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Evusheld – dual antibodies for reducing the risk of SARS-CoV-2

The first generation of mRNA vaccines that were developed against SARS-CoV-2 were designed to reduce the risk of people becoming seriously ill, requiring hospitalization or dying from complications related to COVID-19. The vaccines were developed against the original strain of SARS-CoV-2, which became widespread in the first half of 2020.

Since that time, SARS-CoV-2 has mutated into different strains, or variants. The mRNA vaccines still continue to provide a high degree of protection from serious complications, hospitalizations and death. Getting booster shots as recommended by local public health authorities is a very good idea. However, the effectiveness of these vaccines appears to be gradually diminishing as SARS-CoV-2 continues to mutate. 

Another route of potential protection from SARS-CoV-2 is the use of an antiviral treatment such as Paxlovid (a combination of the drugs nirmatrelvir and ritonavir) in people who have been recently infected with SARS-CoV-2 and who are at high risk for developing serious symptoms of COVID-19.

Monoclonal antibodies

In addition to vaccines and Paxlovid, clinical trials have found that another way to reduce the risk for developing serious symptoms of COVID-19 is to receive injections of antibodies that have been designed to attack SARS-CoV-2. These injections are developed from antibodies found in the blood of people who have survived coronavirus infection—either by the virus that caused an outbreak of SARS (severe acute respiratory syndrome) in 2003 or the more recent virus responsible for the present pandemic (SARS-CoV-2), as both viruses are related. Scientists have modified the antibodies to make them remain in the circulatory system at high levels for much longer than normal (likely for months).

Antibodies that are created in a lab (from clones of B-cells) in large quantities for the treatment of viral infections, cancer and other conditions are called monoclonal antibodies.

Enter Evusheld

The latest monoclonal antibody product approved in Canada is Evusheld. This is the brand name of two antibodies (tixagevimab and cilgavimab) that are used together. The antibodies in Evusheld were tested in a randomized placebo-controlled clinical trial called Provent with more than 5,000 participants at risk for developing serious symptoms of COVID-19. Researchers found that a single dose of both antibodies was able to significantly reduce the risk of developing symptomatic COVID-19.

Study details

Researchers recruited participants between November 2020 and March 2021. The average profile of participants upon entering the study was as follows:

  • 54% men, 46% women
  • age – 43% were 60 years and older, 24% were 65 and older, and 4% were 75 and older
  • major ethno-racial groups: White – 73%; Black – 17%; Asian – 3%
  • body mass index (BMI) – 29 kg/m2

About 75% of all participants had at least one underlying factor that increased their risk for severe COVID-19, including the following:

  • obesity – 42%
  • high blood pressure – 36%
  • smoking – 21%
  • diabetes – 14%
  • asthma – 11%
  • cardiovascular disease (other than high blood pressure) – 8%
  • cancer – 7%
  • chronic obstructive pulmonary disease (COPD) – 5%
  • chronic kidney disease – 5%
  • chronic liver disease – 5%
  • using therapies that weakened the immune system – 3%

Participants were randomly assigned to receive (in a 2-to-1 ratio) either antibodies or placebo. After being injected by a healthcare practitioner, participants were monitored for one to four hours for any signs of side effects.

Participants who were assigned to receive antibodies were given two injections of 1.5 mL of antibodies into muscle (in their buttocks). One injection contained tixagevimab and the other cilgavimab.

People who tested positive for SARS-CoV-2 while being screened for potential recruitment for the study were not allowed into the study.

At the point of study entry, none of the participants enrolled in Provent were vaccinated against COVID-19.

Once people enrolled in the study, nurses contacted them weekly to assess symptoms for possible COVID-19 infection. People with symptoms suggestive of COVID-19 underwent testing for this virus and other assessments. Participants were monitored for at least 83 days and in many cases for up to six months after entering the study.

Results – safety

The term adverse events is used to describe unfortunate events that can occur during a clinical trial. Some of these events are due to side effects of the treatment or drug(s) being used. In other cases, adverse events may occur because of the underlying disease process. Some adverse events may also be caused by issues unrelated to the study, such as accidents.

According to the Provent researchers, “most adverse events were mild or moderate in intensity.” The overall distribution of adverse events was as follows:

People who received Evusheld

  • any adverse event – 35%
  • mild adverse events – 22%
  • moderate adverse events – 11%
  • severe adverse events – 2%

People who received placebo

  • any adverse event – 35%
  • mild adverse events – 21%
  • moderate adverse events – 11%
  • severe adverse events – 2%

Injection site reactions

Injection site reactions—redness, swelling, itchy skin—occurred in 2% of people who received antibodies and 2% of people who received placebo.

Anaphylaxis

Historically, a very small proportion of people who have received monoclonal antibodies for a range of conditions have developed a severe allergic reaction called anaphylaxis. One person developed severe chest pain shortly after being injected with Evusheld. At first, researchers thought that he had anaphylaxis, but investigation and his subsequent course suggested that the chest pain was a manifestation of cardiovascular disease.

There was a total of eight deaths, distributed as follows:

People who received Evusheld

  • two people died from lung complications arising from COVID-19
  • two people died from drug overdoses
  • one person died from heart attack
  • one person died from kidney failure

People who received placebo

  • two people died from drug overdoses

All deaths were investigated and were not caused by the antibodies or the placebo.

Effectiveness

The distribution of people in the study who became infected with SARS-CoV-2, confirmed with polymerase chain reaction (PCR) testing, and who developed COVID-19 was as follows:

  • Evusheld – 0.2%
  • placebo – 1%

Statistical analysis found that people who received Evusheld had a 77% relative reduction in the risk of developing COVID-19. This difference was statistically significant. That is, not likely due to chance alone.

The protective effect of Evusheld was similar among many subgroups of participants regardless of gender, age, ethno-racial background and so on.

Antibody levels

After injection, muscles tend to slowly release a drug or antibody into circulation in the body. In the Provent study, antibody levels reached their peak one month after injection and then gradually declined over the next five months.

Bear in mind

The results from the Provent study suggest that Evusheld can significantly reduce the risk of developing COVID-19. There are additional issues to consider about the deployment of Evusheld, and these are raised in the next report.

—Sean R. Hosein

REFERENCE:

Levin MJ, Ustianowski A, De Wit S, et al. Intramuscular AZD7442 (Tixagevimab-Cilgavimab) for prevention of COVID-19. New England Journal of Medicine. 2022 Jun 9;386(23):2188-2200.