Risk of Second Allergic Reaction to SARS-CoV-2 Vaccines: A Systematic Review and Meta-analysis | Allergy and Clinical Immunology | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

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.

Abstract

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.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

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.

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.

References
1.
Johns Hopkins University Coronavirus Resource Center. COVID-19 map. Accessed September 28, 2021. https://coronavirus.jhu.edu/map.html
2.
Greenhawt  M , Abrams  EM , Shaker  M ,  et al.  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.   J Allergy Clin Immunol Pract. 2021;9(10):3546-3567. doi:10.1016/j.jaip.2021.06.006PubMedGoogle ScholarCrossref
3.
Medicines and Healthcare Products Regulatory Agency. Confirmation of guidance to vaccination centres on managing allergic reactions following COVID-19 vaccination with the Pfizer/BioNTech vaccine. Accessed December 15, 2020. https://www.gov.uk/government/news/confirmation-of-guidance-to-vaccination-centres-on-managing-allergic-reactions-following-covid-19-vaccination-with-the-pfizer-biontech-vaccine
4.
CDC COVID-19 Response Team; Food and Drug Administration.  Allergic reactions including anaphylaxis after receipt of the first dose of Moderna COVID-19 vaccine—United States, December 21, 2020-January 10, 2021.   MMWR Morb Mortal Wkly Rep. 2021;70(4):125-129. doi:10.15585/mmwr.mm7004e1PubMedGoogle ScholarCrossref
5.
Centers for Disease Control and Prevention. What to do if you had an allergic reaction after getting a COVID-19 vaccine. Accessed September 20, 2021. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/allergic-reaction.html
6.
Kelso  JM , Greenhawt  MJ , Li  JT ,  et al.  Adverse reactions to vaccines practice parameter 2012 update.   J Allergy Clin Immunol. 2012;130(1):25-43. doi:10.1016/j.jaci.2012.04.003PubMedGoogle ScholarCrossref
7.
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
8.
Ring  J , Laubenthal  H , Messmer  K .  Incidence and classification of adverse reactions to plasma substitutes.   Klin Wochenschr. 1982;60(17):997-1002. doi:10.1007/BF01716961PubMedGoogle ScholarCrossref
9.
Cardona  V , Ansotegui  IJ , Ebisawa  M ,  et al.  World Allergy Organization anaphylaxis guidance 2020.   World Allergy Organ J. 2020;13(10):100472. doi:10.1016/j.waojou.2020.100472PubMedGoogle Scholar
10.
Sampson  HA , Muñoz-Furlong  A , Campbell  RL ,  et al.  Second symposium on the definition and management of anaphylaxis: summary report–Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.   J Allergy Clin Immunol. 2006;117(2):391-397. doi:10.1016/j.jaci.2005.12.1303PubMedGoogle ScholarCrossref
11.
Iorio  A , Spencer  FA , Falavigna  M ,  et al.  Use of GRADE for assessment of evidence about prognosis: rating confidence in estimates of event rates in broad categories of patients.   BMJ. 2015;350:h870. doi:10.1136/bmj.h870PubMedGoogle ScholarCrossref
12.
Guyatt  GH , Oxman  AD , Kunz  R ,  et al; GRADE Working Group.  GRADE guidelines: 7, rating the quality of evidence—inconsistency.   J Clin Epidemiol. 2011;64(12):1294-1302. doi:10.1016/j.jclinepi.2011.03.017PubMedGoogle ScholarCrossref
13.
The University of Adelaide, JBI. Critical appraisal tools. Accessed September 1, 2021. https://jbi.global/critical-appraisal-tools
