Vaccine development is a long and arduous process, often lasting many years and involving a combination of public and private partnerships. The current system for developing, testing, and regulating vaccines requires that the vaccines demonstrate both safety and efficacy before licensure and that long-term safety is monitored (http://www.historyofvaccines.org/content/articles/vaccine-development-testing-and-regulation; Fig 1). The first step in vaccine discovery involves the identification of a need for a vaccine and an understanding of the mechanism of protective immunity against that disease.
If the vaccine appears promising in preclinical studies, the vaccine sponsor submits an application for an Investigational New Drug to the US Food and Drug Administration (FDA). Law requires that the sponsor describe the manufacturing and testing processes, summarize the laboratory reports, and describe the proposed studies to evaluate the vaccine. As with therapeutic drugs, vaccine evaluation includes phase I through phase III testing. Phase I trials are intended to assess the safety of the candidate vaccine and to determine the type and extent of immune response that the vaccine provokes.
Phase II testing involves several hundred volunteers, some of whom belong to groups at risk for acquiring the disease. These trials generally are randomized and controlled and usually include a placebo group or a standard licensed vaccine when a new vaccine for that disease is being tested.
Phase III vaccine trials are designed to determine whether the vaccine will prevent the disease in question and to assess the vaccine’s safety when administered to many subjects. These studies often involve thousands or tens of thousands of participants, depending on the incidence of disease and the rates of adverse events to be detected. If these studies show the vaccine to be effective and safe, it is then licensed.
Vaccine Safety Is Actively Monitored After Licensure
Once vaccines are licensed, several processes are in place to ensure that the safety of vaccines is monitored. In 1990, the Centers for Disease Control and Prevention (CDC) and FDA established the Vaccine Adverse Events Reporting System (VAERS), a voluntary passive reporting system that serves as a signal detection system for adverse events associated with vaccines (http://vaers.hhs.gov/index). Anyone who suspects an association between a vaccination and an adverse event can report the event to VAERS. The CDC and the FDA then investigate the event. VAERS has successfully identified several adverse events related to vaccination in the past, such as intussusception after administration of the RotaShield (Wyeth Laboratories Inc, Marietta, PA) rotavirus vaccine, which was identified in 1999, leading to the ultimate withdrawal of that vaccine from the market.
In 1990, the CDC also established the Vaccine Safety Datalink (VSD) to monitor vaccine safety. The VSD is composed of a number of large health provider groups with linked databases with comprehensive information about vaccines administered and health care encounters. Because the VSD involves millions of individuals, it can be used to detect rare events and was used to study the possible, but subsequently disproven, association between Guillain–Barré syndrome and meningococcal vaccination. Another parallel system to the VSD is the Post-Licensure Rapid Immunization Safety Monitoring system. This system uses health insurance claims data from 107 million individuals to actively monitor vaccine safety. In addition, the CDC has also established the Clinical Immunization Safety Assessment Project, a group of academic health care centers, to address specific questions about vaccine safety from individual health care providers (http://www.cdc.gov/vaccinesafety/activities/cisa.html).
In summary, vaccines are comprehensively evaluated before their licensure. They are developed and tested in large numbers of subjects, regulated by the FDA, and carefully monitored after licensure through a comprehensive safety surveillance system funded by the CDC and the FDA. In rare instances in which safety concerns are identified, regulatory or other actions to safeguard public health are taken.