Risk of Second Allergic Reaction to SARS-CoV-2 Vaccines: A Systematic Review and Meta-analysis

Derek K Chu; Elissa M Abrams; David B K Golden; Kimberly G Blumenthal; Anna R Wolfson; Cosby A Stone, Jr; Matthew S Krantz; Marcus Shaker; Matthew Greenhawt

doi:10.1001/jamainternmed.2021.8515

. 2022 Feb 21;182(4):376–385. doi: 10.1001/jamainternmed.2021.8515

Risk of Second Allergic Reaction to SARS-CoV-2 Vaccines

A Systematic Review and Meta-analysis

Derek K Chu ^1,^2,^3,⁴, Elissa M Abrams ⁵, David B K Golden ⁶, Kimberly G Blumenthal ⁷, Anna R Wolfson ⁷, Cosby A Stone Jr ⁸, Matthew S Krantz ⁸, Marcus Shaker ^9,¹⁰, Matthew Greenhawt ^11,^✉

¹Department of Medicine, McMaster University, Hamilton, Ontario, Canada

²Department of Health Research Methods, Evidence & Impact, McMaster University, Hamilton, Ontario, Canada

³The Research Institute of St Joe’s Hamilton, Hamilton, Ontario, Canada

⁴Evidence in Allergy Group, Hamilton, Ontario, Canada

⁵Section of Allergy and Immunology, Department of Pediatrics and Child Health, The University of Manitoba, Winnipeg, Manitoba, Canada

⁶Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland

⁷Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston

⁸Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee

⁹Section of Allergy and Immunology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire

¹⁰Dartmouth Geisel School of Medicine, Hanover, New Hampshire

¹¹Food Challenge and Research Unit, Section of Allergy and Clinical Immunology, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora

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.

^✉

Corresponding author.

PMCID: PMC8861900 PMID: 35188528

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.

This systematic review and meta-analysis of case studies and case reports assesses the risk of severe immediate allergic reactions to a second dose of SARS-CoV-2 mRNA vaccine among persons with immediate allergic reactions to their first vaccine dose.

Introduction

SARS-CoV-2 vaccination effectively reduces the risk of infection and severe COVID-19 outcomes. With more than 8.6 billion doses administered worldwide, immunization is a global priority to stem the count of the approximately 274 million infected and 5.3 million dead.¹ Factors associated with facilitating vaccination include increasing vaccine mandates and supply, whereas factors associated with barriers to vaccination include vaccine inequity, hesitancy, disinformation and misinformation, and rare adverse effects, such as severe allergic reactions (which occur in 7.9 per 1 million vaccinations²). Early in the global vaccine rollout, December 9, 2020,³ rare cases of allergic reactions to mRNA vaccines rapidly led to recommendations stating that persons with an immediate allergic reaction to the first dose of an mRNA COVID-19 vaccine should not receive additional doses of either of the mRNA COVID-19 vaccines.^3,4,5 This contraindication is inconsistent with allergy specialist practice parameters, which do not contraindicate readministration of non-COVID vaccines to those with prior vaccine allergic reactions.⁶

The immunology of allergic reactions is commonly understood to imply that, once an initial reaction occurs, repeated exposures reproducibly lead to acute and potentially life-threatening reactions (eg, anaphylaxis to food in those with a food allergy). Although this paradigm has been assumed regarding COVID vaccination, its evidence base has not been critically appraised. We systematically reviewed the literature on the risk of a second severe allergic reaction after SARS-CoV-2 vaccination.

