North Bethesda, MD—Fear of side effects or adverse reactions is one of the most common concerns expressed by Americans who refuse to get COVID-19 vaccines. Among the worst of those are severe allergic reactions, which, albeit rare, have been reported with the mRNA and other vaccines.

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is sponsoring an ongoing clinical trial to determine if those who are generally highly allergic or have a mast-cell disorder are at increased risk for an immediate, systemic allergic reaction to the Moderna or Pfizer-BioNTech COVID-19 vaccines. The hope is that increased information might combat vaccine hesitancy.

If a systemic allergic reaction, defined as one that affects parts of the body beyond the injection site, occurs after vaccination, researchers will assess whether the reactions are more frequent in participants who are highly allergic or have a mast-cell (MC) disorder than in participants with no allergic history. In mast-cell disorder, certain white blood cells behave abnormally or are overly active, causing life-threatening reactions that appear as severe allergic reactions.

The phase II trial, Systemic Allergic Reactions to SARS-CoV-2 Vaccination, also will seek to determine whether a genetic pattern or other factors can predict who is at most risk. 

“The public understandably has been concerned about reports of rare, severe allergic reactions to the Moderna and Pfizer-BioNTech COVID-19 vaccines,” said Anthony S. Fauci, MD, NIAID director. “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.”

With millions of Americans having received the mRNA vaccines, which were given emergency use authorization by the FDA, most of the rare, severe allergic reactions have occurred in people with a history of allergies, with many of those reporting previous anaphylaxis.

About 3,400 adults up to age 69 years will be enrolled at 35 academic allergy-research centers nationwide. About 60% of study participants, group 1, must have either a history of severe allergic reactions or a diagnosis of a mast-cell disorder, while 40% of participants, group 2, will not.

For group one participants, the specific types of allergic reactions, which must have occurred in the past 5 years, are related to food, insect stings, or allergen immunotherapy and require treatment with epinephrine; or are immediate allergic reactions to a vaccine or one or more drugs.

Group 2 will enroll people with no history of any allergic reactions or allergic disease and no history of an MC disorder. About two-thirds of participants in each group will be female, because severe allergic reactions to vaccines in general―and the Moderna and Pfizer-BioNTech COVID-19 vaccines in particular―mainly occur in females.

Site investigators are allergists trained to recognize and treat anaphylaxis, and emergency medications, oxygen, and medical equipment will be available to treat allergic reactions as needed. Participants will be observed for at least 90 minutes after each injection—as opposed to 15 to 30 minutes in routine immunization—in case any type of reaction occurs.

Study staff will collect blood, urine, and nasal swabs from participants before each injection, and blood and urine after each injection. Follow-up calls will also be used to assess participants’ health, with the last one 7 days after the final vaccine dose.

Results are expected late this summer.

In terms of MC disorder, a study of two cases early this year, reported in the Journal of Allergy & Clinical Immunology, provided “initial evidence that mRNA COVID-19 vaccines are safe in patients with mastocytosis and MC activation symptoms, including anaphylaxis,” according to the authors from Harvard Medical School with Portuguese colleagues.

“Because some of the vaccines contain polyethylene glycol (PEG), a rare cause of IgE-mediated and complement-mediated anaphylaxis, “it has been speculated that PEG could be involved in the initial anaphylactic events,” those researchers write. “Although patients with MC activation disorders including mastocytosis are at risk for MC activation and anaphylaxis when exposed to certain drugs and procedures, there is no evidence of increased sensitization or reactivity to PEG. Patients with MC activation disorders may be good candidates for mRNA severe acute respiratory syndrome coronavirus 2 vaccines whenever indicated, with premedication, in an appropriate setting (hospital with available intensive care unit) and under medical surveillance.”

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