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What risk factors and mechanisms can help explain documented allergic reactions to Food and Drug Administration–authorized mRNA COVID-19 vaccines?
In this case series of 22 patients with suspected vaccine allergy receiving clinical skin prick testing (SPT) and basophil activation testing (BAT) to the whole vaccine and key components (ie, polyethylene glycol [PEG] and polysorbate 80), none exhibited immunoglobulin (Ig) E–mediated allergy to components via SPT. However, most had positive BAT results to PEG, and all had positive BAT results to their administered mRNA vaccine, with no patient sample having detectable PEG IgE.
These findings suggest that non–IgE-mediated allergic reactions to PEG may be responsible for many documented cases of allergy to mRNA vaccines.
As of May 2021, more than 32 million cases of COVID-19 have been confirmed in the United States, resulting in more than 615 000 deaths. Anaphylactic reactions associated with the Food and Drug Administration (FDA)–authorized mRNA COVID-19 vaccines have been reported.
To characterize the immunologic mechanisms underlying allergic reactions to these vaccines.
Design, Setting, and Participants
This case series included 22 patients with suspected allergic reactions to mRNA COVID-19 vaccines between December 18, 2020, and January 27, 2021, at a large regional health care network. Participants were individuals who received at least 1 of the following International Statistical Classification of Diseases and Related Health Problems, Tenth Revision anaphylaxis codes: T78.2XXA, T80.52XA, T78.2XXD, or E949.9, with documentation of COVID-19 vaccination. Suspected allergy cases were identified and invited for follow-up allergy testing.
FDA-authorized mRNA COVID-19 vaccines.
Main Outcomes and Measures
Allergic reactions were graded using standard definitions, including Brighton criteria. Skin prick testing was conducted to polyethylene glycol (PEG) and polysorbate 80 (P80). Histamine (1 mg/mL) and filtered saline (negative control) were used for internal validation. Basophil activation testing after stimulation for 30 minutes at 37 °C was also conducted. Concentrations of immunoglobulin (Ig) G and IgE antibodies to PEG were obtained to determine possible mechanisms.
Of 22 patients (20 [91%] women; mean [SD] age, 40.9 [10.3] years; 15 [68%] with clinical allergy history), 17 (77%) met Brighton anaphylaxis criteria. All reactions fully resolved. 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 these 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. No PEG IgE was detected; instead, PEG IgG was found in tested individuals who had an allergy to the vaccine.
Conclusions and Relevance
Based on this case series, women and those with a history of allergic reactions appear at have an elevated risk of mRNA vaccine allergy. Immunological testing suggests non–IgE-mediated immune responses to PEG may be responsible in most individuals.
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Accepted for Publication: June 6, 2021.
Published: September 17, 2021. doi:10.1001/jamanetworkopen.2021.25524
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Warren CM et al. JAMA Network Open.
Corresponding Author: Kari C. Nadeau, MD, PhD, Sean N. Parker Center for Allergy and Asthma Research at Stanford University, 240 Pasteur Dr, BMI Room 1755, Palo Alto, CA 94304 (firstname.lastname@example.org).
Author Contributions: Dr Nadeau had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: A. Lee, Shah, Do, Chang, Park, Shamji, Schilling, Sindher, Tsai, Akdis, Nadeau.
Acquisition, analysis, or interpretation of data: Warren, Snow, A. Lee, Shah, Heider, Blomkalns, Betts, Buzzanco, Gonzalez, Chinthrajah, Do, Dunham, G. Lee, O'Hara, Sisodiya, Smith, Galli, Akdis.
Drafting of the manuscript: Warren, Snow, A. Lee, Shah, Heider, Dunham, Park, Shamji, Sindher, Smith, Nadeau.
Critical revision of the manuscript for important intellectual content: Warren, Snow, A. Lee, Shah, Blomkalns, Betts, Buzzanco, Gonzalez, Chinthrajah, Do, Chang, G. Lee, O'Hara, Shamji, Schilling, Sisodiya, Tsai, Galli, Akdis, Nadeau.
Statistical analysis: Snow, Heider.
Obtained funding: Tsai, Nadeau.
Administrative, technical, or material support: Warren, Snow, Blomkalns, Betts, Buzzanco, Gonzalez, Chinthrajah, O'Hara, Park, Shamji, Schilling, Sisodiya, Tsai, Nadeau.
Supervision: Warren, Chinthrajah, Dunham, Sisodiya, Galli, Akdis, Nadeau.
Conflict of Interest Disclosures: Dr Warren reported receiving personal fees from Alladapt Immunotherapeutics and Food Allergy Research Education outside the submitted work. Dr Chinthrajah reported receiving grants from the National Institute of Allergy and Infectious Diseases, Food Allergy Research & Education, Astellas, Regeneron, and Stanford Maternal and Child Health Research Institute and serving on the advisory boards of Alladapt Therapeutics, Novartis, Genentech, Sanofi, Allergenis, and Nutricia outside the submitted work. Dr Sindher reported receiving grants from the National Institutes of Health, Regeneron, DBV Technologies, Aimmune, Novartis, the Consortium of Food Allergy Research, and Food Allergy Research & Education and serving on the advisory committee for AstraZeneca and DBV Technologies during the conduct of the study. Dr Tsai reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Galli reported receiving grants from the National Institute of Allergy and Infectious Diseases during the conduct of the study. Dr Akdis reported receiving grants from Novartis, Scibase, Allergopharma, the Swiss National Science Foundation, and the European Commission Horizon 2020 CURE outside the submitted work. Dr Nadeau reported receiving grants from the National Institute of Allergy and Infectious Diseases, the National Heart, Lung, and Blood Institute, the National Institute of Environmental Health Sciences, and Food Allergy Research & Education; serving as director of the World Allergy Organization; serving as advisor for Cour Pharma; serving on the national scientific committee of Immune Tolerance Network and the National Institutes of Health clinical research centers; being cofounder of Before Brands, Latitude, Alladapt, and IgGenix outside the submitted work; and having patents for an oral formula for decreasing food allergy risk and treatment for food allergy, for granulocyte-based methods for detecting and monitoring immune system disorders issued, for methods and assays for detecting and quantifying pure subpopulations of white blood cells in immune system disorders, and for microfluidic device and diagnostic methods for allergy testing based on detection of basophil activation pending. No other disclosures were reported.
Funding/Support: This study was supported by grant U19AI104209 from the Asthma and Allergic Diseases Cooperative Research Centers, grant R01AI140134 from the National Institutes of Health, the National Institute of Allergy and Infectious Disease SARS Vaccine study, the Parker Foundation, the Crown Foundation, and the Sunshine Foundation.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We would also like to acknowledge Vanitha Sampath, PhD (Sean N. Parker Center for Allergy and Asthma Research, Stanford University), for her extensive contributions throughout the manuscript preparation and submission processes. She was compensated for her time.
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