Updated March 2: As the number of people receiving shots of the Pfizer-BioNTech and Moderna COVID-19 vaccines grows, so have reports of possible allergic reactions.
Allergy experts tell Allergic Living that it’s important to get to the bottom of the small number of severe reactions to the mRNA-based COVID-19 vaccines reported to date. But they also suspect there may well be more than one cause for the reactions.
While these reactions have generally been characterized as “anaphylaxis” in public health reports, Dr. Eric Macy, an allergist-immunologist at Kaiser Permanente in San Diego, and Dr. James Baker, a University of Michigan allergist-immunologist, said separately that they expect some of the reactions won’t prove to involve allergies and IgE antibodies. Instead, some cases may involve immune system mast cells being activated in a non-allergic fashion.
There has been considerable speculation that an allergy to polyethylene glycol (PEG), a component that envelops and protects the vaccine’s mRNA, may explain the reactions. Yet drug allergy expert Macy says it’s too soon to conclude that, stressing that true allergies to PEG “are vanishingly rare.”
Agreeing it’s too soon to blame PEG, Baker notes there is still incomplete information about those who reacted, including blood and lab tests to determine if symptoms were allergic in nature or had another cause. “We haven’t seen anything specific from the reactions that have occurred that would identify a cause,” says Baker, director of UMichigan’s food allergy center and a vaccine expert.
But one area of investigation will soon be underway. The U.S. National Institute of Allergy and Infectious Diseases (NIAID) is close to launching a multi-center study in March to find out whether people with allergies are indeed at any higher risk of a reaction than those without allergies.
In the meantime, the bigger risk may be that widespread attention on a few reports of reactions out of 48 million U.S. shots given (as of Feb. 28) may unnecessarily deter those with allergies from getting vaccinated, many allergists say.
“The vaccine is remarkably safe. People are doing well with it,” Baker says. He notes by comparison the coronavirus’s tragic impact. On Feb. 23, the U.S. reached 500,000 COVID-19 deaths.
Allergy Study Soon to Launch
To try to pinpoint who is at risk for reacting to the mRNA vaccines, NIAID is working on a study involving the Centers for Disease Control and Prevention (CDC) and the U.S. Food and Drug Administration (FDA). The study, to be conducted at several allergy centers, will enroll people with a history of severe allergies to foods, medications or insect stings to be vaccinated. Their rate of any serious reactions to the vaccine will be compared to a control group of people without allergies.
Volunteers will be asked for a detailed medical history and have their blood drawn before and after receiving the vaccine, which will be injected under close medical supervision. If there are reactions, researchers will search for clues in the blood and urine about what physiological processes are occurring, says Dr. Alkis Togias, NIAID’s branch chief of Allergy, Asthma and Airway Biology.
At the end of December, the rate of anaphylaxis to the COVID-19 vaccines approved for emergency use was about 1 in 100,0000 or 1 in 200,000, higher than the 1.31 in 1 million previously reported in an analysis with other vaccines, Togias says. That study, a three-year review of adverse reports to a national vaccine database, found that 85 percent of the 33 people who reacted had a history of atopic disease, particularly asthma, but also allergies or anaphylaxis.
With the mRNA COVID-19 vaccines, “the majority of people who have had severe reactions are giving a history of allergies,” Togias says. “How severe those allergies are, we don’t know.”
If the NIAID study does conclude that people with allergies have a higher risk of reacting, the next steps would be determining if some component of the vaccine is to blame.
“What we hope we will find is the rate is very low, and there is no difference in these groups,” Togias says. “But what we’re getting right now from the current data makes us concerned that maybe that is not the case, and we need to find out.”
2 Non-Allergic Immune Suspects
In a classic allergic reaction, an individual becomes sensitized to an allergen, and develops IgE antibodies to it. A component like PEG can be such an allergen. When that individual is again exposed to the allergen, the antibodies bind with the allergen, activating mast cells and setting off symptoms such as hives and nausea, and in more serious cases, shortness of breath or wheezing, swelling, and sometimes a sharp drop in blood pressure.
