Advertisement

Association Between Aluminum Exposure From Vaccines Before Age 24 Months and Persistent Asthma at Age 24 to 59 Months

Published:September 28, 2022DOI:https://doi.org/10.1016/j.acap.2022.08.006

      Abstract

      Objective

      To assess the association between cumulative aluminum exposure from vaccines before age 24 months and persistent asthma at age 24 to 59 months.

      Methods

      A retrospective cohort study was conducted in the Vaccine Safety Datalink (VSD). Vaccination histories were used to calculate cumulative vaccine-associated aluminum in milligrams (mg). The persistent asthma definition required one inpatient or 2 outpatient asthma encounters, and ≥2 long-term asthma control medication dispenses. Cox proportional hazard models were used to evaluate the association between aluminum exposure and asthma incidence, stratified by eczema presence/absence. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) per 1 mg increase in aluminum exposure were calculated, adjusted for birth month/year, sex, race/ethnicity, VSD site, prematurity, medical complexity, food allergy, severe bronchiolitis, and health care utilization.

      Results

      The cohort comprised 326,991 children, among whom 14,337 (4.4%) had eczema. For children with and without eczema, the mean (standard deviation [SD]) vaccine-associated aluminum exposure was 4.07 mg (SD 0.60) and 3.98 mg (SD 0.72), respectively. Among children with and without eczema, 6.0% and 2.1%, respectively, developed persistent asthma. Among children with eczema, vaccine-associated aluminum was positively associated with persistent asthma (aHR 1.26 per 1 mg increase in aluminum, 95% CI 1.07, 1.49); a positive association was also detected among children without eczema (aHR 1.19, 95% CI 1.14, 1.25).

      Conclusion

      In a large observational study, a positive association was found between vaccine-related aluminum exposure and persistent asthma. While recognizing the small effect sizes identified and the potential for residual confounding, additional investigation of this hypothesis appears warranted.

      Keywords

      What's New
      In a large observational study, a positive association was found between vaccine-related aluminum exposure and persistent asthma. While recognizing the small effect sizes identified and the potential for unmeasured confounding, additional investigation of this hypothesis appears warranted.
      While the safety
      Institute of Medicine
      Adverse Effects of Vaccines: Evidence and Causality.
      and effectiveness
      • Whitney CG
      • Zhou F
      • Singleton J
      • et al.
      Benefits from immunization during the vaccines for children program era—United States, 1994-2013.
      of the childhood immunization schedule are supported by extensive scientific evidence, and vaccination coverage among US children remains high relative to historical benchmarks, maintaining high coverage requires preserving public confidence in vaccine safety.
      National Vaccine Advisory Committee
      Assessing the state of vaccine confidence in the United States: recommendations from the National Vaccine Advisory Committee: approved by the National Vaccine Advisory Committee on June 9, 2015 [corrected].
      In the United States and globally, parents have expressed concern about the safety of the immunization schedule,
      • Kempe A
      • Saville AW
      • Albertin C
      • et al.
      Parental hesitancy about routine childhood and influenza vaccinations: a national survey.
      including regarding the safety of repeated exposure to nonantigen vaccine components such as aluminum. A small but increasing number of parents have refused, delayed, or spread out vaccination
      • Hill HA
      • Yankey D
      • Elam-Evans LD
      • et al.
      Vaccination coverage by age 24 months among children born in 2016 and 2017—National Immunization Survey-Child, United States, 2017-2019.
      ; this practice increases risk of vaccine-preventable diseases
      • Gardner L
      • Dong E
      • Khan K
      • et al.
      Persistence of US measles risk due to vaccine hesitancy and outbreaks abroad.
      and vaccine-associated febrile seizures
      • Hambidge SJ
      • Newcomer SR
      • Narwaney KJ
      • et al.
      Timely versus delayed early childhood vaccination and seizures.
      without yielding any scientifically proven safety advantage.
      Aluminum is integral to many vaccines, enhancing immunogenicity and effectiveness.
      • Baylor NW
      • Egan W
      • Richman P.
      Aluminum salts in vaccines–US perspective.
      Aluminum adjuvants have a well-established safety profile,
      • Goullé JP
      • Grangeot-Keros L.
      Aluminum and vaccines: current state of knowledge.
      and are used in many vaccines given in early childhood.
      • Glanz JM
      • Newcomer SR
      • Daley MF
      • et al.
      Cumulative and episodic vaccine aluminum exposure in a population-based cohort of young children.
      However, data from animal studies suggest the theoretical possibility that aluminum adjuvants could influence allergy risk through inducing a T helper 2 cell (Th2)-biased immune response.
      • Hogenesch H.
      Mechanism of immunopotentiation and safety of aluminum adjuvants.
      ,
      • Sastry M
      • Zhang B
      • Chen M
      • et al.
      Adjuvants and the vaccine response to the DS-Cav1-stabilized fusion glycoprotein of respiratory syncytial virus.
      In allergic asthma, common in children,
      • Akinbami LJ
      • Simon AE
      • Schoendorf KC.
      Trends in allergy prevalence among children aged 0-17 years by asthma status, United States, 2001-2013.
      Th2 lymphocytes mediate airway inflammation and hyper-responsiveness.
      • Robinson DS.
      The role of the T cell in asthma.
      Childhood asthma is a clinical diagnosis, made based upon recurrent episodes of symptomatic airflow obstruction, responsiveness to therapies (eg, inhaled corticosteroids and short-acting beta2-agonists), and exclusion of other causes.
      National Asthma Education Prevention Program
      Expert panel report 3 (EPR-3): guidelines for the diagnosis and management of asthma-summary report 2007.
      The Institute of Medicine, in response to public concern about the safety of the childhood immunization schedule, endorsed studying the risk of chronic conditions such as asthma following vaccination, while acknowledging methodologic challenges with doing so.
      Institute of Medicine
      Childhood Immunization Schedule and Safety: Stakeholder Concerns, Scientific Evidence, and Future Studies.
      The Vaccine Safety Datalink (VSD) is a long-standing research network established to conduct postlicensure observational studies of vaccine safety.
      • McNeil MM
      • Gee J
      • Weintraub ES
      • et al.
      The Vaccine Safety Datalink: successes and challenges monitoring vaccine safety.
      Preparatory to the current study, we evaluated the completeness of VSD immunization data,
      • Daley MF
      • Shoup JA
      • Newcomer SR
      • et al.
      Assessing potential confounding and misclassification bias when studying the safety of the childhood immunization schedule.
      the availability of vaccine-associated aluminum data,
      • Glanz JM
      • Newcomer SR
      • Daley MF
      • et al.
      Cumulative and episodic vaccine aluminum exposure in a population-based cohort of young children.
      and the feasibility of studying the safety of the schedule.
      • Glanz JM
      • Newcomer SR
      • Jackson ML
      • et al.
      White paper on studying the safety of the childhood immunization schedule in the Vaccine Safety Datalink.
      Our study objective was to examine the association between cumulative vaccine-associated aluminum exposure before age 24 months and persistent asthma incidence at age 24 through 59 months.

