the developing immune system. To conduct its review, the committee had to establish a clear statement of the question before it, as well as a manageable scope of inquiry. Both “multiple immunization” and “immune system dysfunction” must be defined for the purposes of this report. First, multiple immunization has several possible meanings. A single dose of vaccine may present multiple antigens for a single disease (e.g., polio or pneumococcal vaccines) or multiple antigens for multiple diseases (e.g., measles-mumps-rubella [MMR] vaccine). Also, individual doses of several separate vaccines may be administered at a single health care visit. And further “repeat” doses of a single vaccine are administered, alone or with other vaccines, at specified intervals (e.g., 2, 4, and 6 months of age). The committee intended its primary focus to be on exposure to multiple vaccine antigens during infancy and childhood. However, as described in the section below on causality, the literature base is not large, and relevant studies often addressed the effects of incremental exposure differences, such as four vaccines compared to three.

The committee restricted its considerations to those vaccines used in the United States. Thus, data regarding BCG vaccine, which is used against tuberculosis in other countries, did not contribute directly to the committee’s causality arguments. (Studies of BCG did, however, help inform the committee’s understanding of the biological arguments for and against the hypotheses.) Nor did the committee address possible effects of smallpox vaccine, which has not been used in the United States for 30 years. The committee included studies of “one vaccine” if it contained antigens against more than one disease or more than one strain of infectious agent. For example, the diphtheria and tetanus toxoids and pertussis (DTP) vaccine—whether whole-cell (DTwP) or acellular (DTaP) preparations—would be considered to represent a “multiple immunization,” as would the polio vaccines, which contain live or killed viruses against three distinct strains of poliovirus.

Second, immune system dysfunction is a broad term. A brief review of the literature about immunization safety indicates that three types of immune system injury are of concern to vaccine safety advocates: risk of infection, risk of allergic diseases, and risk of autoimmune diseases. These concerns have gained prominence due to a generic consideration of biological mechanisms and due to studies, mostly ecological analyses, that are occasionally salient in the lay and scientific literature. The committee considered two possible pathways to adverse outcomes: stimulation of harmful immune responses or suppression of beneficial immune responses. The committee addressed infections only as distinct from those the vaccines are intended to protect against—referred to as heterologous infection—and in lieu of trying to sweep broad categories of allergic and autoimmune diseases, the committee narrowed its focus to specific conditions. It appeared to the committee that much of the concern, and a large component of the evidentiary base, centered around the allergic disease of asthma and the autoimmune form of diabetes—that is, type 1a diabetes, one of two types of



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