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Vaccinovigilance

Lisa Beth Ferstenberg, MD

Vigilance for vaccines is different from vigilance for drugs. We will review the difference between vaccinovigilance and pharmacovigilance—the U.S. Initiative: VAERS, the European Initiative: GACVS, and the European Commissions, Vaccine Adverse Event Reporting, and sources of additional information.

Adverse event reporting, whether associated with a drug or a vaccine, captures information on known or suspected reactions to administered substances; however, in the case of a drug, the substance is usually administered as an intervention for an existing illness or condition, and in the case of a vaccine, it is given to prevent an illness. This critical difference, between intervention and prevention, affects the entire analysis, interpretation, and implications of vigilance data.

In general, severe adverse events to vaccines are rare. Approximately 85% of reported adverse events are mild and self-limiting and usually involve local reactions, such as pain or itching at the site of administration, or systemic reactions, such as fever or irritability. The 15% of reported severe adverse events may include seizures, high fevers, life-threatening illnesses, or death (Web Resource 45-1).

The notable difference between vaccine-related adverse events, whether minor or severe, and those associated with drugs is that vaccine-related adverse events are usually immunologic and signal immune response (Web Resource 45-2). For drugs, however, adverse events more frequently indicate organ toxicity. Since the vaccine’s objective is to elicit an immune response to a target antigen, the emergence of an immunologic or inflammatory response can indicate that the patient is developing a desirable immune response, whereas in drug-related toxicity, the reaction almost invariably indicates an undesirable effect.

The contextual differences between intervention and prevention affect the interpretation of data derived from adverse event reporting. For a drug-related adverse event, the patient presents to the health professional with an array of symptoms, and if new symptoms develop following treatment, there is a reasonable likelihood that the provider following the patient will be informed of their occurrence and will be able to assess them in the context of the illness. Vaccines, however, are often administered en masse to large populations not seeing a provider for a specific complaint. When an adverse event occurs, the patient is less likely to have access to the provider who administered the vaccine, and the provider is less likely to know the patient’s history of prior health or underlying conditions. In addition, little to no information may be available about how many doses of the vaccine have been administered in the population, to whom, and with what results (Hanslik, Boelle, Med Sci [Paris] 2007;23[4]: 391–398).

In addition to safety, establishing vaccine effectiveness requires recognizing the epidemiologic pattern of the disease to be prevented. Ideally, efficacy is expressed as a reduction in the incidence of the infectious disease in vaccinated subjects as compared with the unvaccinated population. In reality, disease reporting in populations is frequently incomplete in both vaccinated and unvaccinated populations; hence, patients who report adverse events to vaccines frequently represent the richest source of data obtainable about the epidemiology of both an infectious disease and its prevention.

Why is this safety and efficacy information not available from clinical trials done before approval? Despite the large sample sizes enrolled in phase I–III clinical trials (patient numbers can be in the tens of thousands), most preapproval clinical trials are designed to limit the number of confounding variables that would make it difficult to interpret the data. Hence, much older and much younger patients may not be enrolled, and patients with a wide variety of comorbidities may have been excluded. Typically, when a new vaccine is first introduced to the market, little may be known about vaccination risks in immunocompromised patients, pregnant women, cancer patients, and patients with serious underlying diseases.

The Vaccine Adverse Event Reporting System (VAERS) used in the United States is the postmarketing safety surveillance program created by the Centers for Disease Control and Prevention (CDC) and the U.S. Food and Drug Administration (FDA) in response to the National Childhood Vaccine Injury Act (NCVIA) of 1986. This law requires health professionals and vaccine manufacturers to report to the Department of Health and Human Services (HHS), of which both CDC and FDA are divisions, specific adverse events that occur following vaccines. The objectives of the program are as follows:

1. To detect new, unusual, or rare adverse events associated with vaccine administration
   
2. To monitor increases in the incidence of known adverse events
   
3. To identify potential patient-associated risk factors that may predispose individuals to vaccineassociated adverse events
   
4. To identify vaccine lots that may be associated with an unusually high rate of adverse events
   
5. To assess the safety of newly licensed vaccines in large diverse populations once they have been released to market

Anyone can report an adverse event through VAERS, including patients and health professionals. The system is a passive surveillance program, which means that it suffers from the following limitations:

1. Underreporting of adverse events
   
2. Differential reporting, which is a pattern of increased reporting when a vaccine is new that falls off with time
   
3. Stimulated reporting, which occurs when a new adverse event is first recognized and a flurry of similar or alleged events are then reported
   
4. Coincidental events, which occurs when an unrelated temporal event is reported as being associated with receipt of a vaccine
   
5. Poor data quality, with a great deal of missing information and lack of patient follow-up
   
6. Lack of denominator data, when information on the number of doses of a vaccine administered in the population is not available

Nevertheless, approximately 30,000 adverse events are reported to VAERS annually, of which only 13% are severe, i.e., associated with disability, hospitalization, life-threatening illnesses, or death (Web Resource 45-1).

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