Review and Feature Article
The Risk of Allergic Reaction to SARS-CoV-2 Vaccines and Recommended Evaluation and Management: A Systematic Review, Meta-Analysis, GRADE Assessment, and International Consensus Approach

https://doi.org/10.1016/j.jaip.2021.06.006Get rights and content

Concerns for anaphylaxis may hamper severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization efforts. We convened a multidisciplinary group of international experts in anaphylaxis composed of allergy, infectious disease, emergency medicine, and front-line clinicians to systematically develop recommendations regarding SARS-CoV-2 vaccine immediate allergic reactions. Medline, EMBASE, Web of Science, the World Health Organizstion (WHO) global coronavirus database, and the gray literature (inception, March 19, 2021) were systematically searched. Paired reviewers independently selected studies addressing anaphylaxis after SARS-CoV-2 vaccination, polyethylene glycol (PEG) and polysorbate allergy, and accuracy of allergy testing for SARS-CoV-2 vaccine allergy. Random effects models synthesized the data to inform recommendations based on the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach, agreed upon using a modified Delphi panel. The incidence of SARS-CoV-2 vaccine anaphylaxis is 7.91 cases per million (n = 41,000,000 vaccinations; 95% confidence interval [95% CI] 4.02-15.59; 26 studies, moderate certainty), the incidence of 0.15 cases per million patient-years (95% CI 0.11-0.2), and the sensitivity for PEG skin testing is poor, although specificity is high (15 studies, very low certainty). We recommend vaccination over either no vaccination or performing SARS-CoV-2 vaccine/excipient screening allergy testing for individuals without history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient, and a shared decision-making paradigm in consultation with an allergy specialist for individuals with a history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient. We recommend further research to clarify SARS-CoV-2 vaccine/vaccine excipient testing utility in individuals potentially allergic to SARS-CoV2 vaccines or their excipients.

Key words

SARS-CoV-2
COVID-19
Vaccination
Adenovirus-vector vaccine
mRNA vaccine
Anaphylaxis
Allergic reactions
Polyethylene glycol
Polysorbate 80
Skin testing
Shared decision making
GRADE
Allergy
Allergy specialist

Abbreviations used

BCC
Brighton Collaboration criteria
CDC
U.S. Centers for Disease Control and Prevention
COVID-19
Coronavirus disease 2019
EUA
Emergency use authorization
GRADE
Grading of Recommendation, Assessment, Development, and Evaluation
IgE
Immunoglobulin E
PEG
Polyethylene glycol
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
VAERS
Vaccine Adverse Event Reaction System

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No funding has been received for this study.