      Methods

      Study Setting

      This retrospective cohort study was conducted in seven medical care organizations (referred to as “sites”) participating in the VSD.
      • McNeil MM
      • Gee J
      • Weintraub ES
      • et al.
      The Vaccine Safety Datalink: successes and challenges monitoring vaccine safety.
      VSD sites are located in Minnesota, Wisconsin, Washington, Oregon, California, and Colorado, and the VSD population of ∼12 million is similar to the US population with respect to demographic and socioeconomic characteristics.
      • Sukumaran L
      • McCarthy NL
      • Li R
      • et al.
      Demographic characteristics of members of the Vaccine Safety Datalink (VSD): a comparison with the United States population.
      The VSD utilizes standardized electronic health record (EHR)-derived data on insurance enrollment, demographic characteristics, medical encounters from all settings, vaccination, and prescribed medications.
      • McNeil MM
      • Gee J
      • Weintraub ES
      • et al.
      The Vaccine Safety Datalink: successes and challenges monitoring vaccine safety.

      Study Population

      The study cohort consisted of all children born from January 1, 2008 through December 31, 2014 receiving care at a VSD site; observation time continued through December 31, 2017. For study inclusion, children were required to have continuous health insurance enrollment at a VSD site from age 42 days through age 23 months. Children were excluded if they had a medical contraindication to one or more vaccines (eg, immunodeficiency, immunosuppression, or receipt of intravenous immunoglobulin) as identified by encounter diagnosis codes. Children were excluded if they were not using a VSD site for preventive care, defined as having less than 2 well-child visits between birth through age 11 months or zero well-child visits between age 12 through 23 months. Also excluded were children who received vaccines not routinely recommended before age 24 months, and children with missing vaccine manufacturer data (for vaccines for which aluminum content varied by manufacturer). Finally, children were excluded if they received a diagnosis of asthma in any setting prior to age 24 months.

      Vaccine-Associated Aluminum Exposure

      Detailed vaccination histories were extracted from EHR data.
      • McNeil MM
      • Gee J
      • Weintraub ES
      • et al.
      The Vaccine Safety Datalink: successes and challenges monitoring vaccine safety.
      Five VSD sites had bidirectional interoperability with state immunization information systems
      • Groom HC
      • Crane B
      • Naleway AL
      • et al.
      Monitoring vaccine safety using the Vaccine Safety Datalink: assessing capacity to integrate data from immunization information systems.
      ; using this process a small number of additional vaccines (<3%) were identified and included. Based on published methods, we used vaccine package inserts, material from the Institute for Vaccine Safety, and the Immunofacts textbook to identify the aluminum content in each licensed vaccine.
      • Glanz JM
      • Newcomer SR
      • Daley MF
      • et al.
      Cumulative and episodic vaccine aluminum exposure in a population-based cohort of young children.
      As shown in Supplementary Table 1, aluminum content differed by vaccine type and manufacturer. For each child, vaccination histories were linked with aluminum content information to calculate the cumulative amount of aluminum adjuvant received from vaccines from birth through age 23 months.

      Primary Outcome Definition

      The primary study outcome was persistent asthma diagnosed at age 24 through 59 months, defined as 1) 1 inpatient or 2 outpatient/emergency encounters with diagnosis codes for asthma; and 2) at least 2 long-term asthma control medication dispensing events.
      National Asthma Education Prevention Program
      Expert panel report 3 (EPR-3): guidelines for the diagnosis and management of asthma-summary report 2007.
      The rationale for selecting persistent asthma as the primary outcome included: it represents a more severe form of asthma
      National Asthma Education Prevention Program
      Expert panel report 3 (EPR-3): guidelines for the diagnosis and management of asthma-summary report 2007.
      ; it is more likely than intermittent asthma to come to clinical attention; this case definition may have higher specificity than definitions which include milder asthma
      • Wakefield DB
      • Cloutier MM.
      Modifications to HEDIS and CSTE algorithms improve case recognition of pediatric asthma.
      ; and persistent asthma prevalence is high enough (3.8% among children <5 years of age)
      • Zahran HS
      • Bailey CM
      • Damon SA
      • et al.
      Vital signs: asthma in children—United States, 2001-2016.
      to study with adequate statistical power. Because it is difficult to clinically distinguish asthma from transient viral-induced wheezing in infants,
      National Asthma Education Prevention Program
      Expert panel report 3 (EPR-3): guidelines for the diagnosis and management of asthma-summary report 2007.
      and to avoid overlapping exposure and risk windows, we excluded children with any asthma diagnosis in inpatient, emergency department, or outpatient settings before age 24 months.

      Covariate Definitions

      Several asthma risk factors were included as potential confounding variables. Prematurity was defined as moderately preterm (32 through 36 completed weeks gestation) or very preterm (<32 completed weeks).
      • Been JV
      • Lugtenberg MJ
      • Smets E
      • et al.
      Preterm birth and childhood wheezing disorders: a systematic review and meta-analysis.
      The definition of food allergies required ≥2 food allergy diagnosis codes (Supplementary Table 2) on separate days and at least one prescription for an epinephrine autoinjector. Severe bronchiolitis, possibly associated with subsequent asthma, was defined as inpatient admission for a nonbacterial acute lower respiratory infection (Supplementary Table 2) before age 12 months. Breast-feeding, found to reduce asthma risk in some but not all studies,
      • Güngör D
      • Nadaud P
      • LaPergola CC
      • et al.
      Infant milk-feeding practices and food allergies, allergic rhinitis, atopic dermatitis, and asthma throughout the life span: a systematic review.
      was also examined as a covariate; however, breast-feeding data were limited to 4 VSD sites which, beginning in late 2013, required EHR documentation of infant feeding. Based on prior work,
      • Güngör D
      • Nadaud P
      • LaPergola CC
      • et al.
      Infant milk-feeding practices and food allergies, allergic rhinitis, atopic dermatitis, and asthma throughout the life span: a systematic review.
      breast-feeding at 6 months was defined as exclusive, some, or none.