Methods

We searched MEDLINE, Embase, and the World Health Organization Global Coronavirus database (a database aggregating published and preprint COVID-19 reports daily from 112 other literature databases), from inception through October 4, 2021, for studies of any design addressing the risk of a second allergic reaction to SARS-CoV-2 vaccines of any severity among individuals who had a prior allergic reaction to a SARS-CoV-2 vaccine (eMethods in the Supplement). We additionally searched Web of Science (all databases) using forward and backward citation analysis to identify any additional relevant records. Studies that detailed delayed (>4 hours after vaccine) reactions or involved SARS-CoV-2 revaccination but did not address individuals with prior allergic reactions were excluded. Three reviewers (D.K.C., M.S., and M.G.) independently and in duplicate screened records using Covidence (Veritas Health Innovation), and 4 reviewers (E.M.A., D.B.K.G., M.S., and M.G.) independently and in duplicate extracted data. Figure 1 details the PRISMA diagram for the literature search and final study selection. Consensus among the reviewers was used to resolve conflicts. We extracted the total number of second dose revaccinations in individuals with an immediate first dose SARS-CoV-2 vaccine allergic reaction, the number of revaccinations tolerated (as indicated by the investigator; this was defined as mild or self-limiting subjective or objective symptoms that either spontaneously resolved or resolved with antihistamine treatment), the number of revaccinations resulting in a severe allergic reaction (eg, described in the studies as either anaphylaxis or as requiring injectable epinephrine administration), and reactions stratified by the severity of initial reaction (anaphylaxis or not). Reaction severity was defined at the study level by the reporting investigator, using Brighton Collaboration criteria,⁷ classification by Ring and Messmer,⁸ World Allergy Organization criteria,⁹ or National Institute of Allergy and Infectious Diseases criteria.¹⁰ Study authors were contacted individually to verify final data extraction, if any cases were duplicated, if the author group had multiple included publications, and to clarify any study design questions. Pooled data were analyzed using random-effects generalized linear models (binomial family, logit link) using Stata, version 14.3 (StataCorp LLC). The primary outcome was the incidence of severe allergic reactions (eg, anaphylaxis) after second vaccination, with 95% exact (Clopper-Pearson) CIs. The secondary outcome included the rate of any immediate nonsevere symptoms occurring (defined in the studies as mild or self-limiting symptoms that were either subjective or objective). Sensitivity analyses included modeling the rate of tolerated vaccine administrations, excluding case reports, plausible assumptions to address missing outcome data or potential overlapping studies, using a fixed-effect model with a bayesian framework (mininimally informative priors: main effect [N(0, 10)], between-study variance [inverse gamma (0.001, 0.001)]). Prespecified subgroup analyses were by risk of bias, graded dosing, skin testing, and premedication. The Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach^11,12 provided assessment of the quality of the body of the evidence, and the Joanna Briggs Institute tool¹³ provided the framework for assessment of risk of bias (eTable 1 in the Supplement). Publication bias was assessed through GRADE, assessment of the search comprehensiveness, and inspection of funnel plots for small effects. Heterogeneity was assessed using methods recommended by GRADE involving consistency of the point estimates and overlap of 95% CIs given evidence that I² could be misleading in this type of analysis.^11,12 A 2-sided P < .05 was considered statistically significant.

Results

Twenty-two studies (single-group cohorts, case series, and case reports) detailing second-dose SARS-CoV-2 mRNA vaccination for 1366 individuals (87.8% women; mean age, 46.1 years) with a known or suspected prior immediate allergic reaction to a SARS-CoV-2 mRNA vaccine, including 78 persons with prior severe immediate allergic reactions (eg, anaphylaxis) to a SARS-CoV-2 mRNA vaccine, were included.^{14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35} Table 1^{14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35} details the study characteristics. All revaccinations were administered to adults under the guidance of an allergy specialist and used mRNA vaccines. A total of 6 severe reactions occurred (absolute risk, 0.16% [95% CI, 0.01%-2.94%]; pooled random-effects model; moderate-certainty evidence; Figure 2); 1360 patients tolerated the dose (99.84% [95% CI, 97.09%-99.99%]; pooled random-effects model). Although 4 of the cases of severe immediate allergic reactions occurred in persons who had severe allergic reactions with their first dose (absolute risk, 4.94% [95% CI, 0.93%-22.28%]; pooled random-effects model; low-certainty evidence; eFigure 1 in the Supplement), none of the other 74 patients with severe immediate allergic reactions to the first dose experienced severe immediate allergic reactions to the second dose. None of the 6 patients with severe immediate allergic reactions died, and 5 recovered rapidly after receiving intramuscular epinephrine (the sixth patient did not seek or receive treatment, despite experiencing a reaction consistent with moderately severe anaphylaxis, and recovered). A total of 232 persons (13.65% [95% CI, 7.76%-22.9%]; pooled random-effects model; moderate-certainty evidence) experienced mild immediate nonsevere symptoms with their second dose (eFigure 2 in the Supplement). Of the 78 persons who had an immediate severe reaction with the first dose, 15 (9.54% [95% CI, 2.18%-33.34%]; pooled random-effects model) experienced mild immediate nonsevere symptoms with their second dose (eFigure 3 in the Supplement). Sensitivity and subgroup analyses, including accounting for studies that permitted the use of graded dosing, premedication, or skin testing, and risk of bias, did not alter the main findings (eTable 2 in the Supplement). Table 2 details the GRADE evidence profile.

