Evaluating Risk, Benefits, and Safety in Vaccine Policy
I. Risk-Benefit Analyses and Vaccine Safety Monitoring

Vaccination is cited as one of history's greatest public health achievements, reducing the incidence of many common diseases, allowing for control of others, and leading to the global eradication of smallpox. Long before contemporary controversies regarding vaccination policy, parents struggled to evaluate the risks and benefits of vaccinating their children. The introduction in the last 10 years of several new vaccines and broad recommendations regarding their use have amplified these concerns and questions, contributing to an atmosphere of mistrust, confusion, and frustration among many parents, policy-makers, and health-care providers.

Vaccine Risk-Benefit Analysis

The clearest benefit of a vaccine is to the individual. Assessing the effectiveness of any particular vaccine in an individual is remarkably difficult. Dr. Susan Coffin and Dr. Robert Nelson write that the heterogeneity of immune responses, particularly in children, influences the precise benefits of any vaccination.1 Moreover, these benefits may also change over time due to genetic variation and other factors. The likelihood of disease exposure, the chance of developing recognized symptoms, and the ability to access medical care also influence the assessment of a vaccine's potential benefits.

Vaccine benefits extend beyond any individual to his/her community. Because vaccination decreases the presence of a target pathogen in a community, high vaccination rates can lead to the reduction of disease incidence in unimmunized individuals as well. This concept is known as "herd immunity." Thus, as vaccination rates in a community increase, individuals who are not immunized because of age, weakened immune systems, or choice receive some protection. This rationale is an important factor in policies recommending or requiring vaccination among large populations, such as all children within a certain age range.

In addition to medical value, vaccination has social and economic benefits. Compared to other medical interventions, vaccination programs are widely viewed as being worthwhile, cost-effective investments within a resource-limited health care environment. Vaccination prevents doctor's visits, hospitalizations, medical procedures, and the risks associated with them. Indirectly, by preventing illness through vaccination, children miss fewer days of school, and parents miss fewer work days, thereby avoiding the indirect costs of lost wages. The magnitude of these benefits varies widely among diseases and vaccines, but this modeling of cost-effectiveness of vaccination programs is a central tool in the policy-making process.

At the same time, health officials frequently remind the public that all medical interventions carry some degree of risk. Calling a medical treatment, procedure, pharmaceutical, or vaccine 'safe' does not mean there is zero risk associated with it. The U.S. Food and Drug Administration defines a safe product as "one that has acceptable risks, given the magnitude of the benefit expected in a specific population and within the context of alternatives available."2 Determining what degree of risk is 'acceptable' is a particular challenge for regulators and policy-makers.

Vaccine Clinical Trials and Licensing - An Overview

As vaccines are developed, they undergo several stages of clinical testing, a process that from initial discovery to a licensed vaccine can last as long as 15-20 years. The vast majority of vaccine candidates are rejected during this process. Results from clinical testing constitute the factual base for risk assessment. Researchers must distinguish between any adverse reactions in research subjects caused directly by the vaccine and unrelated events that may have occurred by coincidence.

Following in vitro experiments and computer simulations, researchers test the vaccine candidate on animals including mice, guinea pigs, rabbits, and non-human primates. If these laboratory tests are successful, the researchers apply to the Food and Drug Administration (FDA) to begin clinical studies of the vaccine candidate in human subjects. Institutional Review Boards (IRBs) at the institutions sponsoring the research approve, monitor, and review the studies to ensure the protection of human subjects.3

While the clinical research process for a vaccine can vary considerably depending on the product, the general sequence is as follows. Phase I trials are small, involving as few as10-20 volunteers. The purpose of these trials is to assess basic safety and identify the most common adverse events.4 Phase II trials are larger, randomized, and controlled to collect additional information on safety and potential efficacy. They involve several hundred participants and last from several months to several years.5 Together, the data collected from Phases I and II are used to determine the vaccine's final composition, the number of doses necessary, and the adverse event profile.

If trials show the product to be safe and effective, the vaccine candidate moves onto Phase III testing. These trials involve thousands of volunteers and last several years. A control group is utilized so that the side effect profile can be identified with clarity. Though the large subject pool enables the detection of uncommon adverse events, recognizing very rare safety concerns is an ongoing challenge for researchers of vaccines and pharmaceuticals alike.6

If Phase III trial results are favorable, the vaccine manufacturer then applies to the FDA for two different licenses. One license is for the vaccine (product license) and the second is for the production facilities (establishment license).7 The Center for Biologics Evaluation and Research (CBER) at the FDA reviews clinical trial data on safety and efficacy, proposed product labeling, production facilities, and manufacturing protocols. With expert advice from its Vaccines and Related Biological Products Advisory Committee (VRBPAC), the FDA makes a final decision regarding licensure.

