Evusheld – issues to consider

As mentioned earlier in this issue of TreatmentUpdate, a combination of two antibodies designed to attack SARS-CoV-2, sold under the brand name Evusheld, has been approved in Canada and the U.S. In a large clinical trial called Provent, Evusheld significantly reduced the risk of unvaccinated people developing COVID-19. How should Evusheld be deployed? It may be worth considering the following issues in order to reflect on that question.

Immune suppression

The main clinical trial that tested Evusheld enrolled people who were likely to have a poor immunological response to infection with SARS-CoV-2 or to vaccines for this infection. According to AstraZeneca, the manufacturer of Evusheld, such people are likely from the following populations or have the risk factors listed below:

• age 60 and older
• obesity
• immune suppressed (we will return to this point later)
• have a history of adverse reactions to vaccines (in general)
• have congestive heart failure
• have chronic obstructive pulmonary disorder (COPD)
• have chronic kidney disease
• have chronic liver disease

In Canada, Evusheld is meant to be used in adults and adolescents (age 12 and older). In order for Evusheld to reduce the risk of SARS-CoV-2 infection and the subsequent development of COVID-19, the product monograph notes that potential users should not have been recently exposed to people infected with this virus. According to AstraZeneca, a potential user should fulfill the following categories:

• “be immune compromised and unlikely to mount an adequate immune response to COVID-19 vaccines”
• be someone “for whom COVID-19 vaccination is not recommended”

In practice, doctors are likely to restrict the use of Evusheld to people who are immune suppressed. Generally, these are people who are taking medicines to weaken their immune systems, such as the following:

• people who have a transplanted organ
• some people who are being treated for rheumatoid arthritis, Crohn’s and colitis, severe psoriasis and other inflammatory conditions

HIV

Evusheld was not tested in people with HIV. At any rate, research from Canada and other high-income countries with universal health care systems, has found that people with HIV who are taking potent HIV treatment (ART) and who have a suppressed viral load and at least modestly elevated CD4+ cell counts generally respond well to COVID-19 vaccines. Such people do not appear to be at high risk for severe illness, hospitalization or death arising from COVID-19.

Potential side effects

There was a very small imbalance in adverse events relating to cardiovascular issues in the Provent study. The distribution of such events was as follows:

• Evusheld – 0.7% (23 people)
• placebo – 0.3% (5 people)

Note that twice as many people received Euvsheld as did placebo in that study.

Cardiovascular events that occurred in the study included the following:

• abnormal heart rhythms
• heart attack
• heart pain
• coronary artery disease (note that this takes many years to develop and is extremely unlikely to have occurred because of exposure to Evusheld)

There was also a slight excess of neurological issues, some of which appear to be related to cardiovascular disease (such as stroke), that occurred. Overall, less than 1% of people who received Evusheld developed such issues.

All of the participants in the study who developed cardiovascular or neuro-vascular-related adverse events either had a history of such events or risk factors for them when they entered the study.

Another study (as yet unpublished) called Storm Chaser also tested Evusheld. During this study no one developed cardiovascular adverse events. However, participants in Storm Chaser were younger than those in Provent and tended to have fewer cardiovascular risk factors.

According to Camille Kotton, MD, of Harvard University Medical School, who reviewed the findings from Provent, “Overall, the benefit of additional protection for immunocompromised patients seems to outweigh the potential risk for cardiac events.”

It may also be useful for doctors to weigh the risks and benefits of Evusheld on a case-by-case basis with their patients who have cardiovascular disease risk factors.

The issue of variants

SARS-CoV-2 continues to infect many people and produce new variants. These variants have changes to their genetic makeup (called mutations) and subtle changes to the structure of the virus. Altogether these changes can help some variants better evade antibodies and other measures taken by the immune system to contain the virus. They can also help the virus evade the monoclonal antibodies that are used to help prevent COVID-19.

In late February 2022, the U.S. Food and Drug Administration (FDA) recommended that the dose of Evusheld be doubled in cases where doctors were trying to prevent infections with the SARS-CoV-2 variants BA.1 and BA.1.1, which are part of the Omicron variant family.

The Omicron variant has also spawned a number of other subvariants, such as BA.2, 3, 4 and 5 (there are others). It is possible that in the coming months new subvariants or entirely new variants may form and spread.

Scientists at the Institut Pasteur in Paris and other research centres in France have been monitoring antibodies in blood samples from people who received Evusheld and other treatments. They have extracted these antibodies from blood samples and tested them against variants of SARS-CoV-2.

They found that Evusheld antibodies in those blood samples were able to attack the variant BA.1. in 19 out of 29 people and the variant BA.2 in 29 out of 29 people.

Participants had previously been vaccinated with at least three doses of an mRNA vaccine (usually from Pfizer-BioNTech). All participants either had disorders in which their immune systems attacked parts of the body or had received organ transplants. As a result, all participants were receiving medication to partially weaken their immune systems.

Four out of the 29 Evusheld recipients developed COVID-19. In three of these cases, the infection was caused by the Omicron variant and symptoms were mild. These cases occurred between 15 and 21 days after Evusheld injections.

A fourth person was infected with the subvariant BA.1 and developed severe symptoms of COVID-19 three weeks after receiving Evusheld. This person was hospitalized.

Researchers did not provide circumstances as to how participants became infected and this was not a randomized clinical trial, so the results have to be interpreted cautiously. Nevertheless, the report by the Institut Pasteur scientists suggests that 25 out of 29 people who received Evusheld subsequently had a reduced risk for developing COVID-19.

Extending Evusheld’s potential

In the Provent study, Evusheld was used as a form of pre-exposure prophylaxis (PrEP) against SARS-CoV-2. Interim results from another study called Tackle suggest that doubling the dose of Evusheld, from 300 mg to 600 mg, can reduce the risk of progression to severe illness in people who are treated early in the course of SARS-CoV-2 infection. It is possible that AstraZeneca may seek approval from regulatory agencies to use Evusheld in this way.

For the future

The study from the Institut Pasteur underscores the complexity of the current pandemic. Scientists can develop vaccines, drugs and monoclonal antibodies against SARS-CoV-2 and to varying degrees these interventions provide protection from developing severe COVID-19 or dying. However, as the virus continues to mutate, it is likely that a broad range of second-generation interventions—better antiviral drugs, vaccines and monoclonal antibodies—will be needed.

—Sean R. Hosein

REFERENCES:

1. 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. 
2. Takashita E, Kinoshita N, Yamayoshi S, et al. Efficacy of antiviral agents against the SARS-CoV-2 Omicron subvariant BA.2. New England Journal of Medicine. 2022 Apr 14;386(15):1475-1477.
3. Bruel T, Hadjadj J, Maes P, et al. Serum neutralization of SARS-CoV-2 Omicron sublineages BA.1 and BA.2 in patients receiving monoclonal antibodies. Nature Medicine. 2022; in press.
4. Kotton CN. Belt and Suspenders: Vaccines and tixagevimab/cilgavimab for prevention of COVID-19 in immunocompromised patients. Annals of Internal Medicine. 2022; in press.
5. Loo YM, McTamney PM, Arends RH, et al. The SARS-CoV-2 monoclonal antibody combination, AZD7442, is protective in nonhuman primates and has an extended half-life in humans. Science Translational Medicine. 2022 Mar 9;14(635):eabl8124.