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December 29, 2021

Questions Remain About Who Will Get Monoclonal Antibodies for COVID-19 Preexposure Prophylaxis

JAMA. 2022;327(3):207-208. doi:10.1001/jama.2021.23557
JAMA Medical News Audio (18:20)
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Every day for weeks this past fall, Brian Koffman, MD, would Google “AZD7442, AZD7442, AZD7442.”

He finally hit pay dirt December 8, when he discovered that the US Food and Drug Administration had authorized AstraZeneca’s long-acting monoclonal antibody combination, AZD7442 (Evusheld), for COVID-19 preexposure prophylaxis in adults and children at least 12 years old who don’t have an adequate immune response to COVID-19 vaccination or can’t be fully vaccinated.


Although the FDA has authorized other companies’ monoclonal antibody products for COVID-19 postexposure prophylaxis and for the treatment of mild to moderate COVID-19 in patients at risk of developing more severe disease, AZD7422 is the first to receive Emergency Use Authorization (EUA) for preexposure prophylaxis, or PrEP.

“My reaction was a combination of incredible excitement, relief, and what are my next steps to make sure I can get it for myself and my community?” said the 70-year-old Koffman, a retired family physician in Chula Vista, California, who was diagnosed with chronic lymphocytic leukemia (CLL) in 2005 and cofounded the nonprofit CLL Society in 2013.

Who Is It for?

The FDA authorized AZD7442, which is administered in 2 intramuscular injections, 1 of tixagevimab and 1 of cilgavimab, for 2 groups of people:

  • Those whose medical condition or immunosuppressive therapy has left them with a moderate to severely compromised immune system that might not adequately respond to COVID-19 vaccination. They might be receiving treatment for solid tumor or blood cancers, immunosuppressive therapy to prevent rejection of a solid organ transplant, or chimeric antigen receptor (CAR)–T cell therapy, according to the FDA’s AZD7442 fact sheet for clinicians.

  • Individuals who’ve had severe reactions to a COVID-19 vaccine or its components and, therefore, can’t get fully vaccinated.

Who Is It Not for?

Under an EUA, a product can be used only for the indications outlined in the authorization and not off-label.

As the FDA said in its press release announcing the EUA for AZD7442, “Pre-exposure prevention with Evusheld is not a substitute for vaccination in individuals for whom COVD-19 vaccination is recommended.”

Healthy people who want AZD7442 just because they don’t want to get vaccinated shouldn’t be able to obtain it, although, Koffman said, he expects some will slip through.

Numbers Don’t Add Up

Number of doses the federal government has bought from AstraZeneca:

  • 600 000 to be distributed to state and territorial health departments at no cost on a pro rata basis.

  • 100 000 for the Department of Defense.

Number of people in the US who might benefit from AZD7442:

  • As many as 10 million, Myron Cohen, MD, a leader of the National Institutes of Health’s COVID-19 Prevention Network, said in an interview. “You have a pretty big imbalance.” Cohen’s role with the network has been collaborating with industry in the development of monoclonal antibodies.

Save the Dates

AstraZeneca began manufacturing AZD7442 before receiving the EUA, a company spokesperson said in an email.

  • Delivery of first doses: Around the first of the year.

  • Delivery of the last of the 700 000 doses: Spring 2022.

  • Delivery of any more doses? “After the initial 700,000 doses are utilized, we will coordinate with the US government to either continue to supply the federal government doses or begin distributing product via traditional commercial channels,” the spokesperson said.

“We are committed to providing [AZD7442] as quickly as possible to all markets in which we enter firm agreements,” she added, noting that AstraZeneca has also agreed to produce it for countries other than the US. “We already hold inventory of finished product that exceeds near-term forecast demand, and manufacturing capacity has been reserved with significant further quantities of product already in various stages of manufacture in the supply chain.”

She would not say how many AZD7442 doses AstraZeneca expects to produce each month.

