Updated April 8 – Researchers are enrolling participants in a study to determine whether people with severe allergies or a mast cell disorder are at higher risk of allergic reactions to the COVID-19 mRNA vaccines than those without allergies.
The clinical trial, which will enroll 3,400 adults ages 18 to 69 at up to 30 centers across the United States, launched on April 7.
“The public understandably has been concerned about reports of rare, severe allergic reactions to the Moderna and Pfizer-BioNTech COVID-19 vaccines,” said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, the trial’s sponsor.
“The information gathered during this trial will help doctors advise people who are highly allergic or have a mast cell disorder about the risks and benefits of receiving these two vaccines. However, for most people, the benefits of COVID-19 vaccination far outweigh the risks,” said Fauci.
Since the Pfizer-BioNTech and Moderna COVID-19 vaccines rollout began in December 2020, millions of Americans – including those with severe allergies to foods, drugs and insect venom – have received the vaccines without any problems.
But reports of rare cases of anaphylaxis have led to questions about whether people with a history of allergies or mast cell disorders are more likely to have allergic reaction to the vaccines, and if so, why. The majority of anaphylactic reactions have been reported in women and in people with a history of allergies to a wide range of triggers, including foods, drugs, injectable medications or contrast dye.
Most Subjects Will Be Women
The multi-center trial will enroll over 2,000 people adults with a history of severe allergic reactions or mast cell disorder, a condition in which people experience episodes of anaphylaxis without a known allergy trigger. A control group will include nearly 1,400 people without allergies. Two-thirds of participants will be women. [See below: How Can I Enroll?]
Participants will be randomly assigned to receive either the Pfizer vaccine, the Moderna vaccine, or a placebo during their first visit. (The first part of the study is “blinded,” so that neither study subjects nor researchers know who got the actual vaccine with the first shot.)
Everyone gets an actual vaccine shot on the second visit, and three days after receiving that, participants will learn which dose they initially received.
During a visit for a shot, the participants will be observed for 90 minutes by allergists who are able to treat any reactions. Blood, urine and nasal swabs will be taken before each dose is given, and blood and urine will be taken after each shot.
If there are any reactions, researchers will analyze the samples and run genetic tests to try to determine what type of reaction occurred, says Dr. James R. Baker, co-chair of the study and director of the Mary H. Weiser Food Allergy Center at the University of Michigan.
Participants in the placebo group for the first shot will have their second dose scheduled at the appropriate interval, which is three weeks for the Pfizer vaccine and four weeks for Moderna.
“Everyone in this study will receive either the Pfizer or the Moderna vaccines,” Baker says. Results of the study are expected in late summer.
Allergies Vs. Mast Cells Activation
A U.S. Centers for Disease Control and Prevention (CDC) study puts the anaphylaxis rate at 2 to 5 people per one million vaccinations with the Pfizer-BioNTech or Moderna mRNA vaccines.
The rate of reactions to the mRNA vaccines seems a bit higher than the 1.31 in one million previously reported for other vaccines, such as the flu shot. “The rate may be slightly higher, but it’s certainly not orders of magnitude higher,” Baker notes.
With the mRNA vaccines, a study of 65,000 people vaccinated at Massachusetts General Hospital found about 2 percent reported milder symptoms that might indicate an allergic reaction.
Yet the causes of the reactions are unknown. Speculation about triggers has included an IgE-mediated allergy to polyethylene glycol (PEG), an ingredient in the mRNA vaccines. However experts, including Baker, say that is a very rare allergy.
Another explanation could be activation of mast cells through another, non-IgE mediated immune system process, which can mimic an allergic reaction.
Recently, researchers have suggested that some people’s mast cell receptors might be prone to over-responding to the small amounts of mRNA in the vaccines. Reactions involving the direct activation of mast cells tend to be less severe than a typical allergic reaction. “Immune reactions involving mast cell triggers tend to be less explosive than an IgE-mediated reaction,” Baker says.
In the reports of anaphylaxis after the mRNA vaccines, most people have reported what are considered lower-level anaphylactic reactions, including “cutaneous” symptoms such as a face swelling, hives, itching and rash, but not more serious symptoms, nor anaphylactic shock.
In the new clinical trial, if some patients react to the vaccine, researchers will conduct whole genome screening to see if any particular genetic variants are associated with the reactions to the vaccines, and whether people with a history of allergies are more likely to have those variants.
Although further research than this study would be needed, genetic variations in mast cell receptors might help to explain why some people have elevated IgE levels and are “sensitized” to a particular food – but can eat that food without a problem. Yet others, who have similar IgE levels to that food, will experience severe reactions.
“There could be genetic variations in different people that would lead to the activation of mast cells in response to the vaccine, and that might also predispose them to having anaphylaxis or more severe reactions to their allergens,” Baker says.
How Can I Enroll in the Study?
The NIH study includes sites in 20 states, including: Arizona, Arkansas, California, Colorado, Florida, Georgia, Illinois, Iowa, Maryland, Massachusetts, Michigan, Missouri, New York, North Carolina, Ohio, Pennsylvania, Tennessee, Texas, Virginia and Wisconsin. For contacts and locations, visit this ClinicalTrials.gov page (open the ‘show study locations’ tab). Not all centers have yet begun enrolling, so check back for updates.
Participants in the allergy group must have a history within the last five years of a severe reaction to foods, allergen immunotherapy, or insect venom; an immediate allergic reaction to two or more drugs; or a convincing clinical history, including a positive skin test, of a reaction to a drug or vaccine. The study will also include people diagnosed with a mast cell disorder.
People in the non-allergy group must have no history of allergic disorders, including allergic asthma, rhinitis, eczema or chronic hives.
Among those excluded are: people who have taken a biologic therapy within six months of the trial, anyone who has used oral steroids within 28 days, or anyone who has recently had the coronavirus.
For more information on the study:
Visit ClinicalTrials.gov, the study identification number is NCT04761822.