How Vaccine Safety is Monitored

1

Introduction

Safety expectations for vaccines are high because they are administered to healthy and sometimes vulnerable populations such as pregnant women, infants, and the elderly. Also, vaccines are endorsed or required by most governments, further raising safety expectations. Although no biologic or medical intervention is perfectly safe, vaccines are generally very safe and the risks of side effects are almost always greatly outweighed by the benefits derived from vaccination to prevent disease. Vaccine safety is evaluated at all stages in the development of vaccines, including after the vaccines have been approved by regulatory authorities and introduced into widespread use ( Fig. 8.1 ).

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Vaccine development

Safety is important in determining the type of vaccine to be developed, the selection of antigens, and all other ingredients in the final product. For example, recombinant hepatitis B vaccines replaced plasma-derived vaccines to avoid theoretical concerns about adventitious agents in blood. For some diseases, such as Ebola and HIV, live attenuated strains of the naturally occurring viruses are not used due to theoretical concerns the vaccine could cause disease. Vaccine ingredients are carefully scrutinized for real or potential risks from adventitious agents and the potential to cause adverse events.

Regulatory authorities require manufacturers to assure safety, purity, and potency of all vaccine products. Prior to testing experimental vaccines in humans, products are characterized by physical, chemical, and biological methods. Animal studies are conducted to identify potential toxicities. Novel adjuvants usually require more extensive safety testing in animal studies prior to obtaining approval for human studies. If the vaccine is intended for use in women of reproductive age and/or pregnant women, animal studies are conducted to assess potential adverse effects on pregnancy outcomes.

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Investigational new drug (IND) application

Prior to conducting human studies, vaccine developers must submit all of the data from the preclinical studies and the plans for conducting human studies to regulatory authorities in the form of an IND application. The regulatory authorities [Food and Drug Administration (FDA) in the United States, European Medicines Agency (EMA) in Europe] require the organization, manufacturer, or individual developing the vaccine to demonstrate that the preclinical data support clinical trials. An IND application contains information about the vaccine, the methods for manufacturing, quality control testing, potential study subjects, toxicology data and clinical protocols, and investigators expertise. The sponsor of the trial must annually report adverse events and rapidly report serious or unexpected adverse events to the regulatory agency. The regulatory agency typically specifies “stopping rules,” which will halt the trials if serious adverse events occur at predetermined unacceptable levels.

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Clinical trials

Phase I trials typically include 20–100 healthy subjects and, from a safety standpoint, are designed to ensure there is no gross toxicity and to gather safety data on dose-related immune response. Phase II clinical trials typically include 10–100 and up to 1000 health subjects. These studies are designed to assess common, short-term side effects and explore interactions between the investigational vaccine and already licensed vaccines, and may involve different age groups. Phase III clinical trials typically include 1,000–20,000 or more persons to evaluate efficacy and safety. The incremental phases of clinical trials minimize exposure of study participants to theoretical risks from previously untested vaccines, which could have unanticipated adverse effects.

Clinical trials are the gold standard for assessing safety as they are randomized (some people get the new vaccine being investigated and some do not, based solely on chance) and double blind (neither the patients nor the investigators know who received the study vaccine). Double blind, randomized trials greatly reduce potential confounding and bias because host factors predisposing to adverse effects should be equally distributed to the different study groups. These studies are usually restricted to healthy individuals of a restricted age group and the results may not be generalizable to the entire population.

The strict inclusion and exclusion criteria in most trials result in uncertainty regarding safety in groups that were excluded from the trials such as persons with concurrent medical conditions. Limited follow-up of clinical trial participants limits the ability to identify adverse health outcomes with delayed onset. The size of clinical trials limits the ability to evaluate uncommon adverse events. For a medical condition that occurs at a background rate of 1 in 1,000 a trial with 50,000 persons would be required to identify a doubling of risk ( Table 8.1 ). Missing a doubling of this risk for such an event would result in 4,000 persons potentially affected every year in the United States, about 5,100 persons potentially affected every year in Europe, and about 23,000 persons affected every year in India if the vaccine was administered to all infants.

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Regulatory approval

If a vaccine is shown to be safe and effective in clinical trials, the vaccine sponsor or manufacturer submits an application to national regulatory authorities (NRA) for licensure or registration of the vaccine. In the United States this application is called a biological license application and is submitted to the FDA. In Europe, the application is called a marketing authorization and is submitted to the EMA, which provides approval for European Union Member States as well as European Economic Area countries. The World Health Organization (WHO) can prequalify vaccines for licensure for countries that lack rigorous NRAs. However, the vaccine still requires licensure in each country where it will be used. NRAs must meet with WHO to review the licensure application and provide authorization. National Immunization Technical Advisory Groups (NITAGs), where they exist (about half of countries in Africa), can provide recommendations to NRAs in making vaccine licensure decisions. Ultimately, the Minister of Health must sign off on licensure before the vaccine can be used in the country.

NRAs carefully review the results of clinical trials as well as the chemistry, manufacturing and controls, description of the manufacturing facility, and results of tests to demonstrate manufacturing consistency and product specifications. NRAs review and approve package labeling and advertising to help assure that the vaccine will be used in accordance with the approval granted to the manufacturers. Careful consideration is also given to the manufacturing facility to ensure that the facility can consistently produce a vaccine that is safe, pure, and potent. Regulations typically cover the facility’s personnel, quality control, buildings, equipment, containers, records, and distribution procedures. Manufacturers must meet current Good Manufacturing Practices (cGMP) standards to ensure that vaccine manufacturing practices utilize advances in processes, techniques, and vaccine production technology that improve over time. NRAs often regularly inspect vaccine manufacturing facilities and require manufacturers to conduct tests on every lot of vaccine prior to release to assure the absence of contamination. Also, manufacturers must store samples of every lot for future testing in the event of safety or potency concerns raised after the vaccine has been used.