Table 1. Characteristics of the Included Studies.

Source and country	Design	Female, %	Median or mean age, y	Total second doses			Total No. of patients			Included patients with anaphyl to first dose	Graded dosing	Skin testing used	Premedication allowed	Total second doses deferred	Comments
Source and country	Design	Female, %	Median or mean age, y	Administered	With nonsevere symptoms	With anaphyl	Anaphyl after first dose and received a second dose	Anaphyl after both first and second dose	Anaphyl after first dose and deferred second dose	Included patients with anaphyl to first dose	Graded dosing	Skin testing used	Premedication allowed	Total second doses deferred	Comments
Tuong et al,¹⁴ 2021; US	Case series	100	42.8 (range, 21-64)	15	6	2	1	0	0	Yes	Yes	Yes	No	0	Both cases of anaphyl occurred on the last step of a multidose desensitization; 1 of these patients had positive Moderna vaccine testing results indicating allergy, with negative excipient testing results indicating no allergy
Krantz et al,¹⁵ 2021; US and Denmark	Case series	100	44.8 (range, 29-54)	4^a	0	0	4	0	0	Yes	No	Yes	Yes	0	After verification with the authors, the US numbers represented their initial patients, who were included with additional patients who became part of a larger multicenter report in the study by Krantz et al¹⁷; therefore, these reflect only the Danish patients
Rasmussen et al,¹⁶ 2021; Denmark	Case series	88.5	46 (range, 18-88)	30	0	0	4	0	0	Yes	No	Yes	No	1	25 Patients received the AstraZeneca vaccine with their first dose and tolerated an mRNA vaccine with their second dose
Krantz et al,¹⁷ 2021; US	Case series	86	43 (SD, 14)	159	32	0	19	0	13	Yes	No	Yes	Yes	30	Included 8 patients from the Krantz et al¹⁵ study and 11 patients from the Wolfson et al¹⁸ study; per discussion with the authors, no adjustments to these totals were made; potentially duplicated cases were adjusted in the data from the other articles
Wolfson et al,¹⁸ 2021; US	Case series	89	40.9 (SD, 13.6)	58^b	15	3	3	3	2	Yes	No	Yes	Yes	7	The 3 patients with anaphyl had anaphyl to the first dose, but had negative skin testing results; 1 of the patients had a grade 2 reaction but did not seek care or treatment; 11 patients had Ring and Messmer grade 2 reactions, but only 6 were treated with epinephrine initially; there were 56 patients in this report, including 8 patients with first dose anaphyl, who were also part of the Krantz et al study¹⁷; we accounted for duplication among the patients with anaphyl but not the other patients; we present the primary estimates based on excluding only the unique patients (which were only those with anaphyl) from the Wolfson et al study,¹⁸ but did perform sensitivity analysis that included them