      Statistical Analyses

      All analyses were stratified by eczema status, based on the following considerations: 1) eczema, an early manifestation of atopy, is strongly associated with asthma risk; and 2) any effect of vaccine-associated aluminum on asthma risk might be modified by underlying allergy predisposition. Eczema was defined as ≥2 eczema diagnosis codes (Supplementary Table 2) on separate days between birth through age 11 months, and at least one prescription for a topical steroid or topical calcineurin inhibitor.
      Cox proportional hazard regression models were used to test the association between cumulative vaccine-associated aluminum received birth through age 23 months and persistent asthma diagnosed at age 24 through 59 months. Aluminum was represented on a continuous scale in milligrams (mg). Days at risk was defined as the time from second birthday to the date of the following censoring events: meeting the case definition, disenrolling from a VSD site, reaching age 60 months, or study end on December 31, 2017. Models were adjusted for sex, birth month/year, race/ethnicity, VSD site (treated as a fixed effect), medical complexity (defined using the Pediatric Medical Complexity Algorithm
      • Simon TD
      • Haaland W
      • Hawley K
      • et al.
      Development and validation of the Pediatric Medical Complexity Algorithm (PMCA) version 3.0.
      ), prematurity, food allergy, severe bronchiolitis, and 2 measures of health care utilization (number of emergency department visits, and number of outpatient visits after excluding well-child and emergency department visits). In fully adjusted models, we tested for the interaction between aluminum and VSD site.
      Kaplan-Meier survival curves were plotted by 1 mg increments of aluminum exposure to assess asthma incidence by age after 24 months. We assessed the functional form of vaccine-associated aluminum as a continuous variable by examining martingale residuals with a Kolmogorov-type supremum test.
      • Lin DY
      • Wei LJ
      • Ying Z.
      Checking the Cox model with cumulative sums of martingale-based residuals.
      In this context, a departure from linearity is indicated by a value of P < .05. The proportional hazards assumption was evaluated with martingale residual plots, Schoenfeld residual plots, global goodness-of-fit tests, and supremum tests from the Cox models. Additionally, we plotted graphically and calculated numerically the adjusted log hazard ratio for cumulative vaccine-associated aluminum in 1 mg categories, with estimates and 95% confidence intervals (CI) plotted. To assess the effect of individual covariates on the exposure-outcome association, we conducted a stepwise regression, using all covariates in the main model, recalculating the adjusted hazard ratio with the sequential addition of each covariate.
      We conducted several secondary analyses. We conducted an analysis eliminating children with cumulative aluminum values at the extremes (<1 mg or ≥5 mg aluminum) while treating aluminum as continuous between 1 and 5 mg. We conducted an analysis treating cumulative aluminum as dichotomous, comparing exposure ≤3.00 mg to >3.00 mg, as has been done previously.
      • Glanz JM
      • Clarke CL
      • Daley MF
      • et al.
      The childhood vaccination schedule and the lack of association with type 1 diabetes.
      Because health care utilization may differ between fully vaccinated and under-vaccinated children (who may be under-vaccinated due to vaccination barriers or parental choice), we conducted an analysis restricted to fully vaccinated children. In a separate analysis, breast-feeding data were included as a covariate among children for whom breast-feeding data were available. Because of the acknowledged challenge in diagnosing asthma in young children,
      National Asthma Education Prevention Program
      Expert panel report 3 (EPR-3): guidelines for the diagnosis and management of asthma-summary report 2007.
      we conducted a secondary analysis with the outcome of interest defined as persistent asthma at age 36 through 59 months. All covariates used in main analyses were included in secondary analyses.
      Another secondary analysis explored an alternative exposure definition, maximum single-day vaccine-associated aluminum.
      • Glanz JM
      • Newcomer SR
      • Daley MF
      • et al.
      Cumulative and episodic vaccine aluminum exposure in a population-based cohort of young children.
      For each child in the cohort, the total aluminum from all vaccines received on a given day was summed. This amount in mg was divided by the child's weight in kilograms (kg) on the same day. For the small number of children who did not have a same-day weight, the child's weight was imputed if at least 2 weights were available from within 90 days of the vaccination date, using exponentially weighted moving average techniques. Cox models stratified by eczema status and adjusted for covariates were used to test the association with persistent asthma.
      Finally, we examined all-cause injuries as a negative control outcome.
      • Lipsitch M
      • Tchetgen Tchetgen E
      • Cohen T.
      Negative controls: a tool for detecting confounding and bias in observational studies.
      ,
      • Arnold BF
      • Ercumen A
      • Benjamin-Chung J
      • et al.
      Brief report: negative controls to detect selection bias and measurement bias in epidemiologic studies.
      While the relevant encounter diagnosis codes for injuries (Supplementary Table 2) were closely modeled on prior studies,
      • Mehrabadi A
      • Dodds L
      • MacDonald NE
      • et al.
      Association of maternal influenza vaccination during pregnancy with early childhood health outcomes.
      codes for poisonings (such as from medications, vaccines, drugs, and alcohol) were excluded from the outcome definition. A case was defined as the first occurrence of an all-cause injury at 24 through 59 months of age in emergency department or inpatient settings.
      • Mehrabadi A
      • Dodds L
      • MacDonald NE
      • et al.
      Association of maternal influenza vaccination during pregnancy with early childhood health outcomes.
      One VSD site, representing 4.6% of the overall cohort, did not contribute to the negative control outcome, due to unavailability of some emergency department data; otherwise the cohort was identical to the primary outcome analyses. Retaining the covariates from the primary analyses, Cox models were used to examine the relationship between vaccine-associated aluminum and all-cause injuries.
      Power analyses were conducted assuming an alpha of .05, r-squared value of 0.2, and standard deviation (SD) of aluminum exposure of 0.80 mg. The r-squared value represents the association between aluminum exposure and other measured covariates. Assuming a sample size of 14,000 children with eczema and an asthma prevalence of 5% among these children,
      • Akinbami LJ
      • Simon AE
      • Schoendorf KC.
      Trends in allergy prevalence among children aged 0-17 years by asthma status, United States, 2001-2013.
      the minimum detectable adjusted hazard ratio would be 1.13. Assuming a sample size of 186,000 children without eczema and an asthma prevalence of 1% among these children,
      • Akinbami LJ
      • Simon AE
      • Schoendorf KC.
      Trends in allergy prevalence among children aged 0-17 years by asthma status, United States, 2001-2013.
      the minimum detectable adjusted hazard ratio would be 1.08.

      Research Ethics

      The human subjects review board at each participating site approved the study, and informed consent was not required.

