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Risk of Second Allergic Reaction to SARS-CoV-2 VaccinesA Systematic Review and Meta-analysis

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

Question  What is the risk of an immediate severe allergic reaction to a second dose of a SARS-CoV-2 mRNA vaccine among individuals who had an immediate allergic reaction of any severity to their first dose?

Findings  In this systematic review and meta-analysis of 22 studies including 1366 patients revaccinated under the supervision of an allergist, there was a low incidence (0.16%) of immediate severe allergic reactions associated with receiving a second dose of SARS-CoV-2 mRNA vaccine among individuals who had an immediate allergic reaction to their first dose. There were no deaths.

Meaning  This study suggests that there is a low risk of a severe immediate allergic reaction associated with a second SARS-CoV-2 mRNA vaccine dose among persons who had an immediate allergic reaction to their first dose.


Importance  Vaccination against SARS-CoV-2 is a highly effective strategy to prevent infection and severe COVID-19 outcomes. The best strategy for a second dose of vaccine among persons who had an immediate allergic reaction to their first SARS CoV-2 vaccination is unclear.

Objective  To assess the risk of severe immediate allergic reactions (eg, anaphylaxis) to a second dose of SARS-CoV-2 mRNA vaccine among persons with immediate allergic reactions to their first vaccine dose.

Data Sources  MEDLINE, Embase, Web of Science, and the World Health Organization Global Coronavirus database were searched from inception through October 4, 2021.

Study Selection  Included studies addressed immediate allergic reactions of any severity to a second SARS-CoV-2 vaccine dose in persons with a known or suspected immediate allergic reaction (<4 hours after vaccination) after their first SARS-CoV-2 vaccine dose. Studies describing a second vaccine dose among persons reporting delayed reactions (>4 hours after vaccination) were excluded.

Data Extraction and Synthesis  Paired reviewers independently selected studies, extracted data, and assessed risk of bias. Random-effects models were used for meta-analysis. The GRADE (Grading of Recommendation, Assessment, Development, and Evaluation) approach evaluated certainty of the evidence.

Main Outcomes and Measures  Risk of severe immediate allergic reaction and repeated severe immediate allergic reactions with a second vaccine dose. Reaction severity was defined by the reporting investigator, using Brighton Collaboration Criteria, Ring and Messmer criteria, World Allergy Organization criteria, or National Institute of Allergy and Infectious Diseases criteria.

Results  Among 22 studies of SARS-CoV-2 mRNA vaccines, 1366 individuals (87.8% women; mean age, 46.1 years) had immediate allergic reactions to their first vaccination. Analysis using the pooled random-effects model found that 6 patients developed severe immediate allergic reactions after their second vaccination (absolute risk, 0.16% [95% CI, 0.01%-2.94%]), 232 developed mild symptoms (13.65% [95% CI, 7.76%-22.9%]), and, conversely, 1360 tolerated the dose (99.84% [95% CI, 97.09%-99.99%]). Among 78 persons with severe immediate allergic reactions to their first SARS-CoV-2 mRNA vaccination, 4 people (4.94% [95% CI, 0.93%-22.28%]) had a second severe immediate reaction, and 15 had nonsevere symptoms (9.54% [95% CI, 2.18%-33.34%]). There were no deaths. Graded vaccine dosing, skin testing, and premedication as risk-stratification strategies did not alter the findings. Certainty of evidence was moderate for those with any allergic reaction to the first dose and low for those with severe allergic reactions to the first dose.

Conclusions and Relevance  In this systematic review and meta-analysis of case studies and case reports, the risk of immediate allergic reactions and severe immediate reactions or anaphylaxis associated with a second dose of an SARS-CoV-2 mRNA vaccine was low among persons who experienced an immediate allergic reaction to their first dose. These findings suggest that revaccination of individuals with an immediate allergic reaction to a first SARS-CoV-2 mRNA vaccine dose in a supervised setting equipped to manage severe allergic reactions can be safe.

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Article Information

Accepted for Publication: December 26, 2021.

Published Online: February 21, 2022. doi:10.1001/jamainternmed.2021.8515

Corresponding Author: Matthew Greenhawt, MD, MBA, MSc, Food Challenge and Research Unit, Section of Allergy and Clinical Immunology, Children’s Hospital Colorado, University of Colorado School of Medicine, 13123 E 16th Ave, Aurora, CO 80045 (matthew.greenhawt@childrenscolorado.org).

Author Contributions: Drs Chu and Greenhawt had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Chu, Abrams, Stone, Krantz, Shaker, Greenhawt.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Chu, Abrams, Golden, Stone, Krantz, Shaker, Greenhawt.

Critical revision of the manuscript for important intellectual content: Chu, Abrams, Golden, Blumenthal, Wolfson, Krantz, Shaker, Greenhawt.

Statistical analysis: Chu, Abrams, Greenhawt.

