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Surveillance of Safety of 3 Doses of COVID-19 mRNA Vaccination Using Electronic Health Records

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

Question  Is a third dose of US Food and Drug Administration–authorized COVID-19 mRNA vaccines safe?

Findings  This cohort study of electronic health record data for 47 999 individuals receiving 3-dose mRNA COVID-19 vaccines found no significant increase in the reporting of severe adverse events (ie, anaphylaxis, cerebral venous sinus thrombosis, myocarditis, and pericarditis) after the third vaccine dose compared with before vaccination and after prior doses. Significantly increased reporting was found for low-severity adverse events (ie, fatigue, lymphadenopathy, nausea, and headache).

Meaning  These findings suggest that third-dose vaccination with COVID-19 mRNA vaccines may be safe.


Importance  Recent reports on waning of COVID-19 vaccine–induced immunity have led to the approval and rollout of additional doses and booster vaccinations. Individuals at increased risk of SARS-CoV-2 infection are receiving additional vaccine doses in addition to the regimen that was tested in clinical trials. Risks and adverse event profiles associated with additional vaccine doses are currently not well understood.

Objective  To evaluate the safety of third-dose vaccination with US Food and Drug Administration (FDA)–approved COVID-19 mRNA vaccines.

Design, Setting, and Participants  This cohort study was conducted using electronic health record (EHR) data from December 2020 to October 2021 from the multistate Mayo Clinic Enterprise. Participants included all 47 999 individuals receiving 3-dose COVID-19 mRNA vaccines within the study setting who met study inclusion criteria. Participants were divided into 2 cohorts by vaccine brand administered and served as their own control groups, with no comparison made between cohorts. Data were analyzed from September through November 2021.

Exposures  Three doses of an FDA-authorized COVID-19 mRNA vaccine, BNT162b2 or mRNA-1273.

Main Outcomes and Measures  Vaccine-associated adverse events were assessed via EHR report. Adverse event risk was quantified using the percentage of study participants who reported the adverse event within 14 days after each vaccine dose and during a 14-day control period, immediately preceding the first vaccine dose.

Results  Among 47 999 individuals who received 3-dose COVID-19 mRNA vaccines, 38 094 individuals (21 835 [57.3%] women; median [IQR] age, 67.4 [52.5-76.5] years) received BNT162b2 (79.4%) and 9905 individuals (5099 [51.5%] women; median [IQR] age, 67.7 [59.5-73.9] years) received mRNA-1273 (20.6%). Reporting of severe adverse events remained low after the third vaccine dose, with rates of pericarditis (0.01%; 95% CI, 0%-0.02%), anaphylaxis (0%; 95% CI, 0%-0.01%), myocarditis (0%; 95% CI, 0%-0.01%), and cerebral venous sinus thrombosis (no individuals) consistent with results from earlier studies. Significantly more individuals reported low-severity adverse events after the third dose compared with after the second dose, including fatigue (2360 individuals [4.92%] vs 1665 individuals [3.47%]; P < .001), lymphadenopathy (1387 individuals [2.89%] vs 995 individuals [2.07%]; P < .001), nausea (1259 individuals [2.62%] vs 979 individuals [2.04%]; P < .001), headache (1185 individuals [2.47%] vs 992 individuals [2.07%]; P < .001), arthralgia (1019 individuals [2.12%] vs 816 individuals [1.70%]; P < .001), myalgia (956 individuals [1.99%] vs 784 individuals [1.63%]; P < .001), diarrhea (817 individuals [1.70%] vs 595 individuals [1.24%]; P < .001), fever (533 individuals [1.11%] vs 391 individuals [0.81%]; P < .001), vomiting (528 individuals [1.10%] vs 385 individuals [0.80%]; P < .001), and chills (224 individuals [0.47%] vs 175 individuals [0.36%]; P = .01).

Conclusions and Relevance  This study found that although third-dose vaccination against SARS-CoV-2 infection was associated with increased reporting of low-severity adverse events, risk of severe adverse events remained comparable with risk associated with the standard 2-dose regime. These findings suggest the safety of third vaccination doses in individuals who were eligible for booster vaccination at the time of this study.

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Article Information

Accepted for Publication: February 22, 2022.

Published: April 14, 2022. doi:10.1001/jamanetworkopen.2022.7038

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2022 Niesen MJM et al. JAMA Network Open.

Corresponding Authors: Venky Soundararajan, PhD, nference, One Main St, East Arcade, Cambridge, MA 02142 (venky@nference.net); Andrew Badley, Division of Infectious Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (badley.andrew@mayo.edu).

Author Contributions: Drs Soundararajan and Badley 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. Drs Niesen, Pawlowski, and O’Horo made equal contributions.

Concept and design: Niesen, Pawlowski, O’Horo, Challener, Silvert, Lenehan, Swift, Speicher, Halamka, Venkatakrishnan, Soundararajan, Badley.

Acquisition, analysis, or interpretation of data: Niesen, Pawlowski, O’Horo, Silvert, Donadio, Virk, Gordon, Geyer, Badley.

Drafting of the manuscript: Niesen, Pawlowski, Silvert, Donadio, Venkatakrishnan, Soundararajan.

Critical revision of the manuscript for important intellectual content: Niesen, Pawlowski, O’Horo, Challener, Lenehan, Virk, Swift, Speicher, Gordon, Geyer, Halamka, Soundararajan, Badley.

Statistical analysis: Niesen, Pawlowski, Silvert, Donadio, Gordon.

Administrative, technical, or material support: O’Horo, Silvert, Gordon, Halamka, Badley.

Supervision: Niesen, O’Horo, Venkatakrishnan, Soundararajan, Badley.

Conflict of Interest Disclosures: Drs Niesen and Soundararajan reported being employees of nference, which is collaborating with biopharmaceutical companies on data science initiatives unrelated to this study. Dr Pawlowski reported receiving personal fees from nference outside the submitted work. Dr O’Horo reported receiving grants from nference and Mitre, receiving consulting fees from Bates College, and owning privately purchased stock from Doximity outside the submitted work. Dr Silvert reported receiving personal fees from nference as an employer during the conduct of the study and outside the submitted work. Dr Lenehan reported employment by nference. Dr Virk reported receiving personal fees from Moderna outside the submitted work. Dr Swift reported receiving grants from the Pfizer Healthcare Worker Exposure Response and Outcomes (HEROE) vaccine registry via Duke University outside the submitted work. Dr Badley reported receiving grants from the National Institute of Allergy and Infectious Diseases, Amfar, and Mayo Clinic; consulting fees for AbbVie, Gilead Sciences, Freedom Tunnel, PineTree Therapeutics, Primmune Therapeutics, Immunome, MarPam Pharma, Rion, Symbiosis, and Flambeau Diagnostics; and personal fees from Corvus Pharmaceuticals, Equillium, CSL Behring, Excision BioTherapeutics, ReachMD, PeerVoice, and Medscape; owning equity for scientific advisory work in Zentalis, Rion, and nference; and serving as founder and president of Splissen Therapeutics. No other disclosures were reported.

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