      Results

      As illustrated in eFigure 1, from an initial population of 398,191 children, 15,036 (3.8%) did not meet inclusion criteria, 30,976 (7.8%) had vaccine-related exclusions, and 25,188 (6.3%) were excluded due to asthma diagnosed prior to age 24 months. The final study cohort comprised 326,991 children, among whom 14,337 (4.4%) were diagnosed with eczema before age 12 months.
      The demographic and clinical characteristics of the study cohort are presented in Table 1. As shown, a greater proportion of the cohort with eczema was male and non-Hispanic Black or Asian race/ethnicity compared to the cohort without eczema. The median age at a censoring event (ie, the length of follow-up since birth) was 60.0 months (interquartile range [IQR] 43.0, 60.0) for the eczema cohort and 60.0 months (IQR 43.0, 60.0) for the no eczema cohort.
      Table 1Demographic and Clinical Characteristics of the Study Cohort, Stratified by Eczema Status, Vaccine Safety Datalink
      CharacteristicDiagnosed With Eczema
      Eczema diagnosed prior to 12 months of age.
      Not Diagnosed With EczemaP Value
      Total in cohort, n14,337312,654
      Child's sex, n (%)<.001
       Female5726 (39.9)157,233 (50.3)
       Male8611 (60.1)155,421 (49.7)
      Birth year, n (%).069
       20081989 (13.9)43,656 (14.0)
       20092036 (14.2)44,476 (14.2)
       20102075 (14.5)44,742 (14.3)
       20112174 (15.2)44,714 (14.3)
       20122077 (14.5)45,205 (14.5)
       20131999 (13.9)44,888 (14.4)
       20141987 (13.9)44,973 (14.4)
      Child's race and ethnicity, n (%)<.001
       Non-Hispanic White3326 (23.2)135,081 (43.2)
       Non-Hispanic Black1492 (10.4)15,855 (5.1)
       Non-Hispanic Asian5017 (35.0)43,100 (13.8)
       Hispanic2884 (20.1)85,010 (27.2)
       Other race and ethnicity879 (6.1)13,577 (4.3)
       Missing race and ethnicity739 (5.2)20,031 (6.4)
      Prematurity, n (%)<.001
       Term (37 weeks EGA or later)13,518 (94.3)289,935 (92.7)
       Moderately preterm (32–36 weeks EGA)773 (5.4)20,692 (6.6)
       Very preterm (<32 weeks EGA)46 (0.3)2027 (0.6)
      Medical complexity based on PMCA, n (%)<.001
       No complex or chronic conditions12,000 (83.7)272,106 (87.0)
       Non-complex chronic condition1711 (11.9)29,367 (9.4)
       Complex chronic condition626 (4.4)11,181 (3.6)
      Diagnosed with food allergy, n (%)816 (5.7)1457 (0.5)<.001
      Early-life severe bronchiolitis, n (%)104 (0.7)2267 (0.7).997
      Health care utilization through age 23 mos.
       No. of outpatient visits (non-well, non-ED), mean (SD)12.6 (9.1)9.8 (7.8)<.001
       No. of outpatient visits (non-well, non-ED), median (IQR)11.0 (7.0, 16.0)8.0 (5.0, 12.0)<.001
       No. of ED visits, mean (SD)0.8 (1.3)0.6 (1.0)<.001
       No. of ED visits, median (IQR)0.0 (0.0, 1.0)0.0 (0.0, 1.0)<.001
      ED indicates emergency department; EGA, estimated gestational age; IQR, interquartile range; PMCA, Pediatric Medical Complexity Algorithm (asthma diagnoses removed); SD, standard deviation; no., number; and mos., months.
      low asterisk Eczema diagnosed prior to 12 months of age.
      The distribution of cumulative vaccine-associated aluminum received by the study cohort through age 23 months, stratified by eczema status, is presented in Figure 1. The variability in cumulative aluminum was due to either under-vaccination (ie, missing vaccine doses) or the type of vaccine product received (Supplementary Table 1). For children with eczema, the mean and median cumulative vaccine-associated aluminum were 4.07 mg (SD 0.60), and 4.18 mg (IQR 3.97, 4.43), respectively. For children without eczema, the mean and median were 3.98 mg (SD 0.72) and 4.18 mg (IQR 3.93, 4.43), respectively.
      Figure 1
      Figure 1Distribution of cumulative vaccine-associated aluminum received birth through 23 months of age, stratified by eczema status, Vaccine Safety Datalink.
      Among 14,337 children in the cohort with eczema, 859 (6.0%) met the study definition of persistent asthma; the mean age when children met the case definition was 44.2 months (SD 8.7). Among 312,654 children without eczema, 6687 (2.1%) met the study definition of persistent asthma; the mean age when these children met the case definition was 44.9 months (SD 8.7).
      The crude incidence rate of persistent asthma at 24 through 59 months of age by quantity of cumulative vaccine-associated aluminum is shown in Figure 2: as illustrated, the incidence rate appeared to increase with increasing levels of aluminum exposure in the eczema and no eczema cohorts. Results of Cox proportional hazards models are presented in Table 2. Among children with eczema after adjustment for covariates, cumulative vaccine-associated aluminum was positively associated with persistent asthma (adjusted hazard ratio [aHR] 1.26 per 1 mg increase in aluminum, 95% CI 1.07, 1.49). Other covariates which remained significant in the adjusted model included male sex, non-Hispanic Black race/ethnicity, food allergies, and both measures of health care utilization. In a separate model among children without eczema (Table 2), cumulative vaccine-associated aluminum was also positively associated with persistent asthma (aHR 1.19 per 1 mg increase in aluminum, 95% CI 1.14, 1.25). In the fully adjusted models, there was no significant interaction between cumulative aluminum and VSD site in the eczema (P = .14) and no eczema (P = .17) cohorts.
      Figure 2
      Figure 2Crude incidence rate of persistent asthma at 24 through 59 months of age by quantity of vaccine-associated aluminum in milligrams (mg), stratified by eczema status, Vaccine Safety Datalink.
      Table 2The Association Between Cumulative Vaccine-Associated Aluminum Exposure Between Birth and Age 23 Months and Persistent Asthma Diagnosed Between 24 and 59 Months of Age, With Separate Models for the Eczema and No Eczema Cohorts, Vaccine Safety Datalink
      Adjusted Hazard Ratio
      Adjusted for birth month and year, VSD site, and all covariates listed in table.
      (95% CI) for Persistent Asthma
      VariableEczema
      Eczema diagnosed prior to 12 months of age.
      (n = 14,337)
      No eczema (n = 312,654)
      Vaccine-associated aluminum (per mg)1.26 (1.07, 1.49)1.19 (1.14, 1.25)
      Child's sex
       Female1 [Reference]1 [Reference]
       Male1.30 (1.13, 1.50)1.40 (1.33, 1.47)
      Child's race and ethnicity
       Non-Hispanic White1 [Reference]1 [Reference]
       Non-Hispanic Black1.37 (1.07, 1.76)1.81 (1.65, 1.99)
       Non-Hispanic Asian0.93 (0.77, 1.13)1.09 (1.01, 1.18)
       Hispanic1.00 (0.81, 1.24)1.18 (1.11, 1.26)
       Other race and ethnicity1.33 (1.00, 1.78)1.15 (1.02, 1.29)
       Missing race and ethnicity0.82 (0.55, 1.21)1.04 (0.92, 1.17)
      Prematurity
       Term (37 weeks EGA or later)1 [Reference]1 [Reference]
       Moderately pre-term (32–36 weeks EGA)1.32 (1.02, 1.72)1.34 (1.24, 1.46)
       Very pre-term (<32 weeks EGA)1.88 (0.82, 4.30)1.68 (1.39, 2.03)
      Medical complexity based upon PMCA
       No complex or chronic conditions1 [Reference]1 [Reference]
       Non-complex chronic condition0.96 (0.78, 1.18)1.05 (0.97, 1.13)
       Complex chronic condition0.62 (0.44, 0.88)0.67 (0.59, 0.77)
      Diagnosed with food allergy2.40 (1.97, 2.93)4.32 (3.66, 5.10)
      Early-life severe bronchiolitis1.70 (0.95, 3.04)1.40 (1.16, 1.71)
      Health care utilization through age 23 mos.
       No. of outpatient visits (non-well, non-ED)1.02 (1.02, 1.03)1.03 (1.03, 1.03)
       No. of ED visits1.17 (1.12, 1.21)1.16 (1.14, 1.18)
      CI indicates confidence interval; ED, emergency department; EGA, estimated gestational age at the time of delivery; mg, milligram; SD, standard deviation; PMCA, Pediatric Medical Complexity Algorithm (asthma diagnoses removed); no., number; and mos., months.
