If observational data suggest that a particular element of the schedule is associated with a particular adverse outcome in an identifiable subgroup, it could be ethical to conduct a randomized trial of the schedule with such a population, if such a trial does not require some children to receive a reduced schedule that would put them at risk for vaccine-preventable disease. However, as both the potential risks and the benefits are elevated and, moreover, the research community does not currently have a sound idea of the magnitudes of those risks and benefits, it is premature to propose RCTs to evaluate differences in outcomes between these hypothesized groups.

General Feasibility Issues

As detailed in Chapter 3, RCTs to evaluate the introduction of individual vaccinations are conducted within the context of the currently recommended childhood immunization schedule. The committee found no evidence that a trial has ever been conducted to evaluate the entire immunization schedule, for example, to compare administration of the recommended schedule of vaccines with administration of an alternative schedule. To conduct such a trial would require careful consideration of multiple factors. For instance, it has been established that some vaccines are associated with fevers, febrile convulsions, anaphylaxis, and other syndromes, which in some cases are similar to the symptoms of the diseases that they are intended to prevent. These adverse reactions are mostly rare. For example, febrile seizures occur for only 1 of every 3,000 measles, mumps, and rubella (MMR) vaccine doses (IOM, 2012), but a sufficiently large study of the safety of a schedule that omits or delays MMR would likely show an increased risk of seizures in the group receiving the regular doses of MMR. Unless researchers somehow accounted for the occurrence of the more serious preventable diseases, it may appear that nonvaccination is “safer” in this respect. To further complicate matters, the rare unvaccinated child in an otherwise heavily vaccinated area will benefit from community immunity and may thus appear to have done better than his or her peers, some of whom will develop adverse effects, such as fever.

Because vaccination in the United States essentially begins at birth, an RCT of the immunization schedule would have to randomize children either before birth or shortly thereafter. In addition to the many practical difficulties that this raises, randomization before birth means that the trial cannot be conducted solely through interactions with child health care providers, as pregnant women will typically be seeing a pregnancy care provider in the months preceding delivery. Such a trial would also require parents to adhere to their child’s assigned schedule for at least 6 years and to avoid catch-up immunizations in the years that follow to evaluate hypothesized long-term health outcomes, all of which would likely add up to

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