of the suggested biological pathways. Given the safeguards already in place, stakeholder concerns alone are not sufficient reason to embark on costly clinical research, such as new randomized controlled trials (RCTs) or prospective cohort studies, without the existence of supporting signals or evidence of biological plausibility.

Recommendation 6-1: The committee recommends that the Department of Health and Human Services incorporate study of the safety of the overall childhood immunization schedule into its processes for setting priorities for research, recognizing stakeholder concerns, and establishing the priorities on the basis of epidemiological evidence, biological plausibility, and feasibility.

Animal Models

Animal models play a critical role in preclinical studies during development of all medications, including vaccines (Kanesa-thasan et al., 2011). For example, rats and mice are used for investigations into fundamental basic science issues to establish ranges of dosing, to explore immunogenicity, and even to provide perspectives on some clinical outcomes. Studies of acute toxicity, tolerability, and causes of fever have been performed in guinea pigs and rabbits (Kanesa-thasan et al., 2011). Subsequent studies of safety may be carried out in rats or primates, as appropriate (Kanesa-thasan et al., 2011). Animal models may also be useful for studies exploring novel vaccines, the extent of interference with vaccine immunogenicity by concurrently administered vaccines, and the bactericidal qualities of antibodies. In its review of the existing evidence of the immunization schedule and safety, the committee did not explicitly review mechanistic evidence for any health outcomes, such as case studies or existing animal models, and instead points to the excellent work of previous committees in their reviews of individual vaccines (IOM, 2002, 2012). However, various stakeholders expressed interest in the potential use of animal models, and the committee therefore also considered the potential of studies with animal models of disease to advance knowledge of the biological mechanisms by which the childhood immunization schedule might be associated with adverse events.

To use animal models for the biological study of the recommended immunization schedule, however, many challenges must be overcome and limitations must be appreciated. For example, if one is interested in events that are purported to occur long after vaccine administration, such as asthma or food allergy, one must establish the generalizability of animal models of those diseases to the human context. Furthermore, spontaneously occurring models of diseases in animals would have to be developed before

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