      low asterisk Adjusted for birth month and year, VSD site, and all covariates listed in table.
      Eczema diagnosed prior to 12 months of age.
      The crude (ie, unadjusted) relationship between level of aluminum exposure and asthma risk was relatively consistent over time since age 24 months, as illustrated in Kaplan-Meier survival curves (Supplementary Figs. 2 and 3). The functional form of vaccine-associated aluminum as a continuous variable did not appear to violate assumptions of linearity in the log hazard based on plotting martingale residuals (Supplementary Figs. 4 and 5) with a nonsignificant Kolomogorov-type supremum test (P = .506 for eczema cohort; P = .112 for no eczema cohort). The adjusted log hazard and corresponding 95% CIs were examined graphically (Supplementary Figs. 6 and 7) to assess for linearity. The functional form of aluminum was also examined by calculating the unadjusted and adjusted hazard ratios for each 1 mg increment of cumulative vaccine-associated aluminum in the eczema and no eczema cohorts (Supplementary Table 3); as shown, the aluminum-asthma relationship appeared close to linear, although with more variability for the eczema cohort than for the no eczema cohort. The assumption of proportionality of the hazard did not appear to be violated, based on martingale residuals (described above), the Kolmogorov supremum tests (described above), Schoenfeld residuals (Supplementary Figs. 8 and 9), and global goodness-of-fit tests from Schoenfeld plots (P = .923 for the eczema cohort; P = .472 for no eczema cohort). Finally, the effect of covariates on the aluminum-asthma relationship was examined in a stepwise manner; as shown in Supplementary Tables 4 and 5, the hazard ratio values remained consistent with the addition of each covariate.
      Results of secondary analyses are presented in Table 3. There was a significant positive association between vaccine-associated aluminum and persistent asthma when aluminum was treated as a dichotomous (>3.00 mg vs ≤3.00 mg) exposure. A separate analysis was conducted among the fully vaccinated, with 9477 (66.1%) of the eczema and 188,593 (60.3%) of the no eczema cohorts fully vaccinated; in adjusted models restricted to fully vaccinated (Table 3), the association between vaccine-associated aluminum and persistent asthma was not significant for the eczema cohort but remained significant for the no eczema cohort. Breast-feeding data were available for 1913 (13.3%) of the eczema cohort and 42,909 (13.7%) of the no eczema cohort; in these smaller cohorts, vaccine-associated aluminum was not significantly associated with persistent asthma in unadjusted (P = .51 for eczema cohort, P = .06 for no eczema cohort) and adjusted (Table 3) models, although the hazard ratios were similar in size and directionality to the primary analyses. A positive association was also observed when the outcome of interest was defined as persistent asthma at age 36 through 59 months. The negative control outcome is also presented in Table 3; no association was found between vaccine-associated aluminum and all-cause injuries among children with or without eczema.
      Table 3Results for Primary Analyses, Secondary Analyses, and Negative Control Outcome, With Separate Models for the Eczema and No Eczema Cohorts, Vaccine Safety Datalink
      EczemaNo Eczema
      ModelSample Size, nAdjusted Hazard Ratio (95% CI) for Persistent AsthmaSample Size, nAdjusted Hazard Ratio (95% CI) for Persistent Asthma
      Primary analyses (also shown in Table 2)14,3371.26 (1.07, 1.49)312,6541.19 (1.14, 1.25)
      Secondary analyses
       Aluminum exposure as dichotomous (>3.00 mg vs ≤3.00 mg)
      Adjusted for birth month and year, VSD site, sex, race/ethnicity, prematurity, medical complexity, food allergy, early-life severe bronchiolitis, utilization (outpatient, ED).
      14,3371.61 (1.04, 2.48)312,6541.36 (1.21, 1.53)
       Excluding those with aluminum exposure at the extremes (<1 mg or ≥5 mg)
      Adjusted for birth month and year, VSD site, sex, race/ethnicity, prematurity, medical complexity, food allergy, early-life severe bronchiolitis, utilization (outpatient, ED).
      ,
      Vaccine-associated aluminum treated as continuous linear exposure variable.
      14,2251.27 (1.05, 1.53)307,8911.18 (1.11, 1.26)
       Limited to those fully vaccinated with no delays
      Adjusted for birth month and year, VSD site, sex, race/ethnicity, prematurity, medical complexity, food allergy, early-life severe bronchiolitis, utilization (outpatient, ED).
      ,
      Vaccine-associated aluminum treated as continuous linear exposure variable.
      94771.08 (0.82, 1.43)188,5931.12 (1.01, 1.24)
       Limited to those with breast-feeding data available
      Vaccine-associated aluminum treated as continuous linear exposure variable.
      ,
      Adjusted for breast-feeding at 6 months (exclusive, some, or none), birth month and year, VSD site, sex, race/ethnicity, prematurity, medical complexity, food allergy, early-life severe bronchiolitis, utilization (outpatient, ED).
      19131.38 (0.53, 3.60)42,9091.26 (0.99, 1.61)
       Outcome defined as persistent asthma at 36–59 mos.
      Adjusted for birth month and year, VSD site, sex, race/ethnicity, prematurity, medical complexity, food allergy, early-life severe bronchiolitis, utilization (outpatient, ED).
      ,
      Vaccine-associated aluminum treated as continuous linear exposure variable.
      12,9671.22 (1.01, 1.47)280,2051.15 (1.09, 1.22)
      Negative control outcome
       Outcome defined as all-cause injury at 24–59 mos.
      Vaccine-associated aluminum treated as continuous linear exposure variable.
      ,
      Adjusted for birth month and year, VSD site, sex, race/ethnicity, prematurity, medical complexity, food allergy, early-life severe bronchiolitis, utilization (outpatient, ED, inpatient).
      13,8041.03 (0.94, 1.14)298,2761.01 (0.99, 1.03)
      ED indicates emergency department; CI, confidence interval; mos., months; and VSD, Vaccine Safety Datalink.
      low asterisk Adjusted for birth month and year, VSD site, sex, race/ethnicity, prematurity, medical complexity, food allergy, early-life severe bronchiolitis, utilization (outpatient, ED).
      Vaccine-associated aluminum treated as continuous linear exposure variable.
      Adjusted for breast-feeding at 6 months (exclusive, some, or none), birth month and year, VSD site, sex, race/ethnicity, prematurity, medical complexity, food allergy, early-life severe bronchiolitis, utilization (outpatient, ED).
      § Adjusted for birth month and year, VSD site, sex, race/ethnicity, prematurity, medical complexity, food allergy, early-life severe bronchiolitis, utilization (outpatient, ED, inpatient).
      The maximum single-day vaccine-associated aluminum was calculated in mg aluminum per same-day kg body weight. For 94.6% of the cohort, the maximum single-day aluminum occurred at a 2-month vaccination visit (ie, between 42 and 92 days of life). For the eczema cohort, the mean and median maximum single-day aluminum were 0.175 mg/kg (SD 0.035) and 0.176 mg/kg (IQR 0.157, 0.194), respectively; mean and median for the no eczema cohort were 0.175 mg/kg (SD 0.042) and 0.177 mg/kg (IQR 0.156, 0.196), respectively. After adjustment for covariates, no association between maximum single-day aluminum and persistent asthma was detected for the eczema cohort (aHR 1.00, 95% CI 0.89, 1.22). A positive association was detected for the no eczema cohort (aHR 1.06, 95% CI 1.03, 1.10); the adjusted hazard ratio was scaled for a 0.05 mg/kg increase in maximum single-day aluminum.

