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Vaccination

Surveillance for Adverse Events After COVID-19 mRNA Vaccination

Educational Objective
To identify the key insights or developments described in this article

1 Credit CME

JAMA

Published Online: September 3, 2021

Original Investigation

Article Information and Disclosures

Author Affiliations

¹Kaiser Permanente Vaccine Study Center, Kaiser Permanente Northern California, Oakland
²Marshfield Clinic Research Institute, Marshfield, Wisconsin
³HealthPartners Institute, Minneapolis, Minnesota
⁴Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon
⁵Biostatistics Unit, Kaiser Permanente Washington Health Research Institute, Seattle, Washington
⁶Research and Evaluation, Kaiser Permanente Southern California, Pasadena
⁷Harvard Pilgrim Health Care Institute, Boston, Massachusetts
⁸Institute for Health Research, Kaiser Permanente Colorado, Denver
⁹Department of Epidemiology, Colorado School of Public Health, Aurora
¹⁰Ambulatory Care Services, Denver Health, Denver, Colorado
¹¹University of Colorado School of Medicine, Aurora
¹²Immunization Safety Office, Centers for Disease Control and Prevention, Atlanta, Georgia

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Key Points

Question Are mRNA COVID-19 vaccines associated with increased risk for serious health outcomes during days 1 to 21 after vaccination?

Findings In this interim analysis of surveillance data from 6.2 million persons who received 11.8 million doses of an mRNA vaccine, event rates for 23 serious health outcomes were not significantly higher for individuals 1 to 21 days after vaccination compared with similar individuals at 22 to 42 days after vaccination.

Meaning This analysis found no significant associations between vaccination with mRNA COVID-19 vaccines and selected serious health outcomes 1 to 21 days after vaccination, although CIs were wide for some rate ratio estimates and additional follow-up is ongoing.

Abstract

Importance Safety surveillance of vaccines against COVID-19 is critical to ensure safety, maintain trust, and inform policy.

Objectives To monitor 23 serious outcomes weekly, using comprehensive health records on a diverse population.

Design, Setting, and Participants This study represents an interim analysis of safety surveillance data from Vaccine Safety Datalink. The 10 162 227 vaccine-eligible members of 8 participating US health plans were monitored with administrative data updated weekly and supplemented with medical record review for selected outcomes from December 14, 2020, through June 26, 2021.

Exposures Receipt of BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) COVID-19 vaccination, with a risk interval of 21 days for individuals after vaccine dose 1 or 2 compared with an interval of 22 to 42 days for similar individuals after vaccine dose 1 or 2.

Main Outcomes and Measures Incidence of serious outcomes, including acute myocardial infarction, Bell palsy, cerebral venous sinus thrombosis, Guillain-Barré syndrome, myocarditis/pericarditis, pulmonary embolism, stroke, and thrombosis with thrombocytopenia syndrome. Incidence of events that occurred among vaccine recipients 1 to 21 days after either dose 1 or 2 of a messenger RNA (mRNA) vaccine was compared with that of vaccinated concurrent comparators who, on the same calendar day, had received their most recent dose 22 to 42 days earlier. Rate ratios (RRs) were estimated by Poisson regression, adjusted for age, sex, race and ethnicity, health plan, and calendar day. For a signal, a 1-sided P < .0048 was required to keep type I error below .05 during 2 years of weekly analyses. For 4 additional outcomes, including anaphylaxis, only descriptive analyses were conducted.

Results A total of 11 845 128 doses of mRNA vaccines (57% BNT162b2; 6 175 813 first doses and 5 669 315 second doses) were administered to 6.2 million individuals (mean age, 49 years; 54% female individuals). The incidence of events per 1 000 000 person-years during the risk vs comparison intervals for ischemic stroke was 1612 vs 1781 (RR, 0.97; 95% CI, 0.87-1.08); for appendicitis, 1179 vs 1345 (RR, 0.82; 95% CI, 0.73-0.93); and for acute myocardial infarction, 935 vs 1030 (RR, 1.02; 95% CI, 0.89-1.18). No vaccine-outcome association met the prespecified requirement for a signal. Incidence of confirmed anaphylaxis was 4.8 (95% CI, 3.2-6.9) per million doses of BNT162b2 and 5.1 (95% CI, 3.3-7.6) per million doses of mRNA-1273.

Conclusions and Relevance In interim analyses of surveillance of mRNA COVID-19 vaccines, incidence of selected serious outcomes was not significantly higher 1 to 21 days postvaccination compared with 22 to 42 days postvaccination. While CIs were wide for many outcomes, surveillance is ongoing.

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Article Information

Corresponding Author: Nicola P. Klein, MD, PhD, Kaiser Permanente Vaccine Study Center, 1 Kaiser Plaza, 16th Floor, Oakland, CA 94612 (nicola.klein@kp.org).

Accepted for Publication: August 18, 2021.

Published Online: September 3, 2021. doi:10.1001/jama.2021.15072

Author Contributions: Dr Klein had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Klein, Lewis, Goddard, Fireman, Zerbo, Naleway, Nelson, Shimabukuro, DeStefano, Weintraub.

Acquisition, analysis, or interpretation of data: Lewis, Goddard, Fireman, Zerbo, Hanson, Donahue, Kharbanda, Naleway, Nelson, Xu, Yih, Glanz, Williams, Hambidge, Lewin, Shimabukuro, DeStefano, Weintraub.

Drafting of the manuscript: Klein, Lewis, Goddard, Fireman, Weintraub.

