Cumulative and episodic vaccine aluminum exposure in a population-based cohort of young children
Introduction
Along with immunogens, vaccines contain small amounts of preservatives, adjuvants, additives and residual substances from the manufacturing process [1]. Examples of these additional non-antigen vaccine ingredients include formaldehyde, antibiotics, aluminum, squalene, and monosodium l-glutamate. Although evidence from animal studies, pharmacokinetic modeling, observational studies, and clinical investigations support the safety of ingredients in currently licensed vaccines [2], [3], [4], [5], some parents cite vaccine ingredients as a safety concern. These concerns may be contributing to increased rates of undervaccination and adoption of alternative immunizations schedules across the United States [6], [7], [8], [9], [10]. To date, there have been no population-based studies specifically designed to evaluate associations between clinically meaningful outcomes and non-antigen vaccine ingredients, other than thimerosal [11], [12], [13].
Concerns about the safety non-antigen vaccine ingredients may also contribute to more general concern of some parents that the current immunization schedule exposes young children to “too many vaccines too soon”. As recognized by the Institute of Medicine in a review of the feasibility of studying the safety of the immunization schedule, large epidemiological studies represent a logical first step in evaluating these concerns [14]. In addition, a 2009 report by the National Vaccine Advisory Committee (NVAC) recommended a comprehensive safety evaluation of cumulative levels of non-antigen vaccine ingredients as it relates to the recommened schedule [15]. It is possible that such studies could be conducted in the Vaccine Safety Datalink (VSD), an established collaboration of nine managed care organizations (MCOs) where electronic health record (EHR) data are used to conduct observational studies of vaccine safety [16]. In the VSD, large cohorts of children can be assembled to examine potential associations between vaccines and rare adverse events.
In this feasibility study, we conducted an evaluation of the extent to which VSD could be used to conduct a population-based evaluation of the safety of non-antigen vaccine ingredients. We first identified the main non-antigen ingredients in vaccines and determined how well exposure to specific ingredients could be quantified. As an example of how exposure levels could be quantified and categorized, we assessed vaccine-specific aluminum contents among cohorts of children that had been vaccinated according to different schedules. Finally, we assessed the statistical power to evaluate relative risks by level of aluminum exposure over a range of incidence rates.
Section snippets
Setting and study population
Using VSD databases, we identified a study population of children born between 1/1/2004 and 12/31/2011. Children were included if they were continuously enrolled for 12 months and had at least one outpatient visit in the MCO by one year of age. Follow-up for each child stopped at either their second birthday, end of MCO enrollment, or end of the study period (12/31/2012). Cohort exclusion criteria are listed in Fig. 1.
Vaccination data were collected from the VSD files from birth up to age two
Study cohorts and undervaccination
We identified 515,001 children born 2004–2011 with at least one outpatient visit before age 12 months. After exclusions for missing manufacturer data and data entry errors, the final study population included 408,608 (79.3%) children (Fig. 1). The distribution of birth year was approximately uniform across the study period, and 48.76% of the cohort was female. Forty-seven percent (n = 191,716) of the children were undervaccinated for at least one day (accounting for the 30-day grace period), and
Discussion
In this feasibility study, we attempted to ascertain exposure to 34 different non-antigen vaccine ingredients in the VSD study population. Based on data currently available in the VSD, we determined that it would be difficult to study the safety of most vaccine ingredients. For many ingredients, the quantity is not precisely documented in the package insert. While it is possible that this information could be obtained directly from the vaccine manufacturers, it is also possible that the amounts
Conclusions
Despite extensive evidence to support the safety of vaccines, parents appear to have concerns about vaccine ingredients. Based on available data in the VSD, we found that it would be feasible to study aluminum, but not most vaccine ingredients. Before proceeding with any studies, however, consideration would have to be given to the potential effect of confounding variables, biologic plausibility of hypothesized associations, prior evidence, and public health or clinical importance.
Acknowledgments
We acknowledge and thank Katherine Burniece for compiling information from vaccine product inserts for Table 1.
Preliminary results from this study were presented at the Pediatric Academic Society meeting, May 5, 2014, in Vancouver, Canada.
Funding source: The work was funded by contract 200-2012-53582 from the Centers for Disease Control and Prevention Vaccine Safety Datalink infrastructure task order. The findings and conclusions in this report are those of the authors and do not necessarily
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