Exploring rare and serious allergic reactions to mRNA vaccines for COVID-19

There have been reports of relatively rare serious allergic reactions to both the Pfizer-BioNTech and Moderna mRNA-based vaccines. Readers should bear in mind that while these reports can be alarming, they are rare.

Allergists associated with Massachusetts General Hospital and other leading research institutions in the U.S. have cooperated to try to understand why rare and serious allergic reactions to the mRNA vaccines may occur.

Non-COVID vaccines

In general, severe allergic reactions to vaccines are rare. A review of such reactions to vaccines for non-COVID-19 diseases found that they occurred at the rate of about 1 per million people. The risk of severe allergic reactions seemed similar regardless of age and gender.

The allergists noted that the vaccine solution usually contains extra ingredients called excipients, which have the following functions:

  • act as preservatives, preventing the growth of bacteria and fungi
  • protect the vaccine during transport and storage
  • amplify the immune response to the vaccine

Some excipients such as PEG (polyethelene glycol) and the related substance polysorbate help to stabilize the vaccine.

Focus on COVID-19 vaccines

Both the Pfizer-BioNTech and Moderna vaccines contain PEG. The purpose of PEG is to stabilize the mRNA that is at the core of the vaccines. The mRNA is enclosed by tiny fatty particles called lipid nanoparticles. Other COVID-19 vaccines, such as those being developed by AstraZeneca and Janssen, do not use PEG but instead use a related compound called polysorbate 80. Polysorbate 80 and other polysorbates are molecules similar in structure to PEG. Polysorbates are found in many products, including vitamin oils, vaccines and some anticancer drugs.

PEG is also found in some medicines and medical products. These include some medicines for treating constipation (Miralax) and bowel preparation formulations used prior to colonoscopy. A review by the FDA using data collected between 2005 and 2017 found that about four cases of allergic reactions per year were associated with colonoscopy preparations or laxatives. However, the PEG inside the two mRNA vaccines is different from the PEG used in medicines.

Some allergists have speculated that the rare but serious allergic reactions to the Pfizer-BioNTech and Moderna vaccines arise because these vaccines use a formulation of PEG called PEG2000. Furthermore, they add that people who developed serious allergic reactions during clinical trials of the vaccines were sensitized to this formulation of PEG through the use of previous PEG-containing compounds.

Note that the Centers for Disease Control and Prevention (CDC) has developed guidance on helping healthcare providers to recognize signs and symptoms of serious allergic reactions; these appear in our report on that agency’s findings, later in this issue of TreatmentUpdate. The CDC advises that “persons with an immediate allergic reaction to the first dose of an mRNA COVID-19 vaccine should not receive an additional dose of either of the mRNA COVID-19 vaccines.”

Perhaps the most important point that the allergists make is that people with a history of allergic reactions should not be pre-treated with antihistamines prior to receiving COVID-19 vaccinations, as these drugs may initially mask serious symptoms of an allergic reaction to these vaccines.

—Sean R. Hosein


Banerji A, Wickner PG, Saff R, et al. mRNA vaccines to prevent COVID-19 disease and reported allergic reactions: Current evidence and suggested approach. Journal of Allergy and Clinical Immunology: In Practice. 2021; in press.