Temporal Associations Between Immunization With the COVID-19 mRNA Vaccines and Myocarditis: The Vaccine Safety Surveillance System Is Working | Vaccination | JAMA Cardiology | JAMA Network
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Editorial
June 29, 2021

Temporal Associations Between Immunization With the COVID-19 mRNA Vaccines and Myocarditis: The Vaccine Safety Surveillance System Is Working

Author Affiliations
  • 1UT Southwestern Medical Center, Dallas, Texas
  • 2Associate Editor, JAMA Cardiology
  • 3Northwestern Feinberg School of Medicine, Chicago, Illinois
  • 4Section Editor, JAMA Cardiology
  • 5Deputy Editor, JAMA Cardiology
  • 6Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 7Editor, JAMA Cardiology
JAMA Cardiol. 2021;6(10):1117-1118. doi:10.1001/jamacardio.2021.2853

Prior reports of adverse events following immunization for measles, mumps, and rubella, later deemed unsubstantiated, raised significant public alarm and led to vaccine resistance—an effect that lingers to this day. In light of this legacy, as well as ongoing fears related to vaccination leading to variable uptake, especially in populations at higher risk for COVID-19, the editorial decision to publish 2 articles reporting the association of myocarditis following COVID-19 messenger RNA (mRNA) vaccination was not taken lightly.1,2

The 2 case series by Montgomery and coworkers1 and Kim and coworkers2 in the current issue of JAMA Cardiology describe a temporal association between myocarditis and vaccination against SARS-CoV-2 with the Pfizer-BioNTech and Moderna mRNA vaccines. This temporal association does not establish causality, especially because a myocarditis-like syndrome has been seen following SARS-CoV-2 infection. Rather, these case series highlight the need for additional surveillance and investigation.

The editors recognize that publication of these data may contribute to additional public concern regarding immunization because reports of myocarditis following COVID-19 mRNA vaccination have already been reported in the news3 and in peer-reviewed publications.4 Furthermore, concerns regarding vaccine safety are the most common reason cited for lack of vaccination.5 However, as highlighted in the accompanying Editorial from immunization safety experts at the US Centers for Disease Control and Prevention (CDC),6 clinicians discussing immunization with patients should recognize that these case series suggest that the symptomatic events consistent with myocarditis are still very rare and appear to be self-limiting. Given the risks of COVID-19, including the risk of myocarditis from COVID-19 infection, the editors do not believe these case reports are sufficient to interrupt the march toward maximal vaccination against SARS-CoV-2 as expeditiously as possible.

Importantly, we endorse a different perspective: these data are exemplary of a successful formal and informal vaccine surveillance system, a system about which most of our readers may be unaware. Phase 3 clinical trials of vaccine efficacy and safety are able to detect common adverse effects but are not powered to detect more rare events, and it is noteworthy that myocarditis was not reported in the trials of the mRNA vaccines.7-9 A well-developed multipronged postmarketing surveillance system monitors vaccine safety after approval and is designed to detect extremely rare events that occur in less than 1 in 1 million vaccinees. This system includes the Vaccine Adverse Events Reporting System, a voluntary and easily accessible reporting system that archives possible vaccine adverse effects10; the Vaccine Safety Datalink, a hospital network designed to evaluate for increases in background rates of certain possible events11; and the Clinical Immunization Safety Assessment Project, in which the CDC partners with 7 medical research centers to leverage expertise in vaccine safety.12 For COVID-19 vaccines, the CDC also set up the v-safe system, which is offered to vaccine recipients and uses a smartphone app to collect symptoms following immunization.13 In addition, medical researchers across the country, including those highlighted in the Brief Reports published in JAMA Cardiology,1,2 form an informal network of vaccine safety surveillance capable of detecting potential clusters of events for further investigation. Increased engagement with this system by the public will help provide continued critical data for vaccine safety monitoring. In short, a web of safety and surveillance supports vaccine administration, and based on these case reports, that system is working.

Persons with cardiovascular disease are at high risk of complications from COVID-19, and physicians caring for these patients should encourage immunization and help guide patients in their decision-making. In one study, 66% of older adults reported that they would talk to their health care professional first before making a decision regarding immunization.14 In addition to discussing the risks of COVID-19 infection and the efficacy of vaccines, physicians should identify patient concerns regarding vaccine safety and be prepared to discuss these risks with patients.

The rarity of these events, including the identified link between the even rarer cerebral venous sinus thrombosis following the Johnson & Johnson SARS-CoV-2 vaccine, should reassure the public that the system is indeed functioning as designed.15 Strikingly, the potential adverse effects reported thus far are extremely rare. Although the clinical trials of SARS-CoV-2 vaccines showed robust safety, the widespread implementation in which nearly 150 million individuals in the US have been fully vaccinated in 6 months is unheralded. As the pandemic continues and new variants emerge, maintaining confidence in the vaccine safety surveillance system will be critical to maintain public trust in the vaccine. A key part of this confidence includes transparency, with careful critical review and publication of possible links between vaccination and rare adverse events. Moving forward, this level of due diligence will remain a key editorial priority.