Kessel et al,¹⁹ 2021; Israel	Case series	77.8	54.3 (range, 23-75)	18	4	0	7	0	0	Yes	No	Yes	Yes	0	NA
Kelso,²⁰ 2021; US	Case report	100	48.6 (range, 43-56)	3	0	0	3	0	1	Yes	No	Yes	No	1	NA
Mustafa et al,²¹ 2021; US	Case report	100	64 and 39	2	0	0	0	0	0	Yes	Yes	Yes	No	0	NA
Vanijcharoenkarn et al,²² 2021; US	Case series	92	Not specified	73	5	0	4	0	3	Yes	Mixed	Yes	No	15	NA
Robinson et al,²³ 2021; US	Case series	78	Mean age range, 41-43	860	146	0	3	0	3	Yes	No	NS	No	43	There were 358 persons receiving a second dose in this study who did not fill out a postvaccination symptom survey; the authors consider the nonresponders to be missing data; the study was not designed to investigate outcomes of a second dose
Eastman et al,²⁴ 2021; US	Case series	84.8	42 (range, 19-69)	53	17	0	2	0	0	Yes	Mixed	Yes	No	13	NA
Park et al,²⁵ 2021; US	Case report	100	34	1	0	0	1	0	0	Yes	No	Yes	No	0	NA
Arroliga et al,²⁶ 2021; US	Case series	86	39 (range, 23-61)	6	0	0	0	0	2	No	No	No	No	13	There were 8 patients lost to follow-up, and 5 patients deferred receiving a second dose
Loli-Ausejo et al,²⁷ 2021; Spain	Case series	81.8	39 (range, 29.5-56.5)	10	5	0	0	0	0	No	Yes	Yes	Yes	1	NA
Pitlick et al,²⁸ 2021; US	Case series	80	48 (range, 20-90)	44	7	0	4	0	3	Yes	Yes	Yes	No	11	This report includes 8 patients who were initially included as part of an early published case series, but have been included in a single large series of 55 patients
Yacoub et al,²⁹ 2021; Italy	Case series	85.7	47.6 (range, 38-55)	8	3	0	0	0	1	No	No	No	Yes	4	NA
Shavit et al,³⁰ 2021; Israel	Case series	70.9	52 (SD, 16)	6	3	0	0	0	3	No	No	No	Yes	Not specified	NA
Kohli-Pamnani et al,³¹ 2021; US	Case series	87	56 (SD, 16)	16	3	0	1	0	0	Yes	No	Yes	Yes	2	2 Patients had anaphyl to the first dose, one of whom received a second mRNA vaccine dose, but the other opted for the Janssen vaccine for their second dose; both tolerated the second dose
Inoue et al,³² 2021; Japan	Case report	67.1	20 to ≥60	2	0	0	0	0	0	No	No	No	No	Not specified	NA
Warren et al,³³ 2021; US	Case series	91	40.9 (SD, 10.3)	22	0	1	17	1	0	Yes	No	Yes	No	0	This study was not originally intended to investigate revaccination; at the time of publication, only 1 patient received a second dose, and had repeated anaphyl; after discussion with the authors, they reported that the other 20 persons were revaccinated as part of California’s vaccine mandate, with no further severe reactions
Carpenter et al,³⁴ 2021; US	Case report	100	60	1	1	0	0	0	0	No	No	Yes	No	1	NA
Kaplan et al,³⁵ 2021; US	Case series	86.7	48 (range, 19-89)	30	30	0	5	0	0	Yes	Yes	Yes	Yes	8	NA

