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

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  What risk factors and mechanisms can help explain documented allergic reactions to Food and Drug Administration–authorized mRNA COVID-19 vaccines?

Findings  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.

Meaning  These findings suggest that non–IgE-mediated allergic reactions to PEG may be responsible for many documented cases of allergy to mRNA vaccines.

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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Article Information

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 (knadeau@stanford.edu).

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.

References
1.
Shimabukuro  TT , Cole  M , Su  JR .  Reports of anaphylaxis after receipt of mRNA COVID-19 vaccines in the US—December 14, 2020-January 18, 2021.   JAMA. 2021;325(11):1101-1102. doi:10.1001/jama.2021.1967PubMedGoogle ScholarCrossref
2.
US Centers for Disease Control and Prevention. Selected adverse events reported after COVID-19 vaccination. Updated August 2, 2021. Accessed April 21, 2021. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/adverse-events.html
3.
Sampath  V , Rabinowitz  G , Shah  M ,  et al.  Vaccines and allergic reactions: the past, the current COVID-19 pandemic, and future perspectives.   Allergy. 2021;76(6):1640-1660. doi:10.1111/all.14840PubMedGoogle ScholarCrossref
4.
Khan  MS , Ali  SAM , Adelaine  A , Karan  A .  Rethinking vaccine hesitancy among minority groups.   Lancet. 2021;397(10288):1863-1865. doi:10.1016/S0140-6736(21)00938-7PubMedGoogle ScholarCrossref
5.
Rüggeberg  JU , Gold  MS , Bayas  JM ,  et al; Brighton Collaboration Anaphylaxis Working Group.  Anaphylaxis: case definition and guidelines for data collection, analysis, and presentation of immunization safety data.   Vaccine. 2007;25(31):5675-5684. doi:10.1016/j.vaccine.2007.02.064PubMedGoogle ScholarCrossref
6.
Mukai  K , Gaudenzio  N , Gupta  S ,  et al.  Assessing basophil activation by using flow cytometry and mass cytometry in blood stored 24 hours before analysis.   J Allergy Clin Immunol. 2017;139(3):889-899.e11. doi:10.1016/j.jaci.2016.04.060PubMedGoogle ScholarCrossref
7.
Appel  MY , Nachshon  L , Elizur  A , Levy  MB , Katz  Y , Goldberg  MR .  Evaluation of the basophil activation test and skin prick testing for the diagnosis of sesame food allergy.   Clin Exp Allergy. 2018;48(8):1025-1034. doi:10.1111/cea.13174PubMedGoogle ScholarCrossref
8.
Paranjape  A , Tsai  M , Mukai  K ,  et al.  Oral immunotherapy and basophil and mast cell reactivity in food allergy.   Front Immunol. 2020;11:602660. doi:10.3389/fimmu.2020.602660PubMedGoogle Scholar
9.
Castells  MC , Phillips  EJ .  Maintaining safety with SARS-CoV-2 vaccines.   N Engl J Med. 2021;384(7):643-649. doi:10.1056/NEJMra2035343PubMedGoogle ScholarCrossref
10.
Stone  CA  Jr , Liu  Y , Relling  MV ,  et al.  Immediate hypersensitivity to polyethylene glycols and polysorbates: more common than we have recognized.   J Allergy Clin Immunol Pract. 2019;7(5):1533-1540.e8. doi:10.1016/j.jaip.2018.12.003PubMedGoogle ScholarCrossref
11.
Calogiuri  G , Foti  C , Nettis  E , Di Leo  E , Macchia  L , Vacca  A .  Polyethylene glycols and polysorbates: two still neglected ingredients causing true IgE-mediated reactions.   J Allergy Clin Immunol Pract. 2019;7(7):2509-2510. doi:10.1016/j.jaip.2019.05.058PubMedGoogle ScholarCrossref
12.
Stone  CA  Jr , Rukasin  CRF , Beachkofsky  TM , Phillips  EJ .  Immune-mediated adverse reactions to vaccines.   Br J Clin Pharmacol. 2019;85(12):2694-2706. doi:10.1111/bcp.14112PubMedGoogle ScholarCrossref
13.
Wenande  E , Garvey  LH .  Immediate-type hypersensitivity to polyethylene glycols: a review.   Clin Exp Allergy. 2016;46(7):907-922. doi:10.1111/cea.12760PubMedGoogle ScholarCrossref
14.
Meller  S , Gerber  PA , Kislat  A ,  et al.  Allergic sensitization to pegylated interferon-α results in drug eruptions.   Allergy. 2015;70(7):775-783. doi:10.1111/all.12618PubMedGoogle ScholarCrossref
15.
Pfaar  O , Mahler  V .  Allergic reactions to COVID-19 vaccinations—unveiling the secret(s).   Allergy. 2021;76(6):1621-1623. doi:10.1111/all.14734PubMedGoogle ScholarCrossref
16.