Population Surveillance and Safety Monitoring

Monitoring of vaccine-associated adverse events does not end with licensure. Multiple safeguards are in place to monitor vaccine safety as large-scale vaccination programs begin. This surveillance is particularly important as very rare side effects not observed in clinical testing may appear as the vaccine is administered far more broadly than would be feasible to study prior to licensure.

In 1986, Congress passed the National Childhood Vaccine Injury Act (NCVIA) to address growing concerns regarding vaccine manufacturer liability and the long-term stability of the vaccine industry. The NCVIA requires health care providers to distribute vaccine information statements (VIS) to parents of vaccine recipients. These documents provide information on the disease for which protection is provided, as well as the risks and benefits of the vaccine itself.8

The NCVIA also established the National Vaccine Injury Compensation Program (NVICP), a fund that compensates individuals who have been affected by a known adverse event associated with their vaccination. In this 'no-fault' system, claim filers need not prove provider or manufacturer negligence, and settlements are intended to be uniform.

A central component of the NCVIA is the voluntary reporting of suspected vaccine-related adverse events through the Vaccine Adverse Event Reporting System (VAERS). VAERS is a passive surveillance system in which any individual - a physician, a parent, or others - may file an adverse event report to a central database. VAERS accepts reports of all temporal associations, even those highly unlikely to be linked to the administration of vaccines. This information is then used by the FDA and CDC to monitor vaccine safety, conduct research, and analyze trends in reporting.9 VAERS functions primarily as a hypothesis generating tool, identifying signals of problems and prompting further investigations.10 With personal information removed, VAERS data are available to the public. VAERS has a national scope, the potential to identify extremely rare events, and the ability to detect individual vaccine lots with atypical reporting patterns.11

Despite these strengths, VAERS remains an imperfect tool to assess vaccine safety. Adverse events are likely to be underreported, and reports that are made can be inaccurate or erroneous. Because multiple vaccines are often administered at once, the link between a specific vaccine and an adverse event is particularly difficult to identify. An adverse event occurring after vaccination could be from an infection, injury, congenital abnormality, or another concurrent condition, not necessarily the vaccine.12 Therefore, it is extremely difficult to distinguish temporal associations from true side effects, a task for which VAERS data alone is unable to accomplish.

To complement VAERS, the CDC developed the Vaccine Safety Datalink (VSD) project. Eight large managed care organizations have partnered to monitor vaccine safety, linking the comprehensive medical and immunization histories of 5.5 million people.13 The VSD project monitors adverse effects, facilitates hypothesis-generation, and provides data for ongoing safety studies. Like VAERS, however, the VSD project is not weaknesses, included a limited sample size, a relative lack of population diversity, and an underrepresented unvaccinated population.14

-- By Katelin Hoskins, University of Pennsylvania (hoskinsk@nursing.upenn.edu); Updated July 2010.

Continue to II. Risk Communication and Related Ethical Considerations

1 Coffin SE & Nelson RM. (2005). "Optimizing risks and benefits: the case of rotavirus vaccine." Ethics and Research with Children: A Case Based Approach. Ed. Kodish ED. Oxford University Press: USA.
2 U.S. Food and Drug Administration. (2008). The Sentinel Initiative: A National Strategy for Monitoring Medical Product Safety. Available at http://www.fda.gov/oc/initiatives/advance/reports/report0508.html.
3 Plotkin, Stanley A., Walter A. Orenstein, and Paul A. Offit. Vaccines. (pp. 1615-1618). Philadelphia, Pa: Saunders/Elsevier, 2008.
4 Center for Disease Control and Prevention. (2008). History of vaccine safety. Available at http://www.cdc.gov/vaccinesafety/basic/history.htm.
5 Ibid.
6 Coffin SE & Nelson RM. (2005). "Optimizing risks and benefits: the case of rotavirus vaccine." Ethics and Research with Children: A Case Based Approach. Ed. Kodish ED. Oxford University Press: USA.
7 Center for Disease Control and Prevention. (2008). History of vaccine safety. Available at http://www.cdc.gov/vaccinesafety/basic/history.htm.
8 Ibid.
9 Ibid.
10 Pless R. (2000). Vaccine safety: Beyond clinical trials. Medscape Today. Available at http://www.medscape.com/viewprogram/279.
11 Ellenberg SS, Foulkes MA, Midthun K & Goldenthal KL. (2005). Evaluating the safety of new vaccines: summary of a workshop. American Journal of Public Health, 95(5): 800-807.
12 U.S. Food and Drug Administration. (2003). Center for Biologics Evaluation and Research, VAERS Overview. Available at http://www.fda.gov/Cber/vaers/what.htm.
13 Center for Disease Control and Prevention. (2008). History of vaccine safety. Available at http://www.cdc.gov/vaccinesafety/basic/history.htm.
14 Ellenberg SS, Foulkes MA, Midthun K & Goldenthal KL. (2005). Evaluating the safety of new vaccines: summary of a workshop. American Journal of Public Health, 95(5): 800-807.

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