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Abbreviations: Anaphyl, anaphylaxis; NA, not applicable.

^{^a}

This study includes patients who were also reported by Krantz et al.¹⁷ All duplicates have been accounted for, and the unique patients are presented here.

^{^b}

This study includes patients who were also reported by Krantz et al.¹⁷ All duplicate cases of anaphylaxis have been accounted for, with only the unique patients presented here. After discussion with the authors, we were unable to account for all duplicate patients in the denominator of all second doses administered. Thus, for the primary analysis, only the 3 unique patients with anaphylaxis were included as the study denominator. In the sensitivity analysis, this is reported as shown here, which includes the case number as originally published, including potential duplicates.

Figure 2. — ^aFor analysis purposes, this study by Krantz et al¹⁷ was combined with the 3 cases (all anaphylaxis) from Wolfson et al¹⁸ given that these 2 studies had overlap of cases.

Table 2. GRADE Evidence Profile Table.

Outcome	No. of studies	Certainty assessment						Effect			Certainty^b
Outcome	No. of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	No. of events	No. of individuals^a	Rate, % (95% CI)	Certainty^b
Incidence of anaphylaxis to a second dose of the SARS-CoV-2 mRNA vaccine in persons who had an allergic reaction to their first dose	22	Case studies and case reports	Not serious^c	Not serious	Not serious	Not serious	Large effect of tolerating and residual confounding would suggest an effect of reacting when none was detected^d	6	1366	0.16 (0.01-2.94)	+++ (Moderate)
Incidence of anaphylaxis to a second dose of the SARS-CoV-2 mRNA vaccine in persons who had anaphylaxis to their first dose	17	Case studies and case reports	Not serious^c	Not serious	Not serious	Not serious^e	Large effect of tolerating and residual confounding would suggest an effect of reacting when none was detected^d^,^e	4	78	4.94 (0.93-22.28)	++ (Low)
Incidence of mild allergic symptoms to a second dose of the SARS-CoV-2 mRNA vaccine in persons who had an allergic reaction to their first dose	22	Case studies and case reports	Not serious^c	Not serious	Not serious	Not serious	Large effect of tolerating and residual confounding would suggest an effect of reacting when none was detected^d	232	1366	13.65 (7.76-22.9)	+++ (Moderate)

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Abbreviation: GRADE, Grading of Recommendation, Assessment, Development, and Evaluation.

^{^a}

Patient or population: patients receiving second mRNA COVID vaccination after a previous allergic reaction to a mRNA COVID vaccine dose.

^{^b}

GRADE Working Group grades of evidence: high certainty, we are very confident that the true effect lies close to that of the estimate of effect; moderate certainty, we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different; low certainty, our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of effect; and very low certainty, we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. The number of plus symbols indicates the degree of certainty, where more plus symbols indicate a higher degree of certainty.

^{^c}

Risk of bias addressed in subgroup and sensitivity analyses.

^{^d}

A history of allergic reaction to previous COVID vaccination was a priori thought to guarantee a reaction to repeated doses, but far fewer than all individuals who received the second dose had an allergic reaction or anaphylaxis. Furthermore, those receiving a second dose of the vaccine, after an initial allergic reaction, would be at higher likelihood to be intensely monitored for any possible allergic reaction, whereas those without any history of an allergic reaction would not be intensely monitored.

^{^e}

Imprecision in width of 95% CIs and total sample size sufficient to prevent rating up certainty for considerations of residual confounding, but not to rate down; the qualitative effect of the incidence of repeated anaphylaxis being not very high (eg, 100%) is more certain than the quantitative estimate of a mean of 4.9%.

Discussion

This systematic review and meta-analysis found moderate-certainty evidence of a low incidence of severe immediate allergic reactions associated with the second dose of a SARS-CoV-2 mRNA vaccine among individuals with a history of an allergic reaction of any severity to their first mRNA vaccine dose. Revaccination of such persons led to no repeated reactions in most individuals and to nonsevere immediate symptoms in approximately 13.65% individuals.

These findings contradict the common assumption that a history of immediate reaction, including severe immediate allergic reactions, to a prior SARS-CoV-2 mRNA vaccine guarantees another reaction after revaccination. Immunoglobulin E (IgE) can be responsible for such stereotypically reproducible allergic responses—as in the case of allergic reactions to foods—but anaphylaxis can also occur idiosyncratically and nonspecifically owing to non-IgE–dependent mechanisms. Our findings therefore suggest that SARS-CoV-2 mRNA vaccine–induced anaphylaxis may not occur via an IgE-dependent mechanism, something that is also consistent with mechanistic data,²⁷ the lack of any consistent and verifiable specific allergen within SARS-CoV-2 mRNA vaccines,³³ the inability of skin testing of the ingredients of the vaccine to predict immediate allergic reactions to vaccination,¹⁸ and the overall very rare baseline incidence of severe immediate allergic reactions to SARS-CoV-2 vaccines.²

These data should prompt reconsideration of a history of allergic reaction to a prior dose of SARS-CoV-2 mRNA vaccine as a contraindication to a second dose of the vaccine.³⁶ Supervision of second vaccination in a medical setting equipped to manage a severe immediate allergic reaction (as opposed to vaccination occurring in a retail pharmacy or nonmedical-based setting) may be appropriate instead.² Consultation with an allergist prior to the second vaccination, when possible, might be beneficial. Removing barriers to vaccination is paramount to maximizing immunity and thereby protecting individuals and societies against COVID-19.

