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. 2021 Sep 1;4(9):e2125524.
doi: 10.1001/jamanetworkopen.2021.25524.

Assessment of Allergic and Anaphylactic Reactions to mRNA COVID-19 Vaccines With Confirmatory Testing in a US Regional Health System

Christopher Michael Warren  1   2 , Theo Thomas Snow  1 , Alexandra S Lee  1 , Mihir Mukesh Shah  1 , Anja Heider  3 , Andra Blomkalns  4 , Brooke Betts  5 , Anthony S Buzzanco  6 , Joseph Gonzalez  6 , R Sharon Chinthrajah  1   7 , Evan Do  1 , Iris Chang  1 , Diane Dunham  1 , Grace Lee  8 , Ruth O'Hara  9 , Helen Park  10 , Mohamed H Shamji  11   12 , Lisa Schilling  5 , Sayantani B Sindher  1   7 , Deepak Sisodiya  5 , Eric Smith  1 , Mindy Tsai  1   13 , Stephen J Galli  1   13   14 , Cezmi Akdis  3 , Kari C Nadeau  1   7
Affiliations

Assessment of Allergic and Anaphylactic Reactions to mRNA COVID-19 Vaccines With Confirmatory Testing in a US Regional Health System

Christopher Michael Warren et al. JAMA Netw Open. .

Abstract

Importance: 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.

Objective: 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.

Exposures: 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.

Results: 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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Conflict of interest statement

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.

Figures

Figure 1.
Figure 1.. Study Flowchart
aNote that it is possible but not highly probable that some people received a COVID-19 dose outside Stanford Medicine during this time period. Most mRNA vaccine recipients during this time were Stanford-affiliated health care workers because public access to the vaccine was not authorized by the Santa Clara County Health Authorities for residents aged 65 years or older until January 26, 2021. bT78.2XXA, anaphylaxis, initial encounter; T80.52XA, anaphylactic reaction due to vaccination, initial encounter; T78.2XXD, anaphylaxis, subsequent encounter; E949.9, vaccine or biological substance causing adverse effect in therapeutic use.
Figure 2.
Figure 2.. Basophil Activation Testing (BAT) Assay on Example Participant Using Vaccine, Anti–Immunoglobulin E (IgE), and Saline
BAT assay on example participant with allergic reaction to the vaccine. Color indicates intensity of forward scatter and gated cells, with red being greater than orange; orange greater than green, and green greater than blue. FSC-H indicates forward side scatter-height; Comp-FITC-A, compensation–fluorescein isothiocyanate–area.
See this image and copyright information in PMC

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