Conflicts of interest: M. Greenhawt is a consultant for Aquestive; is a member of physician/medical advisory boards for DBV Technologies, Sanofi/Regeneron, Genentech, Nutricia, Novartis, Acquestive, Allergy Therapeutics, Pfizer, US World Meds, Allergenis, Aravax, and Prota, all unrelated to vaccines/vaccine development; is a member of the scientific advisory council for the National Peanut Board; is an associate editor for the Annals of Allergy, Asthma, and Immunology; is member of the Joint Taskforce on Allergy Practice Parameters; and has received honorarium for lectures from ImSci and MedLearningGroup. E. M. Abrams is a collaborator with the Institute for Health Metrics and Evaluation. M. Shaker is a member of the Joint Taskforce on Allergy Practice Parameters; has a family member who is CEO of Altrix Medical; and serves on the Editorial Board of the Journal of Food Allergy and the Annals of Allergy, Asthma, and Immunology. D. Khan is the president elect of the American Academy of Allergy, Asthma, and Immunology. J. Bernstein has received financial support from Sanofi Regeneron, AstraZeneca (unrelated to vaccines/vaccine development), Merck, Optinose, Takeda, CSL Behring, BioCryst, Pharming, the National Institutes of Health (NIH), Taylor Francis, INEOS; is Editor in Chief of the Journal of Asthma; is INEOS Medical Immunosurveillance Director, Vice Chair and Lectureship Chair of the American Academy of Allergy, Asthma, and Immunology (AAAAI) Foundation, Chairman of AFI, American College of Asthma, Allergy, and Immunology (ACAAI) Asthma Chair, Scientific Chair, and Young Investigator Award Chair; and serves of the Board of Directors and Scientific Committee of Interasma. D. Campbell is a part-time employee of DBV Technologies; reports grants from National Health and Medical Research Council of Australia and personal fees from Allergenis, Westmead Fertility Centre, and Financial Markets Foundation for Children. A. K. Ellis has participated in advisory boards for ALK Abello, AstraZeneca (unrelated to vaccines/vaccine development), Aralez, Bausch Health, LEO Pharma, Merck, Novartis, and Pfizer (unrelated to vaccines/vaccine development); has been a speaker for ALK Abello, The ACADEMY, Aralez, AstraZeneca, Medexus, and Mylan; her institution has received research grants from ALK Abello, Aralez, AstraZeneca, Bayer LLC, Green Cross Pharmaceuticals, Medexus, Novartis, Sanofi, and Regeneron; has also served as an independent consultant to Bayer LLC and Regeneron; and is also the Vice President of the Canadian Society of Allergy and Clinical Immunology. A. Fox is a member of the MHRA Expert Working Group of COVID Vaccine Reactions. M. H. Grayson has served on advisory boards for Aimmune, DBV, GSK, and Sanofi (not related to vaccines); has stock options in Invirsa, Inc; serves on the American Academy of Allergy, Asthma, and Immunology COVID-19 Task Force, and the Board of Directors for the American Board of Allergy and Immunology; is chair of the Medical Scientific Council and on the Board of Directors of the Asthma and Allergy Foundation of America; is a member of the Scientific Advisory Committee of the American Lung Association; and is the editor-in-chief elect for the Annals of Allergy, Asthma, and Immunology. C. H. Katelaris received an honorarium for Pfizer atopic dermatitis advisory board participation (not related to vaccines). D. Lang is on the Editorial Board for Allergy and Asthma Proceedings; Topic Editor for DynaMed; Associate Editor for Journal of Asthma; and Delegate to National Quality Forum representing the American Academy of Allergy, Asthma, and Immunology. J. Lieberman has received financial support from the American College of Asthma, Allergy, and Immunology, Aquestive, Aimmune, DBV, Biotest Pharma, and Regeneron; is associate editor of the Annals of Allergy, Asthma, and Immunology; Chair for the American College of Asthma, Allergy, and Immunology Food Allergy Committee; and Medical Director for Food Allergy Alliance of the MidSouth D. Mack is a member of the Board of Directors for the Canadian Society of Allergy and Clinical Immunology; serves on the Editorial Board of the Journal of Food Allergy; has provided consultation and speaker services for Pfizer, Aimmune, Merck, Covis, and Pediapharm; and has been part of an advisory board for Pfizer and Bausch Health; none of these works are related to vaccines. B. Mazer is the Associate Director of Canada’s COVID-19 Immunity Task Force but otherwise has no conflicts to declare. G. Mosnaim received research grant support from AstraZeneca (unrelated to vaccines/vaccine development), GlaxoSmithKline, and Propeller Health; owned stock in Electrocore; served as a consultant and/or member of a scientific advisory board for GlaxoSmithKline, Sanofi-Regeneron, Teva, Novartis, Astra Zeneca (unrelated to vaccines/vaccine development), Boehringer Ingelheim, and Propeller Health; and is the current president of the American Academy of Allergy, Asthma, and Immunology. D. Munblit reports giving paid lectures for Bayer and received funding from the 5-100 Russian Academic Excellence Project. S. Shahzad Mustafa is on the speakers bureaus for Genentech, Regeneron, GSK, AstraZeneca (unrelated to vaccines/vaccine development), and CSL Behring. J. Oppenheimer performs Research/Adjudication for AstraZeneca (unrelated to vaccines/vaccine development), GSK, Sanofi, Novartis; is a consultant for GSK, AstraZeneca (unrelated to vaccines/vaccine development), Sanofi; is associate editor of the Annals of Allergy Asthma Immunology and AllergyWatch; is section editor for Current Opinion of Allergy; receives royalties from UptoDate; and is a Board Liaison for the American Board of Internal Medicine for the American Board of Allergy and Immunology. A. Ramsey is on the speaker’s bureau for Sanofi/Regeneron and GSK. M. Rank has received financial support from the American College of Allergy, Asthma, and Immunology, the National Institutes of Health, and Levin Family Foundation; has served as chair of the American Academy of Allergy, Asthma, and Immunology Health Education Delivery Quality Interest Section; and is Research Director of the Phoenix Children’s Hospital Breathmobile. D. Stukus has received financial support from Aimmune, Before Brands, Abbott Nutrition, the American Academy of Pediatrics, American College of Allergy, Asthma, and Immunology; has served as committee chair for the American Academy of Allergy Asthma and Immunology and American College of Allergy, Asthma, and Immunology. M. L. K. Tang: has received speaker fees from Nestle Health Science, Abbot Nutrition; is a consultant to Bayer Pharmaceuticals and Abbot Nutrition; has received research Grants from National Health and Medical Research Council, Bayer Pharmaceuticals, and Abbott Nutrition; is an inventor on patents related to food allergy treatments; and is an employee at Prota Therapeutics. J. M. Tracy is a shareholder for Johnson & Johnson (purchased more than 10 years prior to this manuscript). P. J. Turner reports grants from UK Medical Research Council, National Institute for Health Research/Imperial Biomedical Research Center, UK Food Standards Agency, End Allergies Together, and Jon Moulton Charity Trust; personal fees and nonfinancial support from Aimmune Therapeutics, DBV Technologies, and Allergenis; personal fees and other from ILSI Europe and UK Food Standards Agency, outside the submitted work; is the current chairperson of the World Allergy Organization Anaphylaxis Committee, and joint chair of the Anaphylaxis Working group of the UK Resuscitation Council. D. Wallace is on the Kaleo-Advisory board; and aids Bryan-Consulting. J. Wang received institutional research funding from Regeneron, DBV, and Aimmune; consultancy fees from DBV, ALK Abello, and Genentech; and is an UpToDate author. M. Worm declares the receipt of honoraria or consultation fees by the following companies: ALK-Abelló Arzneimittel GmbH, Mylan Germany GmbH, Leo Pharma GmbH, Sanofi-Aventis Deutschland GmbH, Regeneron Pharmaceuticals, DBV Technologies S.A, Stallergenes GmbH, HAL Allergie GmbH, Allergopharma GmbH & Co.KG, Bencard Allergie GmbH, Aimmune Therapeutics UK Limited, Actelion Pharmaceuticals Deutschland GmbH, Novartis AG, Biotest AG., AbbVie Deutschland GmbH & Co. KG and Lilly Deutschland GmbH. T. K. Vander Leek has served on advisory boards and received honoraria from Aralez, Bausch Health, and Pfizer (unrelated to vaccines). D. B. K. Golden received speakers bureau honoraria from Genentech, Kaleo; clinical trial support from Genentech, Novartis, Pfizer (unrelated to vaccine/vaccine development), GSK, Regeneron; consulting fees from Aquestive; and royalties from UpToDate (section editor). The rest of the authors declare that they have no relevant conflicts of interest.

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