Kozma  GT , Shimizu  T , Ishida  T , Szebeni  J .  Anti-PEG antibodies: properties, formation, testing and role in adverse immune reactions to PEGylated nano-biopharmaceuticals.   Adv Drug Deliv Rev. 2020;154-155:163-175. doi:10.1016/j.addr.2020.07.024PubMedGoogle ScholarCrossref
17.
Povsic  TJ , Lawrence  MG , Lincoff  AM ,  et al; REGULATE-PCI Investigators.  Pre-existing anti-PEG antibodies are associated with severe immediate allergic reactions to pegnivacogin, a PEGylated aptamer.   J Allergy Clin Immunol. 2016;138(6):1712-1715. doi:10.1016/j.jaci.2016.04.058PubMedGoogle ScholarCrossref
18.
Banerji  A , Wickner  PG , Saff  R ,  et al.  mRNA vaccines to prevent COVID-19 disease and reported allergic reactions: current evidence and suggested approach.   J Allergy Clin Immunol Pract. 2021;9(4):1423-1437.PubMedGoogle ScholarCrossref
19.
Badiu  I , Geuna  M , Heffler  E , Rolla  G .  Hypersensitivity reaction to human papillomavirus vaccine due to polysorbate 80.   BMJ Case Rep. 2012;2012:bcr0220125797. doi:10.1136/bcr.02.2012.5797PubMedGoogle Scholar
20.
Hong  L , Wang  Z , Wei  X , Shi  J , Li  C .  Antibodies against polyethylene glycol in human blood: a literature review.   J Pharmacol Toxicol Methods. 2020;102:106678. doi:10.1016/j.vascn.2020.106678PubMedGoogle Scholar
21.
Takayama  R , Inoue  Y , Murata  I , Kanamoto  I.   Characterization of nanoparticles using DSPE-PEG2000 and soluplus.   Colloids Interfaces. 2020;4(3):28. doi:10.3390/colloids4030028Google ScholarCrossref
22.
Bruusgaard-Mouritsen  MA , Johansen  JD , Garvey  LH .  Clinical manifestations and impact on daily life of allergy to polyethylene glycol (PEG) in ten patients.   Clin Exp Allergy. 2021;51(3):463-470. doi:10.1111/cea.13822PubMedGoogle ScholarCrossref
23.
Cabanillas  B , Akdis  C , Novak  N .  Allergic reactions to the first COVID-19 vaccine: a potential role of Polyethylene glycol?   Allergy. 2021;76(6):1617-1618.PubMedGoogle ScholarCrossref
24.
Zhou  ZH , Stone  CA  Jr , Jakubovic  B ,  et al.  Anti-PEG IgE in anaphylaxis associated with polyethylene glycol.   J Allergy Clin Immunol Pract. 2021;9(4):1731-1733.e3. doi:10.1016/j.jaip.2020.11.011PubMedGoogle ScholarCrossref
25.
Clark  S , Wei  W , Rudders  SA , Camargo  CA  Jr .  Risk factors for severe anaphylaxis in patients receiving anaphylaxis treatment in US emergency departments and hospitals.   J Allergy Clin Immunol. 2014;134(5):1125-1130. doi:10.1016/j.jaci.2014.05.018PubMedGoogle ScholarCrossref
26.
McNeil  MM , Weintraub  ES , Duffy  J ,  et al.  Risk of anaphylaxis after vaccination in children and adults.   J Allergy Clin Immunol. 2016;137(3):868-878. doi:10.1016/j.jaci.2015.07.048PubMedGoogle ScholarCrossref
27.
Baden  LR , El Sahly  HM , Essink  B ,  et al; COVE Study Group.  Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.   N Engl J Med. 2021;384(5):403-416. doi:10.1056/NEJMoa2035389PubMedGoogle ScholarCrossref
28.
Polack  FP , Thomas  SJ , Kitchin  N ,  et al; C4591001 Clinical Trial Group.  Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine.   N Engl J Med. 2020;383(27):2603-2615. doi:10.1056/NEJMoa2034577PubMedGoogle ScholarCrossref
29.
Thompson  MG , Burgess  JL , Naleway  AL ,  et al.  Interim estimates of vaccine effectiveness of BNT162b2 and mRNA-1273 COVID-19 vaccines in preventing SARS-CoV-2 infection among health care personnel, first responders, and other essential and frontline workers—Eight U.S. locations, December 2020-March 2021.   MMWR Morb Mortal Wkly Rep. 2021;70(13):495-500. doi:10.15585/mmwr.mm7013e3PubMedGoogle ScholarCrossref
30.
Turner  PJ , Jerschow  E , Umasunthar  T , Lin  R , Campbell  DE , Boyle  RJ .  Fatal anaphylaxis: mortality rate and risk factors.   J Allergy Clin Immunol Pract. 2017;5(5):1169-1178. doi:10.1016/j.jaip.2017.06.031PubMedGoogle ScholarCrossref
31.
Al-Aly  Z , Xie  Y , Bowe  B .  High-dimensional characterization of post-acute sequelae of COVID-19.   Nature. 2021;594(7862):259-264. doi:10.1038/s41586-021-03553-9PubMedGoogle ScholarCrossref
32.
Taquet  M , Geddes  JR , Husain  M , Luciano  S , Harrison  PJ .  6-Month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records.   Lancet Psychiatry. 2021;8(5):416-427. doi:10.1016/S2215-0366(21)00084-5PubMedGoogle ScholarCrossref
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