      Discussion

      This investigation was undertaken to address parents’ vaccine safety concerns,
      • Kempe A
      • Saville AW
      • Albertin C
      • et al.
      Parental hesitancy about routine childhood and influenza vaccinations: a national survey.
      and in response to an Institute of Medicine call for studies of the safety of the immunization schedule,
      Institute of Medicine
      Childhood Immunization Schedule and Safety: Stakeholder Concerns, Scientific Evidence, and Future Studies.
      including an explicit recommendation to research the safety of repeated exposure to immunogenic adjuvants.
      Institute of Medicine
      Childhood Immunization Schedule and Safety: Stakeholder Concerns, Scientific Evidence, and Future Studies.
      In a retrospective cohort study of more than 325,000 children born between 2008 and 2014 and followed through 2017, we found a positive association between cumulative vaccine-associated aluminum before age 24 months and persistent asthma at age 24 through 59 months among children with and without eczema. When vaccine-associated aluminum was examined as an acute exposure (eg, maximum single-day), a small positive association was found for children without eczema. In secondary analyses with more restrictive inclusion criteria and correspondingly smaller sample size, positive associations were observed in some but not all analyses. Data on dietary aluminum intake were unavailable.
      While many studies have demonstrated the effectiveness and safety of aluminum adjuvants,
      • Goullé JP
      • Grangeot-Keros L.
      Aluminum and vaccines: current state of knowledge.
      ,
      • Willhite CC
      • Karyakina NA
      • Yokel RA
      • et al.
      Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide and its soluble salts.
      they are biologically complex: desired and undesired effects may depend on aluminum type, dose, route of exposure, concomitant antigen, host characteristics, and other factors.
      • Willhite CC
      • Karyakina NA
      • Yokel RA
      • et al.
      Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide and its soluble salts.
      It is theoretically possible that exposure to aluminum through vaccination could produce an immune profile biased toward Th2 and away from T helper 1 cell (Th1) immune responses.
      • Hogenesch H.
      Mechanism of immunopotentiation and safety of aluminum adjuvants.
      ,
      • Sastry M
      • Zhang B
      • Chen M
      • et al.
      Adjuvants and the vaccine response to the DS-Cav1-stabilized fusion glycoprotein of respiratory syncytial virus.
      This hypothesis is a speculative one, because it is based on limited data from animal studies
      • Hogenesch H.
      Mechanism of immunopotentiation and safety of aluminum adjuvants.
      ,
      • Sastry M
      • Zhang B
      • Chen M
      • et al.
      Adjuvants and the vaccine response to the DS-Cav1-stabilized fusion glycoprotein of respiratory syncytial virus.
      and has not to our knowledge been investigated in humans. A Th2-biased immune response could, again in theory, increase risk of allergic diseases such as asthma, while decreasing risk of autoimmune diseases, such as type 1 diabetes mellitus (T1DM), which are thought to be Th1-mediated.
      • Shao F
      • Zheng P
      • Yu D
      • et al.
      Follicular helper T cells in type 1 diabetes.
      In a recent study, also conducted in the VSD using similar methods, we found a small but statistically significant reduction in T1DM incidence among children exposed to higher levels of vaccine-associated aluminum.
      • Glanz JM
      • Clarke CL
      • Daley MF
      • et al.
      The childhood vaccination schedule and the lack of association with type 1 diabetes.
      It is notable that the direction of effect (ie, reduced incidence of T1DM)
      • Glanz JM
      • Clarke CL
      • Daley MF
      • et al.
      The childhood vaccination schedule and the lack of association with type 1 diabetes.
      was in the direction hypothesized based on the current understanding of T helper cell response to aluminum adjuvants.
      • Hogenesch H.
      Mechanism of immunopotentiation and safety of aluminum adjuvants.
      ,
      • Sastry M
      • Zhang B
      • Chen M
      • et al.
      Adjuvants and the vaccine response to the DS-Cav1-stabilized fusion glycoprotein of respiratory syncytial virus.
      Aluminum adjuvants are used in vaccines precisely because they can generate an acute immunologic response with long-lasting effect. Additionally, experimental animal models of asthma can be produced using aluminum adjuvants, with acute and chronic phenotypes developed.
      • Alessandrini F
      • Musiol S
      • Schneider E
      • et al.
      Mimicking antigen-driven asthma in rodent models-how close can we get?.
      For example, mice develop asthma-like allergic airway inflammation when given a protein (chicken ovalbumin) and aluminum adjuvant via peritoneal injection, followed by subsequent airway exposure to ovalbumin.
      • Alessandrini F
      • Musiol S
      • Schneider E
      • et al.
      Mimicking antigen-driven asthma in rodent models-how close can we get?.
      Given the many differences between experimentally produced asthma in animals and naturally occurring asthma in humans, there are limits to how much can be extrapolated. However, it appears biologically plausible that the intended effect of aluminum adjuvants (ie, enhanced immunogenicity against vaccine-preventable diseases) is not the only biologic effect of parenteral administration of aluminum adjuvants in early childhood.
      Although surveillance methods have changed over time, asthma prevalence in US children appeared to steadily increase during the 1980s and 1990s; since 2001, prevalence has shown little to no increase.
      • Zahran HS
      • Bailey CM
      • Damon SA
      • et al.
      Vital signs: asthma in children—United States, 2001-2016.
      ,
      • Moorman JE
      • Akinbami LJ
      • Bailey CM
      • et al.
      National surveillance of asthma: United States, 2001-2010.
      ,
      • Moorman JE
      • Rudd RA
      • Johnson CA
      • et al.
      National surveillance for asthma—United States, 1980-2004.
      There are many environmental and genetic risk factors for asthma,
      National Asthma Education Prevention Program
      Expert panel report 3 (EPR-3): guidelines for the diagnosis and management of asthma-summary report 2007.
      and any contribution from vaccine-associated aluminum has not been proven or supported through replication. However, because most aluminum-containing vaccines were added to the routine schedule prior to 2001 (eg, diphtheria, tetanus, and acellular pertussis; hepatitis B; some formulations of Haemophilus influenzae type b [Hib]; and pneumococcal conjugate vaccines), observed national trends in asthma prevalence during childhood are not incongruous with the effect estimates observed here.
      Using observational data to study the long-term health effects of aluminum adjuvants poses many challenges.
      Institute of Medicine
      Childhood Immunization Schedule and Safety: Stakeholder Concerns, Scientific Evidence, and Future Studies.
      ,
      • Glanz JM
      • Newcomer SR
      • Jackson ML
      • et al.
      White paper on studying the safety of the childhood immunization schedule in the Vaccine Safety Datalink.
      One particularly salient challenge is the fact that other sources of aluminum exposure, such as through diet, are not captured and cannot be estimated using EHR data. Because aluminum is present in infant formula, breast milk, and food, all infants are exposed to some amount of dietary aluminum.
      • Corkins MR
      AAP Committee on Nutrition
      Aluminum effects in infants and children.
      However, a recent report concluded that “little to none of ingested aluminum appears to be absorbed” through the gastrointestinal tract,