14.
Tuong  LC , Capucilli  P , Staicu  M , Ramsey  A , Walsh  EE , Shahzad Mustafa  S .  Graded administration of second dose of Moderna and Pfizer-BioNTech COVID-19 mRNA vaccines in patients with hypersensitivity to first dose.   Open Forum Infect Dis. 2021;8(12):ofab507. doi:10.1093/ofid/ofab507PubMedGoogle Scholar
15.
Krantz  MS , Bruusgaard-Mouritsen  MA , Koo  G , Phillips  EJ , Stone  CA  Jr , Garvey  LH .  Anaphylaxis to the first dose of mRNA SARS-CoV-2 vaccines: don’t give up on the second dose!   Allergy. 2021;76(9):2916-2920. doi:10.1111/all.14958PubMedGoogle ScholarCrossref
16.
Rasmussen  TH , Mortz  CG , Georgsen  TK , Rasmussen  HM , Kjaer  HF , Bindslev-Jensen  C .  Patients with suspected allergic reactions to COVID-19 vaccines can be safely revaccinated after diagnostic work-up.   Clin Transl Allergy. 2021;11(5):e12044. doi:10.1002/clt2.12044PubMedGoogle Scholar
17.
Krantz  MS , Kwah  JH , Stone  CA  Jr ,  et al.  Safety evaluation of the second dose of messenger RNA COVID-19 vaccines in patients with immediate reactions to the first dose.   JAMA Intern Med. 2021;181(11):1530-1533. doi:10.1001/jamainternmed.2021.3779PubMedGoogle ScholarCrossref
18.
Wolfson  AR , Robinson  LB , Li  L ,  et al.  First-dose mRNA COVID-19 vaccine allergic reactions: limited role for excipient skin testing.   J Allergy Clin Immunol Pract. 2021;9(9):3308-3320. doi:10.1016/j.jaip.2021.06.010PubMedGoogle ScholarCrossref
19.
Kessel  A , Bamberger  E , Nachshon  L , Rosman  Y , Confino-Cohen  R , Elizur  A .  Safe administration of the Pfizer-BioNtTech COVID-19 vaccine following an immediate reaction to the first dose.   Allergy. 2021;76(11):3538-3540. doi:10.1111/all.15038PubMedGoogle ScholarCrossref
20.
Kelso  JM .  Misdiagnosis of systemic allergic reactions to mRNA COVID-19 vaccines.   Ann Allergy Asthma Immunol. 2021;127(1):133-134. doi:10.1016/j.anai.2021.03.024PubMedGoogle ScholarCrossref
21.
Mustafa  SS , Ramsey  A , Staicu  ML .  Administration of a second dose of the Moderna COVID-19 vaccine after an immediate hypersensitivity reaction with the first dose: two case reports.   Ann Intern Med. 2021;174(8):1177-1178. doi:10.7326/L21-0104PubMedGoogle ScholarCrossref
22.
Vanijcharoenkarn  K , Lee  FE , Martin  L , Shih  J , Sexton  ME , Kuruvilla  ME .  Immediate reactions following the first dose of the SARS-CoV2 mRNA vaccines do not preclude second dose administration.   Clin Infect Dis. 2021;73(11):2108-2111. doi:10.1093/cid/ciab448PubMedGoogle Scholar
23.
Robinson  LB , Landman  AB , Shenoy  ES ,  et al.  Allergic symptoms after mRNA COVID-19 vaccination and risk of incomplete vaccination.   J Allergy Clin Immunol Pract. 2021;9(8):3200-3202.e1. doi:10.1016/j.jaip.2021.05.031PubMedGoogle ScholarCrossref
24.
Eastman  J , Holsworth  A , Kelbel  T , Pebbles  T , Hartog  N.   Cohort experience of second messenger RNA vaccine dose tolerance after an initial-dose reaction.   Ann Allergy Asthma Immunol. Published online October 23, 2021. doi:10.1016/j.anai.2021.10.023PubMedGoogle Scholar
25.
Park  HJ , Montgomery  JR , Boggs  NA .  Anaphylaxis after the Covid-19 vaccine in a patient with cholinergic urticaria.   Mil Med. 2021;usab138. doi:10.1093/milmed/usab138PubMedGoogle Scholar
26.