Unanswered Questions

Echoing the FDA’s news release about the product’s EUA, the AstraZeneca spokesperson said that “individuals who believe they are candidates for [AZD7442] should reach out to their health care provider.”

The problem is that “even to this day, it is hard for patients and physicians to understand who might benefit the most. It goes along with the lack of manuscripts” about the AZD7442 clinical trials, said Cohen, who has been fielding emails about COVID-19 PrEP from both patients and physicians for weeks.

The primary data supporting the AZD7442 EUA came from PROVENT (A Phase III Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study in Adults to Determine the Safety and Efficacy of AZD7442 for Pre-exposure Prophylaxis of COVID-19).

Although AstraZeneca announced topline PROVENT results in an August press release and presented updated data at IDWeek 2021 in late September, detailed findings had not yet been published when AZD7442 received an EUA.

“We would like to see published, peer-reviewed papers about the results,” said Cohen, director of the University of North Carolina Institute for Global Health and Infectious Diseases. “The studies that I’m involved with, we kill ourselves to put them in a [preprint] and then in a journal. We just don’t do press releases.”

Only 196 of the 5197 unvaccinated adults who participated in PROVENT had a compromised immune system, although more than 75% of the participants had comorbidities such as obesity or cardiac disease that can diminish the immune response to COVID-19, according to slides provided by AstraZeneca. However, under the EUA, simply having obesity or cardiac disease (or both) isn’t enough to qualify for AZD7442.

Since there won’t be nearly enough AZD7442 to go around to everyone with a compromised immune system, physicians will have to determine which patients have the most pressing need, which isn’t rocket science, Cohen said.

Zero antibodies after 3 vaccine doses, high-dose steroid treatment, and the absence of B cells, which are needed to help fight off infections, are all among factors associated with an especially poor immune response to vaccines, he said. “The NIH has several programs trying to look observationally at who responds to vaccines and who does not.”

After eligible patients get their first AZD7442 dose, another question looms: When is it time to get the second dose? The FDA indicated that the monoclonal antibody combination may be effective for PrEP for 6 months. Preliminary pharmacokinetic modeling that had not been peer-reviewed suggested protection could last up to 12 months. Or is the optimal timing somewhere in between?

The Omicron Wrinkle

Whether monoclonal antibodies can fend off Omicron remains to be seen, since clinical trials took place before the new SARS-CoV-2 variant was first reported November 24 and deemed a variant of concern by the World Health Organization and the US within a week.

In a press release December 16, AstraZeneca reported that a laboratory study conducted by FDA scientists found that the company’s monoclonal antibody combination retained neutralizing activity against the Omicron variant at levels within the range of neutralizing titers found in someone who’d previously been infected with SARS-CoV-2. The researchers tested AstraZeneca’s product against a pseudovirus made with the full Omicron variant spike protein.

A study that wasn’t peer-reviewed found that in the laboratory, Omicron resisted Regeneron’s monoclonal antibody combination of casirivimab and imdevimab (REGEN-COV), which has EUAs for treating COVID-19 and postexposure prophylaxis.

On the other hand, other laboratory research that had not been peer-reviewed found that sotrovimab, GlaxoSmithKline and Vir Biotechnology’s investigational SARS-CoV-2 monoclonal antibody, retained effectiveness against all Omicron spike protein mutations. Sotrovimab is being studied for PrEP in hematopoietic stem cell transplant recipients.

Competition’s Coming

AZD7442 is likely to have competition in the COVID-19 PrEP space.

“The bottom line is the FDA opened up the door,” Cohen said.

About 2 weeks before the AstraZeneca product received an EUA for that use, Regeneron applied for one for its casirivimab and imdevimab combination, he said.

Cohen coauthored a recent study that found that compared with placebo, the Regeneron antibodies, which already have EUAs for treating COVID-19 and postexposure prophylaxis, reduced the risk of asymptomatic and symptomatic infection in infected individuals’ household members.

