April 14, 2022
Surveillance of Safety of 3 Doses of COVID-19 mRNA Vaccination Using Electronic Health Records
Michiel J. M. Niesen, PhD1;
Colin Pawlowski, PhD1;
John C. O’Horo, MD2,3; et al
Doug W. Challener, MD2;
Eli Silvert, BSc1;
Greg Donadio, MA1;
Patrick J. Lenehan, BSc1;
Abinash Virk, MD2;
Melanie D. Swift, MD4;
Leigh L. Speicher, MD5;
Joel E. Gordon, MD6;
Holly L. Geyer, MD7;
John D. Halamka, MD8;
A. J. Venkatakrishnan, PhD1;
Venky Soundararajan, PhD1;
Andrew D. Badley, MD2,9
Author Affiliations
Article Information
JAMA Netw Open. 2022;5(4):e227038. doi:10.1001/jamanetworkopen.2022.7038
COVID-19 Resource Center
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.
Abstract
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.
This cohort study assesses adverse events associated with a third dose of mRNA COVID-19 vaccine using data from electronic health records (EHRs).
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