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Krantz MS, Kwah JH, Stone CA, 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. Published online July 26, 2021. doi:10.1001/jamainternmed.2021.3779
Allergic reactions after messenger RNA (mRNA) COVID-19 vaccines have been reported to be as high as 2%, with anaphylaxis occurring in up to 2.5 per 10 000 individuals.1 There is uncertainty as to whether to administer a second dose of mRNA COVID-19 vaccine after a first-dose reaction.2,3 In this study, we examine the safety of the second dose of Pfizer-BioNTech or Moderna vaccine in those with a history of immediate and potentially allergic reactions to the first dose.
This multicenter, retrospective study conducted by Massachusetts General Hospital (Boston), Brigham and Women’s Hospital (Boston, Massachusetts), Vanderbilt University Medical Center (Nashville, Tennessee), Yale School of Medicine (New Haven, Connecticut), and University of Texas Southwestern Medical Center (Dallas) from January 1, 2021, to March 31, 2021, included patients with an immediate allergic reaction to the Pfizer-BioNTech or Moderna vaccine, which was defined as: (1) symptom onset within 4 hours of dose 1, (2) at least 1 allergic symptom, and (3) referral for an allergy/immunology consultation with in-clinic or telehealth assessment (eMethods in the Supplement). Anaphylaxis was scored using the Brighton and the National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network criteria.4,5 Confirmed anaphylaxis required meeting at least 1 of these 2 criteria.
The primary outcome was second dose tolerance, which was defined as either: (1) no immediate symptoms after second dose administration or (2) symptoms that were mild, self-limited, and/or resolved with antihistamines alone. For any individuals who did not have their second dose observed by allergy/immunology departments, phone calls elicited clinical details. This study was approved by the Mass General Brigham human research committee with waiver of informed consent.
There were 189 patients who participated in this study (mean [SD] age, 43 (14) years; 163 women [86%]) (Table). Of the mRNA COVID-19 vaccine first-dose reactions evaluated, 130 (69%) were to Moderna and 59 (31%) to Pfizer-BioNTech. The most frequently reported first-dose reactions were flushing or erythema (53 [28%]), dizziness or lightheadedness (49 [26%]), tingling (46 [24%]), throat tightness (41 [22%]), hives (39 [21%]), and wheezing or shortness of breath (39 [21%]). Thirty-two (17%) met anaphylaxis criteria.
A total of 159 patients (84%) received a second dose. Antihistamine premedication before the second dose was given in 47 patients (30%). All 159 patients, including 19 individuals with first-dose anaphylaxis, tolerated the second dose. Thirty-two (20%) reported immediate and potentially allergic symptoms that were associated with the second dose that were self-limited, mild, and/or resolved with antihistamines alone.
This multisite US study supports the safety of Pfizer-BioNTech or Moderna vaccine second dose administration in patients who report immediate and potentially allergic reactions after the first dose. Although mild symptoms were reported in 20% of patients with second dose administration, all patients who received a second dose safely completed their vaccination series and could use mRNA COVID-19 vaccines in the future when indicated. Second dose tolerance following reactions to the first dose argues that either many of these initial reactions are not all truly allergic reactions, or supports an allergic, but non–immunoglobulin E–mediated mechanism in which symptoms can typically be abated with premedications.6
Because the Janssen vaccine received emergency use authorization, the US Centers for Disease Control and Prevention recommended that individuals with an immediate and potentially allergic reaction to the first dose of the Pfizer-BioNTech or Moderna mRNA COVID-19 vaccine could receive a Janssen single dose subsequently.2 However, our data suggest that most patients with immediate and potentially allergic reactions to mRNA COVID-19 vaccines tolerate a second dose. Therefore, it may not be necessary to consider this, to our knowledge, largely unstudied alternative mixed series approach. Although earlier work provided a shared framework for the clinical approach,3 our pooled study was limited by its retrospective study design, referral bias, and lack of a shared evaluation protocol among participating institutions.
Accepted for Publication: May 28, 2021.
Published Online: July 26, 2021. doi:10.1001/jamainternmed.2021.3779
Corresponding Author: Kimberly G. Blumenthal, MD, MSc, Massachusetts General Hospital, The Mongan Institute, 100 Cambridge St, 16th Floor, Boston, MA 02114 (email@example.com).
Author Contributions: Drs Krantz, Kwah, and Blumenthal had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Krantz and Kwah are co–first authors, and Drs Banerji and Blumenthal share senior authorship.
Concept and design: Krantz, Kwah, Stone, Phillips, Banerji, Blumenthal.
Acquisition, analysis, or interpretation of data: Krantz, Kwah, Stone, Phillips, Ortega, Blumenthal.
Drafting of the manuscript: Krantz, Kwah, Stone, Phillips, Blumenthal.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Krantz, Stone, Blumenthal.
Obtained funding: Phillips, Blumenthal.
Administrative, technical, or material support: Kwah, Stone, Phillips, Ortega, Banerji, Blumenthal.
Supervision: Krantz, Stone, Phillips, Banerji, Blumenthal.
Conflict of Interest Disclosures: Dr Stone reported grants from the Agency for Healthcare Research and Quality (AHRQ) during the conduct of the study. Dr Phillips reported personal fees from Janssen, Biocyst, Regeneron, Vertex, and UpToDate and grants from the National Institutes of Health (NIH) and grants from NHMRC Australia Monies to institution outside the submitted work. Dr Blumenthal reported grants from NIH/National Institute of Allergy and Infectious Diseases during the conduct of the study. No other disclosures were reported.
Funding/Support: This work was supported by NIH grant K01 AI125631 (Dr Blumenthal), AHRQ/Patient-Centered Outcomes Research Institute grant 1K12HS026395-01 (Dr Stone), and the Massachusetts General Hospital DOM Transformative Scholar Program (Dr Blumenthal).
Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, AHRQ, or MGH.
Additional Contributions: We thank many colleagues at Massachusetts General Hospital (Lacey B. Robinson, MD, MPH, Anna R. Wolfson, MD, Rebecca R. Saff, MD, PhD, Upeka Samarakoon, PhD, MPH), Brigham and Women’s Hospital (Paige G. Wickner, MD, MPH, Lily Li, MD, David I. Hong, MD), Vanderbilt University Medical Center (Grace Koo, MD), Yale School of Medicine (John K. Kuster, MD, Christina C. Price, MD), and University of Texas Southwestern (David A. Khan, MD, Timothy G. Chow, MD, Rebecca Gruchalla, MD, PhD). We thank Christian M. Mancini, BS, Massachusetts General Hospital, for assistance with data analysis. No compensation was received by any of these individuals.
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