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.
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
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Chu DK, Abrams EM, Golden DBK, et al. Risk of Second Allergic Reaction to SARS-CoV-2 Vaccines: A Systematic Review and Meta-analysis. JAMA Intern Med. 2022;182(4):376–385. doi:10.1001/jamainternmed.2021.8515
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?
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.
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.
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.
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.
MEDLINE, Embase, Web of Science, and the World Health Organization Global Coronavirus database were searched from inception through October 4, 2021.
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.
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.
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.3-5 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.
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) approach11,12 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.
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.14-35 Table 114-35 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.
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.
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.
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.
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 (email@example.com).
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.