Background and Overview

Tixagevimab and cilgavimab belong to a category of drugs called monoclonal antibodies (mAbs). Produced as a pair by the British-Swedish company AstraZeneca, these mAbs are distributed together under the trade name Evusheld and given together as two injections - one of each antibody.

As of January 2022, and with the exception of tixagevimab/cilgavimab, all approved COVID mAb treatments are intended for treatment only after a person has become infected with SARS-CoV2 (the virus that causes COVID019). What sets tixagevimab/cilgavimab (EVUSHELD) apart from other mAb treatments is that they are specifically designed for what doctors refer to as pre-exposure prophylaxis.

Defining Pre-Exposure Prophylaxis

Pre-exposure prophylaxis means prevention of disease in people who have not yet been infected. While this might sound similar to the role of the current COVID-19 vaccines, it’s important to point out that tixagevimab/cilgavimab treatments are not a substitute for COVID-19 vaccination in people who can get vaccinated and who will respond well to vaccination.

“Can get vaccinated” means that there is not a valid medical reason preventing you from being vaccinated. In other words, personal, political, religious, and philosophical objections to COVID-19 vaccination, or to vaccination in general, will not qualify you to receive tixagevimab/cilgavimab as a substitute for COVID-19 vaccination.

How Tixagevimab/Cilgavimab Works

Engineered with a very specific three-dimensional shape, tixagevimab/cilgavimab are designed to attach directly to specific locations on a protein on the SARS-CoV2 virus called the spike protein. The SARS-CoV2 virus uses this spike protein to enter the cell and attach to a specific cell protein called ACE-2.

Once the SARS-CoV2 virus is inside an infected cell it reproduces and then spreads to other cells.

By attaching to the spike protein, tixagevimab/cilgavimab effectively prevents the SARS-CoV2 from attaching to ACE-2 found in cells of the body.

In addition to engineering these two antibodies to attach to the binding region of the spike protein, AstraZeneca has engineered these antibodies to last for an extended period of time within the body before being destroyed. As a result, tixagevimab/cilgavimab is considered to be a long-acting treatment, although it is not as long-acting as vaccination.

Effects of Tixagevimab and Cilgavimab on COVID-19

When antibodies, like tixagevimab/cilgavimab, attach to the spike protein of the virus, scientists say that the virus is neutralized. Being neutralized can mean that the virus cannot attach to ACE-2 and infect other body cells. Sometimes, neutralized. can also mean that the virus cannot spread to other people.

Scientists are learning that it is easier to neutralize the SARS-CoV2 virus against attaching to ACE-2 and infecting cells of an infected person than it is to neutralize it against spreading to other people.

In the case of tixagevimab/cilgavimab, the main goal has been to proactively neutralize the virus by effectively preventing it from being able to attach to ACE-2. The combination of tixagevimab and cilgavimab works well in this sense, so the idea is to give these drugs to people prior to infection as a way to protect them from SARS-CoV2.

Defining Passive Vs. Active Immunity

The type of protection produced by mAbs, including tixagevimab/cilgavimab, is called passive immunity. In other words, the body is receiving protection by antibodies that are produced outside of the person whom they protect.

Passive immunity is very different from active immunity, or natural immunity, produced by your immune system as a result of either vaccination or infection by a virus that can cause disease.

The active immunity that is triggered by vaccination involves various types of immune cells, some of which produce antibodies. In many cases, including the case of SARS-CoV2, immunity can be boosted by additional exposures to the disease-causing agent or additional shots of the vaccine.

When this happens, your immune system is better able to identify and fight specific viruses during future exposures. In contrast, passive immunity comes only from the foreign antibodies, like mAbs, being introduced into the person.

As mentioned above, tixagevimab and cilgavimab have been designed to last longer in your body than most antibodies normally would, but they do tend to gradually weaken over. This means that you have good protection against the virus in the days and weeks follow the treatment, but then immunity decreases. In most cases, the body will have less than half the number of antibodies it did when mAb treatment was received.

Unless the treatment is readministered and considering the immune system did not naturally produce antibodies (like they would after receiving a vaccine) antibody levels – and protection - will continue to decrease.

