Immunosuppressed individuals living in the United States and Israel have been among the first to receive a novel new “vaccine” that preventively boosts their defenses against COVID-19 infection with a cocktail of long-acting antibodies.

The vaccine by AstraZeneca, branded as Evusheld, works on the principle of “passive immunization”, and contains two long-acting monoclonal antibodies (tixagevimab and cilgavimab) that bind to the SARS-CoV-2 spike protein preventing the virus from interacting with the human ACE2 receptor, thus reducing the risk of developing symptomatic disease.

The US Food and Drug Administration issued an Emergency Use Authorization for the vaccine in December 2021, for use in individuals who do not develop an adequate immune response after receiving other conventional COVID vaccines.  The US government reserved 700,000 doses at the time, but last week increased the purchase of the antibody combo to 1.7 million doses – at a cost of $855 million. Such treatments could be particularly important in the US, which has had comparatively higher death rates from COVID, per capita, than most other high income countries – something experts link to its comparatively lower vaccination rates.

Israel also has approved the drug and is deploying it through its local health funds, while Bahrain is reportedly about to do so. The European Medicines Agency is evaluating the treatment, which is unlikely to be available quickly in most low- and middle-income countries because of its high price tag of around $500 a dose – in comparison to about $28 for an mRNA vaccine dose.

Evusheld: Targeted at people who do not respond well to vaccines

Evusheld is intended for immunosuppressed people, to directly increase the amount of antibodies in their bodies. The treatment, given in two consecutive intramuscular injections, was reported in clinical trials reviewed by the FDA to have reduced severe morbidity and mortality from COVID by 83%. The trials were before the Omicron variant.

The shots are given prior to exposure to COVID, unlike other monoclonal antibody treatments for COVID, including those produced by Regeneron, GlaxoSmithKline and Eli Lilly.

“Vaccines have proven to be the best defense available against COVID-19. However, there are certain immune-compromised individuals who may not mount an adequate immune response to COVID-19 vaccination, or those who have a history of severe adverse reactions to a COVID-19 vaccine and therefore cannot receive one and need an alternative prevention option,” said Dr. Patrizia Cavazzoni, director of the FDA’s Center for Drug Evaluation and Research, in the December announcement of Evusheld’s approval.

“Today’s action authorizes the use of the combination of two monoclonal antibodies to reduce the risk of developing COVID-19 in these individuals.”

She stressed the treatment is not a substitute for vaccination in individuals for whom COVID-19 vaccination is recommended.

‘Passive immunization’

The jabs operate on the principles of what experts describe as “passive immunization.”

“When we give a regular vaccine, we expect to train the immune system,” Prof. Cyrille Cohen, head of the Immunology Lab at Israel’s Bar-Ilan University, told Health Policy Watch. “We are showing the immune system a pathogen and asking the body to generate antibodies or T-cells against that pathogenic-like substance.”

“In other words, ‘active immunization’ means we are giving the body the opportunity to generate its own antibodies. In contrast, passive immunization is when we take laboratory-made antibodies or those from recovered patients and inject them into the highest risk population to give them an extra layer of protection.

“We are giving them an artificial way to fight the virus because we don’t expect them to generate antibodies on their own,” Cohen explained.

Treatment aimed at stopping hospitalizations of the most vulnerable

The treatment arrived on the market at a time when many fully-vaccinated individuals with underlying medical conditions are being hospitalized with Omicron at the same or even higher rates than the unvaccinated.

“People have to understand that people with deficient immune systems are at mercy of germs that healthy people are not worried about,” Cohen said.

Evusheld is available for people over the age of 12 who weigh at least 40 kg, are not infected with the virus or who have not been recently exposed to the virus, and who suffer from a pre-existing medical condition, including having undergone a bone marrow or organ transplant, as well as undergoing CAR-T or B-cell depletion therapy for cancer or other conditions.  It can be administered regardless of whether an individual was vaccinated previously or not with a conventional jab.

Not all antibody treatments are the same

The first monoclonal antibody treatments entered the public arena with a splash in October 2020, after then-US President Donald Trump, who had been infected with COVID-19, took Regeneron’s polyclonal antibody cocktail, REGEN-COV, a combination of two monoclonal antibodies (casirivimab and imdevimab) designed specifically to block the progress of a COVID-19 infection. At about the same time, the drug was approved by the FDA for compassionate use, and soon after, the treatment received an Emergency Use Authorization.

However, Regeneron and other similar treatments have since failed to perform against Omicron. As a result, in January, the FDA revised its authorization of REGEN-COV and another antibody treatment (bamlanivimab and etesevimab administered together), limiting their use to only when an individuals has already been infected with or exposed to another variant – one that is susceptible to these treatments.

“Because data show these treatments are highly unlikely to be active against the Omicron variant, which is circulating at a very high frequency throughout the United States, these treatments are not authorized for use in any US states, territories and jurisdictions at this time,” Cavazzoni said in a statement.

“In the future, if patients in certain geographic regions are likely to be infected or exposed to a variant that is susceptible to these treatments, then use of these treatments may be authorized in these regions.”

Despite its FDA approval, some researchers have also questioned the use of Evusheld against Omicron:  “Most antibody-based treatments are not effective against Omicron,” said Dr. Erez Garty, head of science communications at Israel’s Davidson Institute of Science Education, located in the Weizmann Institute of Science, saying he is not yet convinced.

“There is lab evidence that Evusheld has a better neutralizing effect against Omicron than some [other] antibody based treatments,” Garty explained. “But this type of treatment is very sensitive to change in variants. With the Omicron subvariant BA2.  now rising we don’t know how effective [the vaccine] will be.”

WHO Recommended treatments

WHO recommended treatments also don’t yet include the so-called passive vaccine of Evusheld – although the Organization has recently approved another monoclonal antibody treatment for already infected patients.

That was Sotrovimab, which received a WHO approval in mid-January, for patients with non-severe COVID-19, but who are at risk for developing severe disease.

François Lamontagne, Professor of Medicine at the Université de Sherbrooke, who sits on WHO’s Guideline Development Group, told Health Policy Watch that Sotrovimab consists of antibodies directed against a specific part of the virus that prevents entry of the virus into cells. This drug is given intravenously, requiring one infusion.

Lamontagne noted, however, that the panel only provided a “weak” recommendation of the treatment because the effectiveness of sotrovimab against Omicron is still uncertain.

WHO also has yet to make a recommendation on two other COVID treatments, Merck’s monulpiravir and Pfizer’s Paxlovid – which operate on different principles.  This despite the fact the drugs are already being widely sold in high income countries.  The pharma companies also have made commitments to sell the drugs at cost to many low- and middle-income countries either bilaterally or via the UN-supported Medicines Patents Pool (MPP), which negotiates licenses with pharma for the use of drugs in resource-constrained settings.

Image Credits: Wikimedia Commons, Eli Lilly.