Limitations

This study has some limitations. First, the data address second-dose SARS-CoV-2 mRNA vaccinations, whereas other vaccine platforms and doses beyond the second dose require further study. Second, there is a risk of imprecision given the limited study numbers and patient numbers detailing these patient outcomes, albeit the absence of reactions in the situation of allergy can be considered as successes, and sensitivity analyses accounting for this led to findings consistent with the main analyses. We speculate that prior work calculating a very low event rate of severe reactions to the first dose (7.9 events per 1 000 000 vaccine doses)² and a contraindication against provision of additional doses to persons with an immediate allergic reaction to a first dose both may explain why there were not more studies available to include in this systematic review and meta-analysis. However, we hope that our analysis provides reassurance that, when immediate reactions to the first dose do occur, it is safe to give second doses in this context and that this would lead to more published research becoming available because this is planned as a living systematic review. Third, while there may be potential overlap of cases between included reports, we resolved cases through correspondence with primary study authors and use of sensitivity analyses. Fourth, some of the component studies were subject to risk of selection bias, but this was mitigated by the findings being consistent in subgroup and sensitivity analyses and for patients with a history of anaphylaxis, for which this might have been less of a concern. Fifth, severe reactions were partly defined as requiring injectable epinephrine, and while other potential definitions could apply, this severity definition is an accepted standard within the allergy field.³⁷ Sixth, all included studies were conducted with allergy specialist guidance, which could limit generalizability.

Conclusions

In this systematic review and meta-analysis of 22 case studies and case reports, the risk of repeated immediate allergic reactions and severe immediate allergic reactions or anaphylaxis associated with a second SARS-CoV-2 mRNA vaccination was low among persons who experienced an allergic reaction to their first dose, although 1 in 7 may have experienced mild symptoms. Although further research is warranted, these findings support the safe revaccination of individuals with an allergic reaction to a first SARS-CoV-2 mRNA vaccine dose in a setting equipped to manage severe allergic reactions, if they were to occur.

Supplement.

eTable 1. Risk of Bias Ratings for Included Studies

eTable 2. Additional Sensitivity Analyses

eFigure 1. Incidence of Repeat Anaphylaxis to SARS-CoV-2 mRNA Vaccination

eFigure 2. Incidence of Non-Severe Symptoms With 2nd Dose SARS-CoV-2 mRNA Vaccination

eFigure 3. Incidence of Non-Severe Symptoms After Anaphylaxis to mRNA COVID-19 Vaccination

eMethods. Registered Systematic Review Protocol

Click here for additional data file.^{(489.7KB, pdf)}

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.2021.06.006 [DOI] [PMC free article] [PubMed] [Google Scholar]
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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.2012.04.003 [DOI] [PubMed] [Google Scholar]
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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.2011.03.017 [DOI] [PubMed] [Google Scholar]
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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/ofab507 [DOI] [PMC free article] [PubMed] [Google 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.14958 [DOI] [PMC free article] [PubMed] [Google Scholar]
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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.2021.06.010 [DOI] [PMC free article] [PubMed] [Google Scholar]
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.15038 [DOI] [PMC free article] [PubMed] [Google Scholar]
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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/L21-0104 [DOI] [PMC free article] [PubMed] [Google Scholar]
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/ciab448 [DOI] [PMC free article] [PubMed] [Google 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.2021.05.031 [DOI] [PMC free article] [PubMed] [Google Scholar]
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.2021.10.023 [DOI] [PMC free article] [PubMed] [Google 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/usab138 [DOI] [PMC free article] [PubMed] [Google 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.2021.42.210069 [DOI] [PubMed] [Google Scholar]
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.0751 [DOI] [PubMed] [Google 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.2021.03.012 [DOI] [PMC free article] [PubMed] [Google Scholar]
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.2021.09.048 [DOI] [PubMed] [Google Scholar]
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.2021.22255 [DOI] [PMC free article] [PubMed] [Google 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.2021.08.417 [DOI] [PMC free article] [PubMed] [Google 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: 10.1101/2021.09.13.21263473 [DOI] [PMC free article] [PubMed]
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.2021.25524 [DOI] [PMC free article] [PubMed] [Google 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.2021.10.009 [DOI] [PMC free article] [PubMed] [Google 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.2021.10.019 [DOI] [PMC free article] [PubMed] [Google 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.2021.01.003 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement.

