Stanford, CA—Fear of allergic reactions is thought to be one of the factors fueling widespread hesitancy related to COVID-19 vaccines. But a new study suggests that those adverse effects are rare, usually mild, and treatable.

“We wanted to understand the spectrum of allergies to the new vaccines and understand what was causing them,” explained the study's senior author, Kari Nadeau, MD, PhD, of Stanford University School of Medicine.

The study, which was published in JAMA Network Open, analyzed 22 potential allergic reactions to the first 39,000 doses of Pfizer-BioNTech and Moderna COVID-19 vaccines administered to healthcare providers at Stanford. The research was undertaken from December 18, 2020, to January 27, 2021, shortly after the vaccines received emergency use authorization from the FDA.

The goal was to characterize the immunologic mechanisms underlying allergic reactions to these vaccines.

Those who received at least one of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision anaphylaxis codes were included; suspected allergy cases were identified and invited for follow-up allergy testing. Of the 22 patients, most, 91%, were women, with a mean age of 40.9 years. The majority, 68%, had a clinical allergy history, and 77% met Brighton anaphylaxis criteria, although all reactions were fully resolved.

Researchers graded allergic reactions using standard definitions, including Brighton criteria. In addition, they conducted skin-prick testing to polyethylene glycol (PEG) and polysorbate 80 (P80). Histamine (1 mg/mL) and filtered saline (negative control) were used for internal validation.

Also used was basophil activation testing after stimulation for 30 minutes at 37°C, and concentrations of immunoglobulin (Ig) G and IgE antibodies to PEG were obtained to determine possible mechanisms.

Results indicate that, of patients who underwent skin-prick tests, 0 of 11 tested positive to PEG, 0 of 11 tested positive to P80, and 1 of 10 (10%) tested positive to the same brand of mRNA vaccine used to vaccinate that individual. Among those same participants, 10 of 11 (91%) had positive basophil activation test results to PEG, and 11 of 11 (100%) had positive basophil activation test results to their administered mRNA vaccine. While no PEG IgE was detected, PEG IgG was found in tested individuals who had an allergy to the vaccine.

“Based on this case series, women and those with a history of allergic reactions appear at an elevated risk of mRNA vaccine allergy,” the authors conclude. “Immunological testing suggests non–IgE-mediated immune responses to PEG may be responsible in most individuals.”

In other words, most of those in the study who developed reactions were allergic to an ingredient that helps stabilize the COVID-19 vaccines but did not demonstrate allergies to the vaccine components that provide immunity to the SARS-CoV-2 virus.

The researchers pointed out that because those allergic reactions occurred through indirect activation of allergy pathways, that makes them easier to mitigate than some other allergic responses.

“It's nice to know these reactions are manageable,” Dr. Nadeau said. “Having an allergic reaction to these new vaccines is uncommon, and if it does happen, there's a way to manage it."

The research also provides a roadmap on how manufacturers can reformulate the vaccines to make them less likely to trigger allergic responses, he added.

Estimated rates of severe vaccine-related anaphylaxis—allergic reactions serious enough to require hospitalization—are 4.7 and 2.5 cases per million doses for the Pfizer and Moderna vaccines, respectively, according to the federal Vaccine Adverse Event Reporting System, which often doesn’t include those that are mild or moderate.

To better understand the frequency and severity of reactions, the research team examined the medical records of healthcare workers who received 38,895 doses of mRNA-based COVID-19 vaccines—31,635 doses were from Pfizer and 7,260 doses from Moderna.

In reviewing medical records, the authors looked for the following symptoms:
• Hives
• Swelling of the mouth, lips, tongue, or throat
• Shortness of breath, wheezing, or chest tightness
• Changes in blood pressure or loss of consciousness

Of the 22 recipients, 15 had physician-documented histories of prior allergic reactions, including 10 to antibiotics, nine to foods, and eight to nonantibiotic medications, with some recipients having multiple allergies.

“What's important is what we didn’t find, as much as what we did find,” Dr. Nadeau said. "It does not seem that the mRNA itself causes the allergic reactions.” Allergic reactions mediated by IgG and basophils can be managed with antihistamines, fluids, corticosteroids, and close observation, according to the study, which suggests that many individuals who have had a reaction to their first vaccine dose can safely receive a second dose under medical supervision.

PEG is widely used as a stabilizer in household products, cosmetics, and medications. The authors suggested that women likely have more exposure, which may possibly explain why they seem to have had more vaccine allergies.

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