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Safety of Vaccines Used for Routine Immunization in the United States

Evidence Reports/Technology Assessments, No. 215

Investigators: Margaret A Maglione, MPP, Courtney Gidengil, MD, MPH, Lopamudra Das, MPH, Laura Raaen, MPH, Alexandria Smith, MPH, Ramya Chari, PhD, Sydne Newberry, PhD, Susanne Hempel, PhD, Roberta Shanman, MLS, Tanja Perry, BHM, and Matthew Bidwell Goetz, MD.

Southern California Evidence-based Practice Center
Rockville (MD): Agency for Healthcare Research and Quality (US); 2014 Jul.
Report No.: 14-E002-EF
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Structured Abstract


To conduct a systematic review of the literature on the safety of vaccines recommended for routine immunization of children, adolescents, and adults in the United States as of 2011.

Data sources:

We included placebo-controlled clinical trials and cohort studies comparing vaccinated and unvaccinated patients. We also included the following types of post-licensure analyses: case-control studies, self-controlled case series, and multivariate risk factor analyses. We conducted an electronic search of PubMed® from inception through August 2013, and reviewed Advisory Committee for Immunization Practices statements, vaccine package inserts, and previously published reviews to identify studies. Scientific Information Packets were requested from vaccine manufacturers.

Review methods:

We reviewed the methodology of the 2011 Institute of Medicine (IOM) consensus report “Adverse Effects of Vaccines: Evidence and Causality” and accepted their findings. We augmented their work with new studies and additional vaccines. For studies not included in the IOM report, we abstracted data on the presence or absence of adverse health outcomes, characteristics of patients, study design, and vaccine description, including brand, potency, dosage, timing, and formulation, where available. We excluded formulations not used in the United States. The McHarm instrument was used to evaluate the quality of adverse events collection and reporting in each study. We were unable to pool results; we rated the overall strength of evidence (SOE) as high, moderate, low, or insufficient by using guidance suggested by the Agency for Healthcare Research and Quality for its Effective Health Care Program.


A total of 20,478 titles were identified; after title, abstract, and full-text review, 166 studies were accepted for abstraction. The vast majority of studies either did not investigate or could not identify risk factors for adverse events (AEs) associated with vaccination. Similarly, the severity of AEs was inconsistently reported, as was information that would make independent severity determination possible.

SOE was high for the following associations in nonpregnant adults: seasonal influenza vaccine and arthralgia, myalgia, malaise, fever, pain at injection site; 2009 monovalent H1N1 vaccine and Guillain-Barré syndrome (GBS); and a lack of association between influenza and pneumococcal vaccines and cardiovascular events in the elderly. Risk of GBS was estimated at 1.6 excess cases per million persons vaccinated. SOE was high for the following associations in children and adolescents: measles, mumps, rubella (MMR) vaccine and febrile seizures in children under age 5; lack of association between MMR vaccine and autism spectrum disorders; and varicella vaccine and disseminated Oka strain varicella zoster virus with associated complications (i.e., meningitis, encephalitis) in individuals with demonstrated immunodeficiencies. There is moderate SOE that vaccines against rotavirus are associated with intussusception in children; risk was estimated as 1 to 5 cases per 100,000 vaccine doses, depending on brand. Moderate-strength evidence exists regarding human papillomavirus vaccine and a lack of association with onset of juvenile rheumatoid arthritis, type 1 diabetes, and GBS. Moderate-strength evidence shows no association between inactivated influenza vaccine and serious AEs in pregnant women.

Evidence was insufficient to make conclusions regarding whether several routinely recommended vaccines are associated with serious conditions such as multiple sclerosis, transverse myelitis, and acute disseminated encephalomyelitis.


There is evidence that some vaccines are associated with serious adverse events; however, these events are extremely rare and must be weighed against the protective benefits that vaccines provide. Careful consideration should be given to the investigation of research gaps, including patient risk factors that may be associated with AEs; however, important factors must be taken into account when determining whether studies are warranted, including the severity and frequency of the AE being studied and the challenges of conducting sufficiently powered studies when investigating rare events.


Prepared for: Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services1, Contract No. 290-2007-10062-I. Prepared by: Southern California Evidence-based Practice Center, Santa Monica, CA

Suggested citation:

Maglione MA, Gidengil C, Das L, Raaen L, Smith A, Chari R, Newberry S, Hempel S, Shanman R, Perry T, Goetz MB. Safety of Vaccines Used for Routine Immunization in the United States. Evidence Report/Technology Assessment No. 215. (Prepared by the Southern California Evidence-based Practice Center under Contract No. 290-2007-10062-I.) AHRQ Publication No. 14-E002-EF. Rockville, MD: Agency for Healthcare Research and Quality; July 2014. www.effectivehealthcare.ahrq.gov/reports/final.cfm. DOI: https://doi.org/10.23970/AHRQEPCERTA215.

This report is based on research conducted by the Southern California Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2007-10062-I). The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services.

The information in this report is intended to help health care decisionmakers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, i.e., in the context of available resources and circumstances presented by individual patients.

This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

None of the investigators have any affiliations or financial involvement that conflicts with the material presented in this report.


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