Vaccination, on the other hand, provides fairly good protection two to three weeks after the first shot better protection two weeks after the second shot (six weeks after the first shot), and even better protection after a third shot.

As a result, we know that tixagevimab/cilgavimab provides better protection for the first couple of weeks after it is administered and vaccination provides better long-term protection.

FDA-Approved Usage of Tixagevimab/Cilgavimab

In December 2021, the US Food and Drug Administration (FDA) granted an emergency use authorization (EUA) of tixagevimab/cilgavimab. The EUA applies to people who are at least 12 years old and weigh at least 40 kg (88 lbs.), are not infected with SARS-CoV-2, and have no known recent exposure to an infected person. Such people can receive tixagevimab/cilgavimab if either of the following circumstances applies:

• The immune system of the person is moderately to severely compromise (due to a medical condition, medications, or other treatments that suppress the immune system). This is because the COVID-19 vaccination may not stimulate an adequate immune response in such people.

• Vaccination with any approved, available COVID-19 vaccine is not recommended for the person (due to the potential of severe adverse reaction to COVID-19 vaccines or components of such a vaccine). An example of a severe adverse reaction is a severe allergic reaction. Common reactions, such as fever, fatigue, pain and irritation at the site of injection, and body aches do not qualify as severe adverse reactions that would disqualify you from receiving a COVID-19 vaccine.

Take home message: While treatment with tixagevimab/cilgavimab (Evusheld) is not as effective as COVID-19 vaccination in healthy people, it can provide an added layer of protection for those who are unable to be vaccinated for medical reasons or who will not respond well to vaccination as a result of pre-existing medical conditions.

Pregnancy and Lactation

Instructions from AstraZeneca and from health authorities indicate that tixagevimab/cilgavimab should be used during pregnancy only if the “potential benefit outweighs the potential risk for the mother and the fetus”. If you fit into one of the categories of people in whom the treatment is approved (history of a severe reaction to COVID-19 vaccines before you could be fully vaccinated, or medical conditions or treatments that will blunt the effects of vaccination on your immunity), then the potential benefit does outweigh the potential risk, for the following reasons:

• Pregnancy increases your risk of developing severe COVID-19 if you do get infected.

• COVID-19 puts your fetus at risk (it is possible that a small number of tixagevimab/cilgavimab antibodies will pass through the placenta, providing the fetus some level of protection.

All of this means that pregnancy is more of a reason to receive monoclonal antibody treatment than to avoid it.

As for nursing mothers, it is unlikely that your newborn will absorb any antibodies that make it into your breastmilk. However, in the case that antibodies do make it all the way to the newborn’s blood, they would be helpful in providing added protection to the fetus.

How Tixagevimab and Cilgavimab are Administered

Tixagevimab and cilgavimab are administered by intramuscular (IM) injection. Rather than being mixed together in the same solution, each antibody is kept in its own container, administered through its own syringe, and are administered at the same time – one immediately after the other. The experience is similar to receiving two vaccine shots in the same appointment, except that you are receiving antibodies, rather than vaccines.

Limitations of Tixagevimab/Cilgavimab

As of January 2022, early data from AstraZeneca show that tixagevimab/cilgavimab retains potency - even against the highly contagious Omicron variant. Over the same period of time, other mAb combinations (including Eli Lilly and Regeneron) have been reported to be losing potency. Despite this apparent retained potency against Omicron, reports also suggest that the supply of tixagevimab/cilgavimab is fairly limited.

Side effects of tixagevimab/cilgavimab treatment tend to be mild and include things like bleeding, bruising, pain, soreness, or swelling at the injection site.

Some reports of heart problems happening subsequent to administration of the treatment have been reported, but these reports have been in people with cardiovascular disease and have not been shown to be the result of the antibody treatment.

References

Evusheld long-acting antibody combination retains neutralizing activity against Omicron variant in independent FDA study. News release. AstraZeneca. Accessed December 30, 2021.

FACT SHEET FOR HEALTHCARE PROVIDERS: EMERGENCY USE AUTHORIZATION FOR EVUSHELDTM (tixagevimab co-packaged with cilgavimab). Accessed December 30, 2021

National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. Retrieved December 26, 2021