Administrative, technical, or material support: Chu, Wolfson, Stone, Krantz, Shaker, Greenhawt.

Supervision: Stone, Greenhawt.

Conflict of Interest Disclosures: Dr Golden reported receiving grants from Pfizer, GSK, Novartis, Genentech, and Regeneron outside the submitted work. Dr Blumenthal reported receiving grants from the National Institutes of Health/National Institute of Allergy and Infectious Diseases, Agency for Healthcare Research and Quality (AHRQ), Massachusetts General Hospital Executive Committe on Research, Department of Medicine (DOM) Transformative Scholar Award, and DOM COVID-19 Junior Investigator Initiative; personal fees from Weekley, Schulte, Valdes, Murman, Tonelli, Piedmont Liability Trust, and Vasios, Kelly & Strollo PA; and royalties from UpToDate Inc outside the submitted work. Dr Stone reported receiving grants from the AHRQ and American Academy of Allergy, Asthma & Immunology Foundation Career Development Award during the conduct of the study. Dr Shaker reported being a member of the Joint Taskforce on Allergy Practice Parameters; having a family member who is CEO of Altrix Medical; being an associate editor for the Annals of Allergy, Asthma & Immunology; and serving on the editorial boards of the Journal of Allergy and Clinical Immunology In Practice and the Journal of Food Allergy. Dr Greenhawt reported serving as a consultant for Aquestive; being a member of physician/medical advisory boards for DBV Technologies, Sanofi/Regeneron, Genentech, Nutricia, Novartis, Acquestive, Allergy Therapeutics, AstraZeneca, ALK-Abello, Pfizer, US World Meds, Allergenis, Aravax, and Prota, all unrelated to vaccines/vaccine development or COVID-19 treatment; being an unpaid member of the scientific advisory council for the National Peanut Board and medical advisory board of the International Food Protein Induced Enterocolitis Syndrome Association; being a member of the Brighton Collaboration Criteria Vaccine Anaphylaxis 2.0 working group; being the senior associate editor for the Annals of Allergy, Asthma & Immunology; being a member of the Joint Taskforce on Allergy Practice Parameters; receiving honoraria for lectures from ImSci, MedLearningGroup, and multiple state/local allergy societies; and receiving past research support ending in 2020 from the AHRQ (K08-HS024599). No other disclosures were reported.

Disclaimer: Dr Abrams reported she is an employee of the Public Health Agency of Canada (PHAC). The views expressed are her own and not that of the PHAC.

Additional Contributions: We would like to thank and acknowledge Shazahd Mustafa, MD, and Allison Ramsey, MD, Rochester Regional Health and University of Rochester, Rochester, New York; Nicholas Hartog, MD, and Kimberly Eastman, MD, Spectrum Health Helen DeVos Children’s Hospital, Grand Rapids, Michigan; Miguel Park, MD, and Mitchell Pitlick, MD, Division of Allergic Diseases, Mayo Clinic, Rochester, Minnesota; Carsten Bindslev-Jensen, MD, PhD, DMSci, and Trine Rasmussen, MD, Odense Research Center for Anaphylaxis, Odense University Hospital, Odense, Denmark; Arnon Elizur, MD, PhD, Institute of Allergy, Immunology and Pediatric Pulmonology, Yitzhak Shamir Medical Center, Zerifin, Israel, and Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel; John Kelso, MD, Division of Allergy, Asthma and Immunology, Scripps Clinic, San Diego, California; Kari Nadeau, MD, PhD, Sean N. Parker Center for Allergy and Asthma Research at Stanford University, Stanford, California; Christopher Warren, PhD, Sean N. Parker Center for Allergy and Asthma Research at Stanford University, Stanford, California, and Center for Food Allergy and Asthma Research, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Anita Kohli-Pamnani, MD, and Pamela L. Kwittken, MD, Allergy, Asthma & Immunology Center LLC, Milford, Connecticut; Sumito Inoue, MD, Department of Cardiology, Pulmonology, and Nephrology, Yamagata University Faculty of Medicine, Yamagata, Japan; Blanka Kaplan, MD, Division of Allergy and Immunology, Northwell Health, Great Neck, New York, and Departments of Pediatrics and Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York; Lacey Robinson, MD, MPH, and Aleena Banerji, MD, Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston; Lene Garvey, MD, PhD, Copenhagen University Hospital–Herlev and Gentofte, Copenhagen, Denmark; Elizabeth Phillips, MD, PhD, Vanderbilt University Medical Center, Nashville, Tennessee; Mona-Rita Yacoub, MD, Unit of Immunology, Rheumatology, Allergy and Rare Diseases, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele, Milan, Italy, and Vita-Salute San Raffaele University, Milan, Italy; and Merin Kuruvilla, MD, Emory University School of Medicine, Atlanta, Georgia, for their assistance with verifying data and study design questions pertaining to their included works. They were not compensated for their contributions.

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