However, there are other reactions that look similar to anaphylaxis, but do not involve IgE antibodies, Macy explains.
One is an immunologic reaction involving the complement system, which normally helps the body attack and clear bacteria.
In this case, IgG antibodies to PEG, which are normally protective, bind to the PEG on the vaccine nanoparticles, activating the complement system and triggering the release of mast and other inflammatory cells.
Macy notes that a third possibility is a reaction to the nanoparticles themselves, which are little bits of messenger RNA encased in lipids (or fatty coating). If a bit of the vaccine, which is meant to be injected into the arm muscle, is accidentally injected into a vein, the nanoparticles could act as an irritant, activating the complement system and triggering mast cell release.
Symptoms of a classic allergic reaction and the other immunologic, but non-IgE mediated reactions “all look pretty similar,” he says. “People may say, ‘Oh, I’m having an allergic reaction.’ But the mechanisms are totally different.”
Need for Data, Other Vaccine Reaction Issues
In addition to studying the broader group of allergic individuals, Baker stresses that it’s important to gather data about the individuals who do report a severe reaction. The enzyme tryptase, for example, is released by mast cells during anaphylaxis. To measure tryptase levels, blood should be drawn within 90 minutes of the reaction starting. Baker says that did not take place with several of those who were sent to the ER after their COVID-19 mRNA inoculation.
On Dec. 28, the CDC updated its guidance to hospitals advising that health-care providers collect blood to measure tryptase and what’s called “terminal complement complex” shortly after a suspected severe allergic reaction. Terminal complement complex measurements can indicate the release of mast cells by the complement system.
Nor should other causes of reactions be discounted yet, Baker says. Certain underlying diseases can predispose people to symptoms such as itching and hives. Other reactions can include vasovagal reactions, which can lead to low blood pressure or fainting, and anxiety-related reactions, causing flushing, shortness of breath, racing heart and lightheadedness.
Allergic sensitization to PEG is not uncommon, since consumers may have exposure through skin creams or constipation remedies. However, as Macy notes, actual allergic reactions to PEG are considered rare.
A December 2020 study led by allergists at Massachusetts General Hospital says that an FDA review of reported PEG anaphylaxis between 2005 and 2017 showed an average of just four cases a year of anaphylactic reactions to PEG.
Baker, Macy and other experts suspect that, ultimately, there will be more than one explanation for the mRNA vaccine reactions. Consider as well: those experiencing reactions have reported a variety of different allergy histories – for instance, one has a biologic drug allergy, another a food allergy. (There are no food proteins in these vaccines.) Yet others who reacted report no prior allergies at all.
Millions of Shots Means More Reactions
On Dec. 30, the CDC updated its vaccine guidance and advised that people who have had an allergic reaction to either PEG or polysorbate to not get vaccinated. Polysorbate is not contained in either the Moderna or Pfizer vaccine, but the chemicals can cross-react.
For those with a history of anaphylaxis to any cause, the CDC says vaccine providers should observe patients for 30 minutes after vaccination. All others are to be monitored for 15 minutes.
The Johnson & Johnson COVID-19 vaccine, more recently approved In the U.S. and Canada, contains polysorbate. So does the U.K.-made AstraZeneca coronavirus vaccine (not yet approved in the U.S.). With the mRNA vaccines, the Mass General-led study recommends skin testing people who have had a severe reaction to PEG in the past.
If a PEG allergy is indeed one cause, you’d likely see a lot more reactions at the second dose of these 2-shot vaccines, Macy says. He notes that was not seen during the Pfizer and Moderna clinical trials. This again raises the question of other possible immune mechanisms.
Health-care workers are to start receiving the second dose of the Pfizer vaccine as soon as this week.
As the vaccines roll out, experts urge people to get the vaccines as soon as possible. The Moderna and Pzifer vaccines do not contain any food, drug or latex, and there’s no reason to avoid the shot because of any particular food or medication allergy. “No allergy to anything other than polyethelene glycol is of any clinical significance,” Macy says.