patients at the onset of the disease to transfer the protective antibodies to them. It is the only antibody-based therapy that adapts to the variants, since anyone who recovers from an infection has antibodies that neutralize this strain.

According to Mr. Lamarre, the best way not to succumb to COVID-19 is to never catch it and get vaccinated.

He adds that the race for variants should one day slow down. The virus cannot continuously mutate without consequences for its own replication. It's a balance, he says. He adds that the virus should eventually become weaker as it mutates, which would make it easier to develop more treatments. However, he points out that this may take several more years.

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