      • Corkins MR
      AAP Committee on Nutrition
      Aluminum effects in infants and children.
      and we are unaware of any studies demonstrating an immunologic response to ingested aluminum in humans. Clearly, more research is needed on the human health effects of aluminum,
      • Corkins MR
      AAP Committee on Nutrition
      Aluminum effects in infants and children.
      ,
      • Mitkus RJ
      • King DB
      • Hess MA
      • et al.
      Updated aluminum pharmacokinetics following infant exposures through diet and vaccination.
      including immunologic effects of injected and ingested aluminum, supplemented when feasible with biomarkers of aluminum exposure.
      • Karwowski MP
      • Stamoulis C
      • Wenren LM
      • et al.
      Blood and hair aluminum levels, vaccine history, and early infant development: a cross-sectional study.
      If future research continues to demonstrate that aluminum ingested through a normal infant diet is minimally absorbed and has negligible immunologic effect, the absence of dietary aluminum data in the present study would not appear to invalidate the current findings.
      While not directly examining vaccine-associated aluminum exposure, several other studies provide additional context. In a VSD study of children born during 1991 through 1997, a positive association was found between receipt of Hib and hepatitis B vaccines and asthma risk, although the relative risks were small (1.18 for Hib, 1.20 for hepatitis B), and were partially accounted for by underlying health care utilization.
      • DeStefano F
      • Gu D
      • Kramarz P
      • et al.
      Childhood vaccinations and risk of asthma.
      In German children at increased risk of atopy born in 1990, asthma risk was lower among children receiving more vaccine doses.
      • Grüber C
      • Illi S
      • Lau S
      • et al.
      Transient suppression of atopy in early childhood is associated with high vaccination coverage.
      Other studies found that early childhood vaccination was not associated with increased asthma risk, but these studies were limited by self-report of vaccination and/or asthma status, exposure to vaccines not currently used, and small sample size.
      • Martignon G
      • Oryszczyn MP
      • Annesi-Maesano I
      Does childhood immunization against infectious diseases protect from the development of atopic disease?.
      ,
      • Thomson JA
      • Widjaja C
      • Darmaputra AA
      • et al.
      Early childhood infections and immunisation and the development of allergic disease in particular asthma in a high-risk cohort: a prospective study of allergy-prone children from birth to six years.
      While negative control outcomes are useful to detect threats to the validity of observational studies,
      • Lipsitch M
      • Tchetgen Tchetgen E
      • Cohen T.
      Negative controls: a tool for detecting confounding and bias in observational studies.
      ,
      • Arnold BF
      • Ercumen A
      • Benjamin-Chung J
      • et al.
      Brief report: negative controls to detect selection bias and measurement bias in epidemiologic studies.
      the interpretation of negative control outcomes can be complex. An ideal negative control outcome is one which shares the potential biases of the primary outcome but cannot plausibly be related to the exposure.
      • Lipsitch M
      • Tchetgen Tchetgen E
      • Cohen T.
      Negative controls: a tool for detecting confounding and bias in observational studies.
      ,
      • Arnold BF
      • Ercumen A
      • Benjamin-Chung J
      • et al.
      Brief report: negative controls to detect selection bias and measurement bias in epidemiologic studies.
      Here, vaccine-associated aluminum cannot reasonably associate with future injuries in children. However, the outcomes of all-cause injuries and persistent asthma could share biases, as both outcomes may be subject to parents’ health-related habits, health seeking behaviors, and overall access to care. The finding of a null negative control outcome in the current study suggests that the primary study finding is not due to potential sources of bias shared with the negative control outcome. It does not mean, however, that other forms of bias cannot be present.
      The current study should be interpreted in the context of important limitations. First, misclassification of vaccine-associated aluminum exposure was possible; this could have occurred, for example, if a hepatitis B vaccine dose given at a birth hospital was not captured within VSD data. If missing exposure data were nondifferential with respect to outcome status, such misclassification would have biased toward a null finding. Second, all forms of aluminum adjuvants, including aluminum hydroxide and aluminum phosphate, were combined into a single measure of exposure, but it is possible that different chemical forms of aluminum have different biologic effects.
      • Willhite CC
      • Karyakina NA
      • Yokel RA
      • et al.
      Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide and its soluble salts.
      Third, while a stringent definition for persistent asthma was chosen,
      • Wakefield DB
      • Cloutier MM.
      Modifications to HEDIS and CSTE algorithms improve case recognition of pediatric asthma.
      case misclassification could have occurred. Childhood asthma is a clinical diagnosis,
      National Asthma Education Prevention Program
      Expert panel report 3 (EPR-3): guidelines for the diagnosis and management of asthma-summary report 2007.
      and it is possible some cases had conditions other than asthma. It is also possible that true cases were missed, such as if children with asthma did not present for care, or children with persistent asthma symptoms were not started on long-term asthma control medications.
      National Asthma Education Prevention Program
      Expert panel report 3 (EPR-3): guidelines for the diagnosis and management of asthma-summary report 2007.
      Children with mild intermittent or exercise-induced asthma were also not included in the case definition. Fourth, as with any observational study, unmeasured confounding could have influenced study results. Breast-feeding data were available for a fraction of the cohort, and data on family history of atopy and second-hand smoke exposure were unavailable. Measures of socioeconomic status such as maternal education and annual household income were also unavailable. It is difficult to predict whether these factors could have resulted in bias toward or away from the null hypothesis.
      Considering the small effect size observed and the limitations described above, particularly related to unmeasured confounding, these findings do not constitute strong evidence for questioning the safety of aluminum in vaccines.
      • Goullé JP
      • Grangeot-Keros L.
      Aluminum and vaccines: current state of knowledge.
      However, additional examination of this hypothesis appears warranted. Studies in other large databases, including in several European countries, may be able to address this question, and differences between European and US immunization schedules could provide helpful variability in aluminum adjuvant exposure. Studies in the VSD and elsewhere could examine allergic diseases other than asthma. Additionally, sophisticated assays of immunologic response following vaccination have recently been developed.
      • Del Giudice G
      • Rappuoli R
      • Didierlaurent AM.
      Correlates of adjuvanticity: a review on adjuvants in licensed vaccines.
      These techniques could be used to better characterize the immunologic response, including patterns of Th1/Th2 response, of vaccinated infants in the United States and provide additional evidence for or against the biologic plausibility of the association found in the current study.