Critical revision of the manuscript for important intellectual content: Lewis, Goddard, Fireman, Zerbo, Hanson, Donahue, Kharbanda, Naleway, Nelson, Xu, Yih, Glanz, Williams, Hambidge, Lewin, Shimabukuro, DeStefano, Weintraub.

Statistical analysis: Lewis, Fireman, Nelson, Xu, Glanz, Lewin, Weintraub.

Obtained funding: Klein, Goddard, Zerbo, Hanson, Donahue, Weintraub.

Administrative, technical, or material support: Goddard, Hanson, Donahue, Yih, Hambidge, Shimabukuro, Weintraub.

Supervision: Klein, Hambidge, Shimabukuro, DeStefano, Weintraub.

Case review and adjudication, vaccine capture in the health record: Lewin.

Conflict of Interest Disclosures: Dr Klein reported receiving grants from the Centers for Disease Control and Prevention (CDC) during the conduct of the study, and grants from Pfizer, Merck, GSK, Sanofi Pasteur, and Protein Science (now SP) outside the submitted work. Ms Hanson reported receiving grants from CDC during the conduct of the study. Dr Donahue reported receiving grants from CDC during the conduct of the study and from Janssen Vaccines & Prevention for a study unrelated to COVID-19 vaccines. Dr Kharbanda reported receiving other from CDC (contract 200-2012-53526) during the conduct of the study. Dr Naleway reported receiving grants from CDC during the conduct of the study and grants from Pfizer outside the submitted work. Dr Nelson reported receiving grants from Moderna outside the submitted work. Dr Yih reported receiving grants from Pfizer outside the submitted work. Dr Williams reported receiving grants from CDC Vaccine Safety Datalink COVID-19 Infrastructure Funding during the conduct of the study. Dr Lewin reported receiving grants from CDC Vaccine Safety Datalink during the conduct of the study. No other disclosures were reported.

Funding/Support: This study was supported by grant funding from the CDC, contract 200-2012-53581/0001.

Role of the Funder/Sponsor: The study sponsor, CDC, participated as a coinvestigator and contributed to protocol development, conduct of the study, interpretation of the data, review and revision of the manuscript, approval of the manuscript through official CDC scientific clearance processes, and the decision to submit the manuscript for publication. CDC authors must receive approval through the CDC scientific clearance process to submit an article for publication. Final decision to submit rested with the first author. The study sponsor did not have the right to direct the submission to a particular journal.

Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the CDC. Mention of a product or company name is for identification purposes only and does not constitute endorsement by CDC.

Additional Contributions: We thank Ed Belongia, MD (Marshfield Clinic Research Institute) for providing clinical expertise for this manuscript. We thank Rachael Burganowski, MS (Kaiser Permanente Washington Health Research Institute), Bradley Crane, MS (Center for Health Research, Kaiser Permanente Northwest), Sungching Glenn, MS (Research and Evaluation, Kaiser Permanente Southern California), Tat’Yana Kenigsberg, MPH (Immunization Safety Office, Centers for Disease Control and Prevention), Erica Scotty, MS (Marshfield Clinic Research Institute), Gabriela Vazquez Benitez, PhD (HealthPartners Institute), Arnold Yee, BS (Kaiser Permanente Vaccine Study Center, Kaiser Permanente Northern California), and Jingyi Zhu, PhD (HealthPartners Institute), for their contributions to data collection and preparation. We thank Nandini Bakshi, MD (The Permanente Medical Group), Tom Boyce, MD (Marshfield Clinic Research Institute), Jennifer Covey, BS (Kaiser Permanente Washington Health Research Institute), Jonathan Duffy, MD (Immunization Safety Office, Centers for Disease Control and Prevention), Stacy Harsh, BSN, RN (Center for Health Research, Kaiser Permanente Northwest), Linda Heeren, BS (Marshfield Clinic Research Institute), Juraj Kavecansky, MD (Kaiser Permanente Northern California, Antioch Medical Center), Mike M. McNeil, MD (Immunization Safety Office, Centers for Disease Control and Prevention), Tanya Myers, PhD (Immunization Safety Office, Centers for Disease Control and Prevention), Matthew E. Oster, MD, MPH (Centers for Disease Control and Prevention, COVID-19 Response), Ashok Pai, MD (Kaiser Permanente Northern California, Oakland Medical Center), and Pat Ross, BA (Kaiser Permanente Vaccine Study Center, Kaiser Permanente Northern California), for their contributions to medical record review and adjudication. We thank Laurie Aukes, RN (Kaiser Permanente Vaccine Study Center, Kaiser Permanente Northern California), Cheryl Carlson, MPH (Research and Evaluation, Kaiser Permanente Southern California), Stephanie Irving, MHS (Center for Health Research, Kaiser Permanente Northwest), Mara Kalter, MA (Center for Health Research, Kaiser Permanente Northwest), Tia Kauffman, MPH (Center for Health Research, Kaiser Permanente Northwest), Erika Kiniry, MPH (Kaiser Permanente Washington Health Research Institute), Leslie Kuckler, MPH (HealthPartners Institute), Denison Ryan, MPH (Research and Evaluation, Kaiser Permanente Southern California), and Lina Sy, MPH (Research and Evaluation, Kaiser Permanente Southern California), for their contributions to overall project management. All non-CDC personnel received financial compensation through CDC Vaccine Safety Datalink grant funding for their work on this project. CDC personnel were not compensated for their role in the study.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
1.00 credit toward the CME [and Self-Assessment requirements] of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.