These are all different components of the vaccine schedule, and any one of these could potentially be related to the number and severity of adverse events. When evaluating the safety of different vaccine schedules, it is hence important to study the whole range of issues, from the timing of a single vaccine to summary metrics based on the timing of dozens of vaccines.

The paper presented in this appendix was commissioned by the Institute of Medicine Committee on the Assessment of Studies of Health Outcomes Related to the Recommended Childhood Immunization Schedule. The paper considers different types of potential questions and concerns about the safety of vaccine schedules and describes different epidemiological study designs and statistical methods that can be used to answer such questions in a scientifically rigorous manner. The core of this paper is a set of proposals for the type of study designs and methods that would be appropriate for the comparative evaluation of vaccine adverse events under different vaccine schedules, and the paper is written in the context of the many difficulties raised by the speakers at the committee meetings held in February and March 2012. Note, though, that it is not a synthesis, an evaluation, or a review of the many excellent presentations made at those meetings. Instead, it should be viewed as complementary information. Note also that the paper does not say anything about the advantages or disadvantages about specific vaccines or vaccine schedules. Rather, the focus is on potential study designs and methods and their ability, or inability, to answer such questions.

DEFINITIONS OF KEY TERMS

Component of the vaccine schedule: some specific feature of the vaccine schedule, such as the age at which one of the vaccines is given or the total amount of immune-stimulating content received from all vaccines in the schedule. Not to be confused with different components of a single vaccine.

Early onset: an adverse event that manifests itself and can be detected within a few weeks after vaccination.

Late onset: an adverse event that does not manifest itself and/or cannot be detected until a few months or years after vaccination.

Potential adverse event: a health event under evaluation in a vaccine safety study, in order to determine if it is caused by the vaccine(s) or not.

VACCINE SCHEDULES, ADVERSE EVENTS, AND DATA SETS

Vaccine Schedules and Their Components

To study the safety of different childhood vaccine schedules is an important but complex task. With dozens of vaccines, many of which have



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