History of Vaccine Safety
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Perhaps the greatest success story in public health is the reduction of infectious diseases resulting from the use of vaccines. Routine immunization has eradicated smallpox from the globe and led to the near elimination of wild polio virus. Vaccines have reduced some preventable infectious diseases to an all-time low, and now few people experience the devastating effects of measles, pertussis, and other illnesses. Prior to approval by the Food and Drug Administration (FDA), vaccines are tested extensively by scientists to ensure they are effective and safe. Vaccines are the best defense we have against infectious diseases; however, no vaccine is 100% safe or effective. Differences in the way individual immune systems react to a vaccine account for rare occasions when people are not protected following immunization or when they experience side effects.1 2 3
As the incidence of infectious diseases continues to decline, some people have become less interested in the consequences of preventable illnesses like diphtheria and tetanus. Instead, they have become increasingly concerned about the risks associated with vaccines. After all, vaccines are given to healthy individuals, many of whom are children, and therefore a high standard of safety is required. Since vaccination is such a common and memorable event, any illness following immunization may be attributed to the vaccine. While some of these reactions may be caused by the vaccine, many of them are unrelated events that occur after vaccination by coincidence. Therefore, the scientific research that attempts to distinguish true vaccine side effects from unrelated, chance occurrences is crucial. This knowledge is necessary to maintain public confidence in immunization programs. As science continues to advance, we strive to develop safer vaccines and improve delivery to protect ourselves against disease more effectively. This overview focuses on vaccine research, how vaccines are licensed, how safety is monitored, and how risks are communicated to the public.1 2 3
The topic of vaccine safety became prominent during the mid 1970s with increases in lawsuits filed on behalf of those presumably injured by the diphtheria, pertussis, tetanus (DPT) vaccine 4. Legal decisions were made and damages awarded despite the lack of scientific evidence to support vaccine injury claims.4 As a result of these decisions, liability and prices soared, and several manufacturers halted production. A vaccine shortage resulted and public health officials became concerned about the return of epidemic disease. To reduce liability and respond to public health concerns, Congress passed the National Childhood Vaccine Injury Act (NCVIA) in 1986. This act was influential in many ways.
Before vaccines are licensed by the FDA, they are tested extensively in the laboratory and with human subjects to ensure their safety. First, computers are used to predict how the vaccine will interact with the immune system. Then researchers test the vaccine on animals including mice, guinea pigs, rabbits, and monkeys. After the vaccine completes these laboratory tests successfully, the FDA approves its use in clinical studies on human subjects. Participation in these studies is completely voluntary. Many individuals choose to contribute their time and energy for the advancement of science. Informed consent is obtained from all participants before they become involved in research. This ensures that they understand the purpose of the study and its potential risks, and are willing to participate. Volunteers agree to receive the vaccine and undergo any medical testing necessary to assess its safety and efficacy.6
Vaccine licensing is a lengthy process that may take 10 years or longer. The FDA requires that vaccines undergo three phases of clinical trials with human subjects before they can be licensed for use in the general public. Phase one trials are small, involving only 20 to 100 volunteers, and last only a few months. The purpose of phase one trials is to evaluate basic safety and identify very common side effects. Phase two trials are larger and involve several hundred participants. These studies last anywhere from several months to two years and collect additional information on safety and efficacy. Data gained from phase two trials can be used to determine the composition of the vaccine, how many doses are necessary, and a profile of common side effects. Unless the vaccine is completely ineffective or causes serious side effects, the trials are expanded to phase three, which involves several hundred to several thousand volunteers. Typically these trials last several years. Because the vaccinated group can be compared to those who have not received the vaccine, researchers are able to identify true side effects.1 3 6 7 8
If the clinical trials demonstrate that the vaccine is safe and effective, the manufacturer applies to the FDA for two licenses: one for the vaccine (product license), and one for the production plant (establishment license). During the application process, the FDA reviews the clinical trial data and proposed product labeling. In addition, the FDA inspects the plant and goes over manufacturing protocols to ensure vaccines are produced in a safe and consistent manner. Only after the FDA is satisfied that the vaccine is safe is it licensed for use in the general population.7
