Elsevier

Vaccine

Volume 33, Issue 48, 27 November 2015, Pages 6736-6744
Vaccine

Cumulative and episodic vaccine aluminum exposure in a population-based cohort of young children

https://doi.org/10.1016/j.vaccine.2015.10.076Get rights and content

Abstract

Background

In addition to antigens, vaccines contain small amounts of preservatives, adjuvants, and residual substances from the manufacturing process. Some parents have concerns about the safety of these ingredients, yet no large epidemiological studies have specifically examined associations between health outcomes and vaccine ingredients, other than thimerosal. This study examined the extent to which the Vaccine Safety Datalink (VSD) could be used to study vaccine ingredient safety in children.

Methods

Children born 2004–2011 were identified in VSD data. Using immunization records, two cohorts were identified: children who were up-to-date and children who were undervaccinated before age 2 years. A database was also created linking vaccine type and manufacturer with ingredient amounts documented in vaccine package inserts. Thirty-four ingredients in two or more infant vaccines were identified. However, only amounts (in mg) for aluminum were consistently documented and commonly contained in infant vaccines. Analyses compared vaccine aluminum exposure across cohorts and determined the statistical power for studying associations between aluminum exposure and hypothetical vaccine adverse events.

Results

Among 408,608 children, mean cumulative vaccine aluminum exposure increased from 1.11 to 4.00 mg between ages 92–730 days. Up-to-date children were exposed to 11–26% more aluminum from vaccines than undervaccinated children. Power analyses demonstrated that safety studies of aluminum could detect relative risks ranging from 1.1 to 5.8 for a range of adverse event incidence.

Conclusions

The safety of vaccine aluminum exposure can be feasibly studied in the VSD. However, possible biological mechanisms and confounding variables would need to be considered before conducting any studies.

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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      That work has not offered nothing new, nothing concrete, in order to solve the dilemma: could vaccine aluminum harm a child's health? In order to support this discussion, we present the conclusion of this paper, i.e. the final sentence, which says: "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 evident, and public health or clinical importance" [16]. To summarize, based on the above, aluminum does not manifest direct toxic effects, and does not induce the formation of ROS, as is considered by other authors [15,17].

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