eTable 1. Risk of Bias Ratings for Included Studies

eTable 2. Additional Sensitivity Analyses

eFigure 1. Incidence of Repeat Anaphylaxis to SARS-CoV-2 mRNA Vaccination

eFigure 2. Incidence of Non-Severe Symptoms With 2nd Dose SARS-CoV-2 mRNA Vaccination

eFigure 3. Incidence of Non-Severe Symptoms After Anaphylaxis to mRNA COVID-19 Vaccination

eMethods. Registered Systematic Review Protocol

Click here for additional data file.^{(489.7KB, pdf)}

[ioi210091r1] 1.Johns Hopkins University Coronavirus Resource Center. COVID-19 map. Accessed September 28, 2021. https://coronavirus.jhu.edu/map.html

[ioi210091r2] 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.2021.06.006 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r3] 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

[ioi210091r4] 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.mm7004e1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r5] 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

[ioi210091r6] 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.2012.04.003 [DOI] [PubMed] [Google Scholar]

[ioi210091r7] 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.2007.02.064 [DOI] [PubMed] [Google Scholar]

[ioi210091r8] 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/BF01716961 [DOI] [PubMed] [Google Scholar]

[ioi210091r9] 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.2020.100472 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r10] 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.2005.12.1303 [DOI] [PubMed] [Google Scholar]

[ioi210091r11] 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.h870 [DOI] [PubMed] [Google Scholar]

[ioi210091r12] 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.2011.03.017 [DOI] [PubMed] [Google Scholar]

[ioi210091r13] 13.The University of Adelaide, JBI. Critical appraisal tools. Accessed September 1, 2021. https://jbi.global/critical-appraisal-tools

[ioi210091r14] 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/ofab507 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r15] 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.14958 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r16] 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/clt2.12044 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r17] 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.2021.3779 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r18] 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.2021.06.010 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r19] 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.15038 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r20] 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.2021.03.024 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r21] 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/L21-0104 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r22] 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/ciab448 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r23] 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.2021.05.031 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r24] 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.2021.10.023 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r25] 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/usab138 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r26] 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.2021.42.210069 [DOI] [PubMed] [Google Scholar]

[ioi210091r27] 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.0751 [DOI] [PubMed] [Google Scholar]

[ioi210091r28] 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.2021.03.012 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r29] 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.2021.09.048 [DOI] [PubMed] [Google Scholar]

[ioi210091r30] 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.2021.22255 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r31] 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.2021.08.417 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r32] 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: 10.1101/2021.09.13.21263473 [DOI] [PMC free article] [PubMed]

[ioi210091r33] 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.2021.25524 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r34] 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.2021.10.009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r35] 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.2021.10.019 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ioi210091r36] 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

[ioi210091r37] 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.2021.01.003 [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Risk of Second Allergic Reaction to SARS-CoV-2 Vaccines

Derek K Chu, MD, PhD

Elissa M Abrams, MD, MPH

David B K Golden, MDCM

Kimberly G Blumenthal, MD, MSc

Anna R Wolfson, MD

Cosby A Stone Jr, MD, MPH

Matthew S Krantz, MD

Marcus Shaker, MD, MSc

Matthew Greenhawt, MD, MBA, MSc

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Data Sources

Study Selection

Data Extraction and Synthesis

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Figure 1. PRISMA Diagram for Study Selection.

Results

Table 1. Characteristics of the Included Studies.

Figure 2. Pooled Incidence of Immediate Severe Allergic Reactions to a Second SARS-CoV-2 mRNA Dose Among Persons Who Had an Immediate Allergic Reaction to Their First SARS-CoV-2 mRNA Vaccine Dose.

Table 2. GRADE Evidence Profile Table.

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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