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 ClinicalTrials.gov and search using study identifier NCT04977479.

References:

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).

The first Food and Drug Administration approval of a treatment for eosinophilic esophagitis, announced in May 2022, marked a vital achievement not only for people with the disease, but also for scientists including a NIAID grantee whose research helped lay a foundation for this milestone.

Eosinophilic esophagitis, or EoE, is a chronic disease characterized by an overabundance of a specific type of white blood cell, an eosinophil, in the esophagus. The disease is driven by allergic inflammation due to food. This inflammation damages the esophagus and prevents it from working properly. For people with EoE, swallowing even small amounts of food can be a painful and worrisome choking experience. EoE is the most common reason people must go to emergency departments for a healthcare provider to remove food stuck in their esophagus. People with EoE are often left to contend with the frustration and anxiety of a sometimes-lengthy list of foods to avoid, a poor quality of life, and a higher risk of depression. In severe cases, a feeding tube may be the only option to ensure proper caloric intake and adequate nutrition. About 160,000 people in the United States are living with EoE.

NIAID funding enabled Marc E. Rothenberg, M.D., Ph.D., at Cincinnati Children’s in Ohio to conduct basic and preclinical research starting in 1999 that uncovered the molecular cause of EoE. This finding suggested the type of drug needed to treat the disorder.

Before 2001, some in the medical community thought EoE was a form of acid reflux disease. Dr. Rothenberg’s lab published a paper that year establishing that EoE is actually an allergic disorder. The paper showed that mice exposed to an inhaled respiratory allergen developed EoE. This helped focus subsequent studies of EoE on the role of allergic inflammation.

A few years later, two seminal papers from Dr. Rothenberg’s lab identified the molecular changes taking place in the esophagus of people with EoE and showed that a cell-signaling molecule called IL-13 was responsible for many of those changes. IL-13 and another cell-signaling molecule, IL-4, together drive allergic inflammation in many diseases.

The first of these two key papers reported the results of an analysis of gene expression in cells on the lining of the esophagus in people with and without EoE. The study identified 574 genes that were copied into RNA “transcripts”—the instructions for making proteins—in greater or smaller numbers in people with EoE than in healthy people. This EoE transcript signature, or transcriptome, served as a key reference for subsequent studies of the disorder.

The second paper demonstrated in 2007 that many of the EoE-associated genes identified in the earlier paper are directly activated by IL-13 in cells lining the esophagus, implicating this molecule as a major regulator of the biological pathways involved in EoE. This finding suggested that IL-13-blocking drugs might effectively treat the disease. The study further showed that 98% of the EoE transcriptome reverted to normal levels of gene expression in people whose EoE was successfully treated with a class of steroid hormones called glucocorticoids. This indicated that the EoE transcriptome changes in response to changes in signs and symptoms of the disease. Dr. Rothenberg and colleagues therefore proposed using the EoE transcriptome to monitor the efficacy and mechanism of action of IL-13-blocking drugs at the molecular level.

Several years later, Dr. Rothenberg designed and led the first clinical trial to test the efficacy of an anti-IL-13 monoclonal antibody for treating EoE. The investigators found that the antibody lowered levels of eosinophils in the esophagus and returned the expression of 29 key genes in the EoE transcriptome to normal levels in most treated participants. This and related molecular analyses from the trial, funded by Novartis Pharma AG of Basel, Switzerland, further supported Dr. Rothenberg’s theory that EoE was driven by IL-13.

These findings contributed to a body of foundational EoE research developed by a multitude of scientists and physicians. This scientific foundation, among many other factors, led Regeneron Pharmaceuticals Inc. of Tarrytown, New York, and Sanofi of Paris to begin testing one of their drugs for the treatment of EoE. The drug, a monoclonal antibody called dupilumab, works by blocking both IL-13 and IL-4.

Ultimately, Regeneron and Sanofi conducted a Phase 3 clinical trial showing dupilumab substantially improved the signs and symptoms of EoE compared to a placebo. Based on these results, FDA approved dupilumab for the treatment of the disease on May 20, 2022, making it the first medicine specifically indicated to treat EoE in the United States.

NIAID-funded basic and translational research continues to contribute to the development of preventive and therapeutic strategies for dozens of allergic, immunologic, and infectious diseases.

References:

A Mishra, et al. An etiological role for aeroallergens and eosinophils in experimental esophagitis. The Journal of Clinical Investigation DOI: 10.1172/JCI10224 (2001).

C Blanchard, et al. Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis. The Journal of Clinical Investigation DOI: 10.1172/JCI26679 (2006).

C Blanchard, et al. IL-13 involvement in eosinophilic esophagitis: Transcriptome analysis and reversibility with glucocorticoids. Journal of Allergy and Clinical Immunology DOI: 10.1016/j.jaci.2007.10.024 (2007).

ME Rothenberg, et al. Intravenous anti–IL-13 mAb QAX576 for the treatment of eosinophilic esophagitis. Journal of Allergy and Clinical Immunology DOI: 10.1016/j.jaci.2014.07.049 (2015).