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Article Information

Corresponding Author: Ann Marie Navar, MD, PhD, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75201 (ann.navar@utsouthwestern.edu).

Published Online: June 29, 2021. doi:10.1001/jamacardio.2021.2853

Conflict of Interest Disclosures: Dr Navar reports grants from Janssen and personal fees from Janssen, AstraZeneca, Sanofi, and Pfizer outside the submitted work. Dr McNally reports personal fees from Amgen, AstraZeneca, Avidity Biosciences, 4D Molecular Therapeutics, Cytokinetics, Janssen, PepGen, Pfizer, Invitae, and Tenaya Therapeutics outside the submitted work and is the founder of Ikaika Therapeutics. No other disclosures were reported.

References
1.
Montgomery  J, Ryan  M, Engler  R,  et al.  Myocarditis following immunization with mRNA COVID-19 vaccines in members of the US military.   JAMA Cardiol. Published online June 29, 2021. doi:10.1001/jamacardio.2021.2833Google Scholar
2.
Kim  HW, Jenista  ER, Wendell  DC,  et al.  Patients with acute myocarditis following mRNA COVID-19 vaccination.   JAMA Cardiol. Published online June 29, 2021. doi:10.1001/jamacardio.2021.2828Google Scholar
3.
Mandavilli  A. C.D.C. is investigating a heart problem in a few young vaccine recipients. New York Times. Published May 22, 2021. Accessed May 23, 2021. https://www.nytimes.com/2021/05/22/health/cdc-heart-teens-vaccination.html
4.
Marshall  M, Ferguson  ID, Lewis  P,  et al.  Symptomatic acute myocarditis in seven adolescents following Pfizer-BioNTech COVID-19 vaccination.   Pediatrics. 2021;e2021052478. doi:10.1542/peds.2021-052478PubMedGoogle Scholar
5.
The Delphi Group at Carnegie Mellon University in partnership with Facebook. COVID-19 Symptom Survey: Topline Report on COVID-19 Vaccination in the United States: Survey waves 6-8, January 10–February 27, 2021. Published March 12, 2021. Accessed June 8, 2021. https://www.cmu.edu/delphi-web/surveys/CMU_Topline_Vaccine_Report_20210312.pdf
6.
Shay  DK, Shimabukuro  TT, DeStefano  F.  Myocarditis occurring after immunization with mRNA-based COVID-19 vaccines.   JAMA Cardiol. Published online June 29, 2021. doi:10.1001/jamacardio.2021.2821Google Scholar
7.
Polack  FP, Thomas  SJ, Kitchin  N,  et al; C4591001 Clinical Trial Group.  Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.   N Engl J Med. 2020;383(27):2603-2615. doi:10.1056/NEJMoa2034577PubMedGoogle ScholarCrossref
8.
Baden  LR, El Sahly  HM, Essink  B,  et al; COVE Study Group.  Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.   N Engl J Med. 2021;384(5):403-416. doi:10.1056/NEJMoa2035389PubMedGoogle ScholarCrossref
9.
Frenck  RW  Jr, Klein  NP, Kitchin  N,  et al; C4591001 Clinical Trial Group.  Safety, immunogenicity, and efficacy of the BNT162b2 Covid-19 vaccine in adolescents.   N Engl J Med. 2021. doi:10.1056/NEJMoa2107456PubMedGoogle Scholar
10.
Vaccine Adverse Event Reporting System. Accessed June 8, 2021. https://vaers.hhs.gov
12.
Clinical Immunization Safety Assessment (CISA) Project. Accessed June 8, 2021. https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/cisa/index.html
13.
V-safe After Vaccination Health Checker. Accessed June 8, 2021. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/vsafe.html
14.
Nikolovski  J, Koldijk  M, Weverling  GJ,  et al.  Factors indicating intention to vaccinate with a COVID-19 vaccine among older U.S. adults.   PLoS One. 2021;16(5):e0251963. doi:10.1371/journal.pone.0251963PubMedGoogle Scholar
15.
See  I, Su  JR, Lale  A,  et al.  US case reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, March 2 to April 21, 2021.   JAMA. Published online April 30, 2021. doi:10.1001/jama.2021.7517Google Scholar
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    1 Comment for this article
    Every possible adverse event of COVID-19 vaccination counts
    Sandro Tsang, PhD | Peoples Open Access Education Initiative
    The reported incidents of myocarditis appear self-limiting and rare. I do agree with the authors that they should still be reported and under surveillance to keep up with a public policy-making principle - transparency. We don't have robust phrase IV evidence yet. In addition, we may not have observed the adverse and beneficial effects of the vaccines long enough. Staying cautious and transparency in reporting of all known effects are probably the best way to convince the public that the COVID-19 vaccines are safe and do good to the population health.
    CONFLICT OF INTEREST: None Reported
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