Arroliga  ME , Dhanani  K , Arroliga  AC ,  et al.  Allergic reactions and adverse events associated with administration of mRNA-based vaccines: a health-care system experience.   Allergy Asthma Proc. 2021;42(5):395-399. doi:10.2500/aap.2021.42.210069PubMedGoogle ScholarCrossref
27.
Loli-Ausejo  D , González de Abreu  JM , Fiandor  A ,  et al.  Allergic reactions after administration of Pfizer-BioNTech COVID-19 vaccine to healthcare workers at a tertiary hospital.   J Investig Allergol Clin Immunol. 2021;0:0. doi:10.18176/jiaci.0751PubMedGoogle Scholar
28.
Pitlick  MM , Sitek  AN , Kinate  SA , Joshi  AY , Park  MA .  Polyethylene glycol and polysorbate skin testing in the evaluation of coronavirus disease 2019 vaccine reactions: early report.   Ann Allergy Asthma Immunol. 2021;126(6):735-738. doi:10.1016/j.anai.2021.03.012PubMedGoogle ScholarCrossref
29.
Yacoub  MR , Cucca  V , Asperti  C ,  et al.  Efficacy of a rational algorithm to assess allergy risk in patients receiving the BNT162b2 vaccine.   Vaccine. 2021;39(44):6464-6469. doi:10.1016/j.vaccine.2021.09.048PubMedGoogle ScholarCrossref
30.
Shavit  R , Maoz-Segal  R , Iancovici-Kidon  M ,  et al.  Prevalence of allergic reactions after Pfizer-BioNTech COVID-19 vaccination among adults with high allergy risk.   JAMA Netw Open. 2021;4(8):e2122255. doi:10.1001/jamanetworkopen.2021.22255PubMedGoogle Scholar
31.
Kohli-Pamnani  A , Zapata  K , Gibson  T , Kwittken  PL .  Coronavirus disease 2019 vaccine hypersensitivity evaluated with vaccine and excipient allergy skin testing.   Ann Allergy Asthma Immunol. 2021;128(1):97-98. doi:10.1016/j.anai.2021.08.417PubMedGoogle Scholar
32.
Inoue  S , Igarashi  A , Morikane  K ,  et al.  Adverse reactions to BNT162b2 mRNA COVID-19 vaccine in medical staffs with a history of allergy.   medRxiv. Preprint posted September 16, 2021. doi:10.1101/2021.09.13.21263473Google Scholar
33.
Warren  CM , Snow  TT , Lee  AS ,  et al.  Assessment of allergic and anaphylactic reactions to mRNA COVID-19 vaccines with confirmatory testing in a US regional health system.   JAMA Netw Open. 2021;4(9):e2125524. doi:10.1001/jamanetworkopen.2021.25524PubMedGoogle Scholar
34.
Carpenter  T , Konig  J , Hochfelder  J , Siegel  S , Gans  M .  Polyethylene glycol and polysorbate testing in 12 patients before or after coronavirus disease 2019 vaccine administration.   Ann Allergy Asthma Immunol. 2021;128(1):99-101. doi:10.1016/j.anai.2021.10.009PubMedGoogle Scholar
35.
Kaplan  B , Farzan  S , Coscia  G ,  et al.  Allergic reactions to coronavirus disease 2019 vaccines and addressing vaccine hesitancy: Northwell Health experience.   Ann Allergy Asthma Immunol. Published online October 24, 2021. doi:10.1016/j.anai.2021.10.019PubMedGoogle Scholar
36.
Centers for Disease Control and Prevention. Interim clinical considerations for use of COVID-19 vaccines currently approved or authorized in the United States. Accessed January 26, 2021. https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html
37.
Dribin  TE , Schnadower  D , Spergel  JM ,  et al.  Severity grading system for acute allergic reactions: a multidisciplinary Delphi study.   J Allergy Clin Immunol. 2021;148(1):173-181. doi:10.1016/j.jaci.2021.01.003PubMedGoogle ScholarCrossref
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close

My Saved Courses

You currently have no courses saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close