Some Reported Allergic Reactions to mRNA COVID-19 Vaccines Were Likely Stress Responses

NIAID Now | February 27, 2023

White card with black text recording two doses of COVID-19 vaccine.

A COVID-19 vaccination record card

Credit: NIAID

NIAID Investigators Demonstrate How Stress Responses Closely Mimic Allergic Reactions

Some responses to the mRNA COVID-19 vaccines reported as severe allergic reactions were likely a recently described, non-allergic condition called immunization stress-related response (ISRR), according to NIAID investigators. The symptoms of ISRR can closely mimic those of a severe allergic reaction known as anaphylaxis, a potentially life-threatening, systemic allergic reaction in which the immune system releases a dangerous flood of chemicals. These findings from a small study are being presented today at the 2023 Annual Meeting of the American Academy of Allergy, Asthma & Immunology in San Antonio. 

As defined by the World Health Organization, ISRR encompasses a range of signs and symptoms that may arise before, during or immediately after immunization and are related to stress from the process of immunization, not to the vaccine product. Some of the manifestations of ISRR are the same as those that occur during anaphylaxis, including a rapid pulse, throat tightness, lightheadedness, trouble breathing, and nausea.

The reported rate of severe allergic reactions to immunization with mRNA COVID-19 vaccines, while estimated to be on the order of just five cases per million doses administered, is still higher than that reported for conventional vaccines. To better understand this phenomenon, NIAID researchers assessed the safety of a second dose of an mRNA COVID-19 vaccine in people who had experienced a systemic allergic reaction after their first dose. The study was led by Muhammad B. Khalid, M.D., a clinical fellow in the NIAID Laboratory of Allergic Diseases, and Pamela A. Frischmeyer-Guerrerio, M.D., Ph.D., the laboratory chief.

The investigators enrolled 16 people ages 16 to 69 years who had a moderate or severe systemic allergic reaction to their first dose of the Moderna or Pfizer-BioNTech COVID-19 vaccine. The study participants were admitted for a minimum of four days to the Intensive Care Unit at the NIH Clinical Center in a closely supervised, safe and controlled environment. There, they received the Pfizer-BioNTech mRNA COVID-19 vaccine and a look-alike injection of placebo in a random order on different days. Neither the participants nor the investigators knew which shot was being given on which day. At admission and during the inpatient stay, participants underwent breathing tests and frequent blood draws so medical staff could discern the details of any allergic or other responses to the vaccine.

People who had an allergic reaction to the first dose of a vaccine would be expected to have an allergic reaction to subsequent doses with equal or greater severity. However, only three participants, or 19%, developed an allergic reaction within minutes of receiving the second dose of vaccine, and one reaction was mild while two were moderate. As expected, no one developed an allergic reaction to the placebo.

By contrast, nine study participants developed a non-allergic reaction within minutes of receiving the vaccine, and 11 developed a non-allergic reaction within minutes of receiving the placebo. The non-allergic reactions included numbness, tingling, dizziness, throat tightness, difficulty swallowing, and temporarily high blood pressure—signs and symptoms consistent with ISRR. Forty-five percent of these reactions were classified as moderate to severe.

To further probe the nature of the volunteers’ responses to mRNA COVID-19 vaccines, the study team administered an open-label booster dose of the Pfizer-BioNTech vaccine and performed skin testing for allergic reactions. Thirteen participants completed this part of the study and another three were scheduled to do so.

The skin testing began with a so-called skin-prick test. A tiny drop of the Pfizer-BioNTech vaccine, a vaccine component called polyethylene glycol (PEG), and a related chemical called polysorbate were placed on the skin, and a small prick was made through each drop into the skin. If this did not elicit a small, short-lived rash indicating an allergic response, the researchers injected a small amount of the vaccine into a superficial skin layer for an intradermal test.

The investigators found that none of the participants reacted to PEG or polysorbate. Two participants reacted to the vaccine during the intradermal test, but only one of these individuals had allergic reactions to every vaccine dose they received before and during the study. The other person had a reported allergic reaction only to the dose they received before entering the study. Taken together, these findings further support the hypothesis that some reports of allergic reactions to the mRNA COVID-19 vaccines were non-allergic responses, and that these methods of testing are not very predictive of who will have a reaction—whether allergic or ISRR—to the vaccine.  

People who have had a suspected allergic reaction to an mRNA COVID-19 vaccine should discuss it with their physician. If it was a true allergic reaction, then the individual should follow current medical advice regarding vaccination allergy. However, if the reaction was more consistent with ISRR, then the person can be reassured they have not had a severe immune reaction to the vaccine and can safely receive subsequent doses.

It is important to realize that ISRR can repeat at subsequent vaccinations. Physicians can suggest interventions that may reduce the symptoms of this condition.

The researchers expect to submit a complete and detailed report of their findings to a peer-reviewed journal for publication. An abstract of the study was published in a supplement to the Journal of Allergy and Clinical Immunology on February 3, 2023. For more information about this research, please visit and search using study identifier NCT04977479.


MB Khalid. COVID-19 mRNA vaccine-induced immunization stress-related response (ISRR) and anaphylaxis: an early look at COVAAR clinical outcomes. Presentation at the AAAAI 2023 Annual Meeting in San Antonio, Texas. Monday, Feb. 27, 2023, at 1 pm CT.

MB Khalid et al. COVID-19 mRNA vaccine-induced immunization stress-related response (ISRR) and anaphylaxis: an early look at COVAAR clinical outcomes. Journal of Allergy and Clinical Immunology DOI: 10.1016/j.jaci.2022.12.687 (2023).

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