After a vaccine is licensed for public use, its safety is monitored continually. The FDA requires all manufacturers to submit samples from each vaccine lot prior to its release. In addition, the manufacturers must provide the FDA with their test results for vaccine safety, potency, and purity. Each lot must be tested because vaccines are sensitive to environmental factors like temperature, and can be contaminated during production. During the last 10 years, the FDA has recalled only three vaccine lots: one was mislabeled, another was contaminated during production, and the third was recalled after the FDA discovered potential manufacturing problems at a production plant.7
While clinical trials provide important information on vaccine safety, the data are somewhat limited because of the small number (hundreds to thousands) of study participants. Rare side effects and delayed reactions may not be evident until the vaccine is administered to millions of people. Therefore, the federal government established a surveillance system to monitor adverse events following vaccination. This project is known as the Vaccine Adverse Event Reporting System (VAERS). More recently, large-linked databases containing information on millions of individuals have been created to study rare vaccine adverse events.1 3
The National Childhood Vaccine Injury Act of 1986 requires health care providers to report certain adverse events that occur following vaccination. As a result, the Vaccine Adverse Event Reporting System was established by CDC and FDA in 1990. VAERS provides a mechanism for the collection and analysis of adverse events (side effects) associated with vaccines currently licensed in the United States. Adverse events are defined as health effects that occur after immunization that may or may not be related to the vaccine. VAERS data are monitored continually to detect unknown adverse events or increases in known side effects..1 9
Approximately 10,000 to 12,000 VAERS reports are filed annually, with one-fifth classified as serious (causing disability, hospitalization, life-threatening illness, or death).1 Anyone can file a VAERS report, including health care providers, manufacturers, and vaccine recipients or their parents or guardians.1 9 Those who have experienced an adverse reaction following immunization are encouraged to seek help from a health care professional when filling out the form.
VAERS forms can be obtained in several ways. Each year the form is mailed to more than 200,000 physicians specializing in pediatrics, family practice, internal medicine, infectious diseases, emergency medicine, obstetrics and gynecology. In addition, copies are sent to health departments and clinics that administer vaccines. The VAERS form requests the following information: the type of vaccine received, the timing of vaccination, the onset of the adverse event, current illnesses or medication, history of adverse events following vaccination, and demographic information about the recipient (age, gender, etc.). The form is pre-addressed and stamped so it can be mailed directly to VAERS. To request a VAERS form or assistance in filling in out, call (800) 822-7967.1 9
A contractor, under the supervision of FDA and CDC, collects the information and enters it into a database. Those reporting an adverse event to VAERS receive a confirmation letter by mail indicating that the form was received. This letter contains a VAERS identification number. Additional information may be submitted to VAERS using the assigned identification number. Selected cases of serious adverse reactions are followed up at 60 days and one year post-vaccination to check the recovery status of the patient. The FDA and CDC have access to VAERS data and use this information to monitor vaccine safety and conduct research studies. VAERS data (minus personal information) are also available to the public.1 9
While VAERS provides useful information on vaccine safety, the data are somewhat limited. Specifically, judgments about causality (whether the vaccine was truly responsible for an adverse event) cannot be made from VAERS reports because of incomplete information. VAERS reports often lack important information such as laboratory results. As a result, researchers have turned more recently to large-linked databases (LLDB) to study vaccine safety. LLDB allow scientists to access the complete medical records of millions of individuals receiving vaccines (all identifying information is deleted to protect the confidentiality of the patient). One example of an LLDB is the Vaccine Safety Datalink (VSD) project described below, which is coordinated by CDC. Studies conducted using LLDBs like the VSD are also known as post-marketing research or phase four clinical trials.1
The April 2004 issue of the Pediatric Infectious Diseases Journal featured an article, Understanding vaccine safety information from the Vaccine Adverse Event Reporting System, that explains the objectives of the Vaccine Adverse Event Reporting System (VAERS) as well as its strengths and limitations.20
Gaps in the scientific knowledge of rare vaccine side effects prompted the CDC to develop the Vaccine Safety Datalink (VSD) project in 1990. This project involves partnerships with eight large managed care organizations (MCOs) to monitor vaccine safety. VSD is an example of a large-linked database (LLDB) and includes comprehensive medical and immunization histories for 5.5 million people annually, which are derived from participating managed care organizations that contain more than nine million members. All vaccines administered within the study population are recorded. Available data include vaccine type, date of vaccination, concurrent vaccinations (those given during the same visit), the manufacturer, lot number, and injection site. Medical records are monitored for potential side effects resulting from immunization. The VSD project allows for planned vaccine safety studies as well as timely investigations of hypotheses. At present, the VSD project is examining potential associations between vaccines and a number of serious conditions. The database is also being used to test new vaccine safety hypotheses that result from the medical literature, VAERS, changes in the immunization schedule, or the introduction of new vaccines. This project is a powerful and cost-effective tool for the ongoing evaluation of vaccine safety.1 10
