Background

Vaccines are considered one of the greatest public health achievements, and the effectiveness of vaccines in controlling the spread of and even eradicating many infectious diseases is widely acknowledged.¹ It is estimated that vaccinations for children born between 1994 and 2013 alone will have prevented over 320 million illnesses and 730,000 deaths from vaccine-preventable diseases and will have saved over $1.3 trillion in societal costs over the children’s lifetimes in the United States.² Vaccination of adults is cost-effective³ and critical to mitigating the economic toll of influenza estimated to be approximately $87 billion per year,⁴ and prevents other illnesses such as invasive pneumococcal disease, hepatitis A, hepatitis B, and herpes zoster.^5–7 As a result, vaccines have improved health outcomes and reduced mortality for adults, in addition to decreasing healthcare costs and preventing an untold amount of suffering.^{4, 8–12} Influenza vaccine and tetanus, diphtheria, and acellular pertussis vaccine (Tdap) during pregnancy reduce the mother’s risk for infection and can protect her infant with transplacental passive immunity against influenza, tetanus, diphtheria, and pertussis (whooping cough) in the critical first several months of life when the infant is too young to be vaccinated.^13–15

Assessment of safety is an essential component of the process for developing and commercializing vaccines that provide these benefits. In the United States, the U.S. Food and Drug Administration (FDA) oversees regulatory review and approval of vaccines.¹⁶ The clinical evaluation of a vaccine typically consists of three phases. Phase I studies are conducted among a small number of participants, generally approximately 20–80, to evaluate safety and tolerability and to generate preliminary immunogenicity data. Phase II studies evaluate the immunogenicity of the vaccine and provide initial estimates of the rates of common adverse events, typically enrolling several hundred participants. Phase III trials, which enroll thousands to tens of thousands of participants, provide individual- and population-based information on a vaccine’s safety and efficacy to support licensure.

After a vaccine is licensed and recommended for use, multiple systems are in place to ensure ongoing assessments of safety through Phase IV studies.¹⁷ These studies include safety surveillance conducted by manufacturers as post-marketing requirements (studies or clinical trials that sponsors are required to conduct under one or more statutes or regulations) or commitments (studies or clinical trials that a sponsor has agreed to conduct, but that are not required by a statute or regulation) to the FDA¹⁸ and the FDA’s Post-Licensure Rapid Immunization Monitoring (PRISM) system (the FDA’s national system for monitoring medical products after they are licensed for use).^19–21 Multiple other Federal databases contribute to surveillance, such as the Vaccine Adverse Event Reporting System (VAERS) (co-managed by the FDA and the Centers for Disease Control and Prevention [CDC]),²² as well as the Vaccine Safety Datalink^{23, 24} and Clinical Immunization Safety Assessment project, which are both managed by the CDC.^{25, 26} Using these vaccine safety monitoring systems, the FDA and CDC may change the terms of vaccine use based on available safety information.²⁷

In 2014, the Office of the Assistant Secretary for Health’s National Vaccine Program Office (which in 2019 became the Office of Infectious Disease and HIV/AIDS Policy [OASH/OIDP]) commissioned the Agency for Healthcare Research and Quality (AHRQ) to develop a report on vaccine safety entitled Safety of Vaccines Used for Routine Immunization in the United States.²⁸ The 2014 report was based on a systematic review and built upon the 2011 Institute of Medicine (IOM; now known as the National Academies of Sciences, Engineering, and Medicine) consensus report Adverse Effects of Vaccines: Evidence and Causality.²⁹ Since the 2014 Agency for Healthcare Research and Quality (AHRQ) report,²⁸ the CDC’s routine immunization schedules for children and adults have continued to evolve, with the inclusion of vaccines newly licensed by the FDA and modified indications and schedules for some existing vaccines (Table 1). These changes include the introduction of several new influenza vaccines; changes in recommended uses of influenza vaccines;³⁰ replacement of the 2- and 4-valent human papillomavirus (HPV) vaccines with the 9-valent HPV vaccine (HPV9), expanded indications for HPV9 to include men and women through 45 years of age;³¹ and two new serogroup B meningococcal vaccines for use among adolescents and high-risk populations.³² Vaccines with novel adjuvants, such as those for the new recombinant zoster vaccine, and the new 2-dose series hepatitis B vaccine with a novel immunostimulatory adjuvant were introduced in 2017.^{33, 34}

In addition to an examination of the research published since the prior report, the current report includes the new vaccines, formulations, and schedules that have been approved since 2014 (Table 1). Note that the use of brand names in this report is for identification purposes only and does not indicate endorsement by AHRQ or OASH/OIDP.

Table 1

Vaccines, populations, and major changes since the 2014 AHRQ vaccine safety report.

The concept of “safety” in medical literature is measured and described as the number, type, and severity of adverse events reported by study participants. For each population in this report—adults (including adults 65 years of age and older), children, and pregnant women—several important questions must be considered when evaluating adverse events associated with vaccines. First, what adverse events have been reported with vaccine use, and what is the certainty of the association? Clinicians, patients, and caregivers want information on the nature and the frequency of potential side effects to help them weigh the benefits of vaccines against potential risks. Another question for stakeholders is the severity of the adverse events, even when events are likely to be very rare. Finally, understanding the risk factors that may be associated with adverse events (e.g., age, sex, race/ethnicity, medical comorbidity, concomitant medications, adjuvants) is important for policymakers and clinicians to potentially modify vaccine recommendations as needed.

Purpose and Scope of the Systematic Review

This report assesses the evidence regarding the safety of vaccines routinely recommended for adults, children, and pregnant women in the United States by systematic review. The list of included vaccines in this report is based on the CDC’s immunization schedules^{35, 36} and comprises those currently licensed by the FDA.³⁷ See Appendix A for all vaccines that are within the scope of this report.

This report does not review the safety of FDA-licensed vaccines that were previously included in the immunization schedules but are no longer recommended or included in current immunization schedules or manufactured for use in the United States, such as the serogroups A, C, W, and Y meningococcal polysaccharide vaccine, 2-valent or 4-valent human papilloma vaccines, or most trivalent influenza vaccines. This report reviews currently recommended vaccines for routine use, and does not include new vaccines in development or under emergency use authorization, such as vaccines for the 2019 coronavirus disease (COVID-19) pandemic.

Finally, the scope of the report does not include the efficacy or effectiveness of vaccines, which must be considered alongside against any risks in decision making about vaccines.³⁸ The report does not provide guidance for patients or providers regarding the use of vaccines, nor does it make practice or policy recommendations on the use of vaccines.