The published data covered 1 month after participants received shots of the Regeneron antibodies or placebo. Subsequent analyses showed that protection was maintained for up to 8 months after participants received the shots, according to a Regeneron press release.

“If Omicron becomes dominant, they’re going to have to switch out another monoclonal,” Cohen noted.

The Upshot

Despite all the questions that remain, “I’m really excited that an agent has received an EUA for preexposure prophylaxis for people who need it,” Cohen said.

Still, he said, “a lot of education of physicians and patients is necessary.”

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Article Information

Conflict of Interest Disclosures: Dr Koffman spoke at a recent press briefing about AZD7442, for which AstraZeneca made a contribution to the CLL Society.

4 Comments for this article
Prioritizing Use of Therapeutic MAbs
Barry Cooper, MD | Heart Transplant Patient
I received a flyer this week from the University of Pennsylvania Transplant Team indicating that "patients who are in the high risk category and have not responded to 3 doses of vaccine (or who have medical contraindications to being vaccinated) will be entered into a lottery system [to determine who will receive the combination monoclonal antibody preparation tixagevimab and cilgavimab".

This raises the question as how one determines that a patient has not responded.

Antibody testing, albeit imperfect, would seem to be a better method than a lottery system to determine how the drug is distributed to transplant
patients who are on "maintenance" doses of immunosuppressive drugs (past the higher doses needed during the initial post transplant period).

Prioritizing and Increasing Limited Resources: Using Mortality and Not Antibody Level Data
Brian Koffman, MDCM | CLL Society
Thank you to JAMA for bringing attention to the issues facing the immunocompromised/immunosuppressed (IC/IS) community.

What is urgently needed for all who might benefit is an adequate supply of Evusheld (tixagevimab/ cilgavimab), the only monoclonal antibody combination (mAb) now authorized for PrEP. Surely a successful effort like the one that resulted in more than adequate vaccine doses could be made again for this potentially lifesaving medication, and others in development for PrEP, for the most vulnerable.

In the meantime there is an uncoordinated national and global response to the present severe shortage, ranging from first-come-first-served in
some locales, to lotteries in others, and still others where committees of experts are rationing the scarce doses based on estimates of who is at the greatest risk.

While CLL Society's priority is advocating for quicker, wider, and more equitable distribution, we favor thoughtful and equitable rationing for now. This should include looking at data on mortality rates with Covid-19, not at antibody responses to vaccination. We do not know what level, if any, of spike protein is protective in the IC/IS community and we have one small study suggesting that serological response to vaccine was not associated with mortality in hematological malignancies (1).

We should and can do better for those who are most likely to have severe disease or die from Covid-19.


1. Pagano L, Salmanton-García J, Marchesi F, et al. COVID-19 in vaccinated adult patients with hematological malignancies. Preliminary results from EPICOVIDEHA [published online ahead of print, 2021 Nov 8]. Blood. 2021;blood.2021014124. doi:10.1182/blood.2021014124

CONFLICT OF INTEREST: AstraZeneca, Lilly and Regeneron have made program grants to the nonprofit CLL Society for our CLL patient education and services
How Do We Increase Availability of Evusheld ASAP?
Stephenie Christos | 51 Year Old Kidney Transplant Patient
I’ve read this article and keep thinking I’m missing a couple of zeros. How could the U.S. only have ordered enough drug for 700,000 people when 7-10 million (most vulnerable) people need this?

I’m just a mom who is also a kidney transplant patient but I (and people like me) have been living in a bubble for almost 2 years. We are following all the covid rules to stay safe and do the right thing and we need help. Finally something comes along that can protect us and they don’t order enough and not until Spring 2022? Not
only have people like me been tucked away, but our families have too. Who can we contact to advocate for us?
Antibody testing
Lewis Birnbaum, BS | Personal
Will Evushield product a positive COVID antibody test or is there a way for patients to know if it is active in their bodies?