To reduce the liability of manufacturers and health care providers, the National Childhood Vaccine Injury Act of 1986 established the National Vaccine Injury Compensation Program. This program compensates individuals who have been injured by vaccines on a "no-fault" basis. No-fault means people filing claims are not required to prove negligence on the part of either the health care provider or the manufacturer to receive compensation. The program covers all routinely recommended childhood vaccinations. Settlements are based on the Vaccine Injury Table, which summarizes the adverse events caused by vaccines. This table was developed by a panel of experts who reviewed the medical literature and identified the serious adverse events that are reasonably certain to be caused by vaccines. Examples of table injuries include anaphylaxis (severe allergic reaction), paralytic polio, and encephalopathy (general brain disorder). The Vaccine Injury Table was created to compensate those injured by vaccines justly while separating out unrelated claims. As more information becomes available from research on vaccine side effects, the Vaccine Injury Table is updated.10 12
Individuals and their families can qualify for compensation in three ways. One is to show that an injury found on the Vaccine Injury Table occurred in the appropriate time interval following immunization. The other two ways to qualify include proving that the vaccine caused the condition or demonstrating that the vaccine worsened or aggravated a pre-existing condition.11 12
In the last decade, numerous changes in vaccine production and administration have reduced the number of side effects and resulted in safer vaccines. A more purified acellular pertussis (aP) vaccine has been licensed for use and has replaced the whole cell pertussis vaccine used in DTP (diphtheria, tetanus, pertussis vaccine). Several studies have evaluated the safety and efficacy of DTaP as compared to DTP and concluded DTaP is effective in preventing disease, and mild and serious side effects occurred less frequently when the DTaP vaccine was given.3 Recent changes in the schedule of polio vaccines also have resulted in fewer reports of serious adverse events. In 1997, the Advisory Committee on Immunization Practices recommended a change in the vaccination schedule to include sequential administration of inactivated polio vaccine (IPV) and oral polio vaccine (OPV).13 This sequential schedule was expected to produce a high level of individual protection against the disease caused by wild polio virus, while reducing by 50 to 70% vaccine-associated paralytic polio (VAPP) that occurs in 8–10 people a year who receive OPV.14 Today, only IPV is on the recommended childhood immunization schedule.
At some point, almost every person in the United States is vaccinated. Therefore, many individuals question how vaccines are made, if they are effective, and whether they are safe.15 People seek answers to these questions from a variety of sources including family, friends, health care providers, the Internet, television, and medical literature. The information they receive is complex and, at times, inaccurate or misleading. Therefore, health professionals have a responsibility to provide accurate, understandable information and to handle vaccine safety concerns appropriately. As mentioned previously, the NCVIA requires all health care providers who administer vaccines to discuss the potential risks and benefits of immunization. In these situations, risk communication is a necessary skill.1
Risk communication involves a dynamic exchange of information among individuals, groups, and institutions. This information must acknowledge and define the risks associated with vaccination in a way the public can understand. This is difficult given the current environment where few people experience the devastation of vaccine-preventable diseases. It is further complicated by the fact that immunization is associated with some degree of personal discomfort when needles are used to administer vaccines.1
In 1996, the Institute of Medicine's Vaccine Safety Forum held a workshop on risk communication and vaccination. Three key concepts emerged:
Several resources are available to address the risks and benefits of vaccination. Federal law requires all health care providers who administer vaccines in the United States to provide vaccine information statements (VISs) to vaccine recipients (or their parent or guardian) prior to each dose. VISs are developed by CDC and contain information on the disease as well as the risks and benefits associated with immunization.
The importance of vaccine safety will continue to grow throughout the 21st century. The development and licensure of new vaccines will add to the already complicated immunization scheduling. Scientists may also perfect new ways of administering immunizations including edible vaccines and needleless injections. However they are formulated or delivered, vaccines will remain the most effective tool we possess for preventing disease and improving public health in the future.
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