Objective. To conduct a systematic review of the literature on the safety of vaccines recommended for routine immunization in the United States, updating the 2014 Agency for Healthcare Research and Quality (AHRQ) report on the topic. Data sources. We searched MEDLINE®, Embase®, CINAHL®, Cochrane CENTRAL, Web of Science, and Scopus through November 9, 2020, building on the prior 2014 report; reviewed existing reviews, trial registries, and supplemental material submitted to AHRQ; and consulted with experts. Review methods. This report addressed three Key Questions (KQs) on the safety of vaccines currently in use in the United States and included in the Centers for Disease Control and Prevention’s (CDC) recommended immunization schedules for adults (KQ1), children and adolescents (KQ2), and pregnant women (KQ3). The systematic review was supported by a Technical Expert Panel that identified key adverse events of particular concern. Two reviewers independently screened publications; data were extracted by an experienced subject matter expert. Studies of vaccines that used a comparator and reported the presence or absence of adverse events were eligible. We documented observed rates and assessed the relative risks for key adverse events. We assessed the strength of evidence (SoE) across the existing findings from the prior 2014 report and the new evidence from this update. The systematic review is registered in PROSPERO (CRD42020180089). Results. A large body of evidence is available to evaluate adverse events following vaccination. Of 56,608 reviewed citations, 189 studies met inclusion criteria for this update, adding to data in the prior 2014 report, for a total of 338 included studies reported in 518 publications. Regarding vaccines recommended for adults (KQ1), we found either no new evidence of increased risk for key adverse events with varied SoE or insufficient evidence in this update, including for newer vaccines such as recombinant influenza vaccine, adjuvanted inactivated influenza vaccine, and recombinant adjuvanted zoster vaccine. The prior 2014 report noted a signal for anaphylaxis for hepatitis B vaccines in adults with yeast allergy and for tetanus, diphtheria, and acellular pertussis vaccines. Regarding vaccines recommended for children and adolescents (KQ2), we found either no new evidence of increased risk for key adverse events with varied SoE or insufficient evidence, including for newer vaccines such as 9-valent human papillomavirus vaccine and meningococcal B vaccine. The prior 2014 report noted signals for rare adverse events—such as anaphylaxis, idiopathic thrombocytopenic purpura, and febrile seizures—with some childhood vaccines. Regarding vaccines recommended for pregnant women (KQ3), we found no evidence of increased risk for key adverse events with varied SoE among either pregnant women or their infants following administration of tetanus, diphtheria, and acellular pertussis vaccines during pregnancy. Conclusion. Across this large body of research, we found no new evidence of increased risk since the prior 2014 report for key adverse events following administration of vaccines that are routinely recommended. Signals from the prior report remain unchanged for rare adverse events, which include anaphylaxis in adults and children, and febrile seizures and idiopathic thrombocytopenic purpura in children. There is no evidence of increased risk of adverse events for vaccines currently recommended in pregnant women. There remains insufficient evidence to draw conclusions about some rare potential adverse events.