      Acknowledgments

      The authors would like to acknowledge the contributions of Joy Hsu, MD, MS at the Asthma and Community Health Branch, Division of Environmental Health Science and Practice, National Center for Environmental Health, Centers for Disease Control and Prevention, for her review and comments on the study protocol and manuscript. The authors Matthew F. Daley and Liza M. Reifler had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
      Financial statement: This research was funded by the Centers for Disease Control and Prevention as part of the Vaccine Safety Datalink project (contract #200-2012-53582 ). Seven VSD sites participated in the study: HealthPartners, Marshfield Clinic, Kaiser Permanente Washington, Kaiser Permanente Northwest, Kaiser Permanente Northern California, Kaiser Permanente Southern California, and Kaiser Permanente Colorado. Co-authors from the Centers for Disease Control and Prevention were involved in study design, interpretation of data, and review and approval of the manuscript. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
      Financial disclosure: Matthew F. Daley, MD: no financial relationships relevant to this article to disclose; Liza M. Reifler, MPH: has an immediate family member who owns stock in Merck, Abbott Laboratories, and AstraZeneca; Jason M. Glanz, PhD: no financial relationships relevant to this article to disclose; Simon J. Hambidge, MD, PhD: no financial relationships relevant to this article to disclose; Darios T. Getahun, MD, PhD: no financial relationships relevant to this article to disclose; Stephanie Irving, MHS: no financial relationships relevant to this article to disclose; James D. Nordin, MD, MPH: no financial relationships relevant to this article to disclose; David L. McClure, PhD: no financial relationships relevant to this article to disclose; Nicola P. Klein, MD, PhD: reports research support from Merck, Pfizer, Sanofi Pasteur, GlaxoSmithKline and Protein Science (now Sanofi Pasteur), all unrelated to the current study; Michael L. Jackson, PhD, MPH: no financial relationships relevant to this article to disclose; Satoshi Kamidani, MD: no financial relationships relevant to this article to disclose; Jonathan Duffy, MD, MPH: no financial relationships relevant to this article to disclose; Frank DeStefano, MD: no financial relationships relevant to this article to disclose

      References

        • Institute of Medicine
        Adverse Effects of Vaccines: Evidence and Causality.
        National Academies Press, Washington, DC2011
        • Whitney CG
        • Zhou F
        • Singleton J
        • et al.
        Benefits from immunization during the vaccines for children program era—United States, 1994-2013.
        MMWR Morb Mortal Wkly Rep. 2014; 63: 352-355
        • National Vaccine Advisory Committee
        Assessing the state of vaccine confidence in the United States: recommendations from the National Vaccine Advisory Committee: approved by the National Vaccine Advisory Committee on June 9, 2015 [corrected].
        Public Health Rep. 2015; 130: 573-595
        • Kempe A
        • Saville AW
        • Albertin C
        • et al.
        Parental hesitancy about routine childhood and influenza vaccinations: a national survey.
        Pediatrics. 2020; 146e20193852
        • Hill HA
        • Yankey D
        • Elam-Evans LD
        • et al.
        Vaccination coverage by age 24 months among children born in 2016 and 2017—National Immunization Survey-Child, United States, 2017-2019.
        MMWR Morb Mortal Wkly Rep. 2020; 69: 1505-1511
        • Gardner L
        • Dong E
        • Khan K
        • et al.
        Persistence of US measles risk due to vaccine hesitancy and outbreaks abroad.
        Lan Infect Dis. 2020; 20: 1114-1115
        • Hambidge SJ
        • Newcomer SR
        • Narwaney KJ
        • et al.
        Timely versus delayed early childhood vaccination and seizures.
        Pediatrics. 2014; 133: e1492-e1499
        • Baylor NW
        • Egan W
        • Richman P.
        Aluminum salts in vaccines–US perspective.
        Vaccine. 2002; 20: S18-S23
        • Goullé JP
        • Grangeot-Keros L.
        Aluminum and vaccines: current state of knowledge.
        Med Mal Infect. 2020; 50: 16-21
        • Glanz JM
        • Newcomer SR
        • Daley MF
        • et al.
        Cumulative and episodic vaccine aluminum exposure in a population-based cohort of young children.
        Vaccine. 2015; 33: 6736-6744
        • Hogenesch H.
        Mechanism of immunopotentiation and safety of aluminum adjuvants.
        Front Immunol. 2012; 3: 406
        • Sastry M
        • Zhang B
        • Chen M
        • et al.
        Adjuvants and the vaccine response to the DS-Cav1-stabilized fusion glycoprotein of respiratory syncytial virus.
        PLoS One. 2017; 12e0186854
        • Akinbami LJ
        • Simon AE
        • Schoendorf KC.
        Trends in allergy prevalence among children aged 0-17 years by asthma status, United States, 2001-2013.
        J Asthma. 2016; 53: 356-362
        • Robinson DS.
        The role of the T cell in asthma.
        J Allergy Clin Immunol. 2010; 126: 1081-1091
        • National Asthma Education Prevention Program
        Expert panel report 3 (EPR-3): guidelines for the diagnosis and management of asthma-summary report 2007.
        J Allergy Clin Immunol. 2007; 120: S94-138
        • Institute of Medicine
        Childhood Immunization Schedule and Safety: Stakeholder Concerns, Scientific Evidence, and Future Studies.
        National Academies Press, Washington, DC2013
        • McNeil MM
        • Gee J
        • Weintraub ES
        • et al.
        The Vaccine Safety Datalink: successes and challenges monitoring vaccine safety.
        Vaccine. 2014; 32: 5390-5398
        • Daley MF
        • Shoup JA
        • Newcomer SR
        • et al.
        Assessing potential confounding and misclassification bias when studying the safety of the childhood immunization schedule.
        Acad Pediatr. 2018; 18: 754-762
        • Glanz JM
        • Newcomer SR
        • Jackson ML
        • et al.
        White paper on studying the safety of the childhood immunization schedule in the Vaccine Safety Datalink.
        Vaccine. 2016; 34: A1-A29
        • Sukumaran L
        • McCarthy NL
        • Li R
        • et al.
        Demographic characteristics of members of the Vaccine Safety Datalink (VSD): a comparison with the United States population.
        Vaccine. 2015; 33: 4446-4450
        • Groom HC
        • Crane B
        • Naleway AL
        • et al.
        Monitoring vaccine safety using the Vaccine Safety Datalink: assessing capacity to integrate data from immunization information systems.
        Vaccine. 2022; 40: 752-756
        • Wakefield DB
        • Cloutier MM.
        Modifications to HEDIS and CSTE algorithms improve case recognition of pediatric asthma.
        Pediatr Pulmonol. 2006; 41: 962-971
        • Zahran HS
        • Bailey CM
        • Damon SA
        • et al.
        Vital signs: asthma in children—United States, 2001-2016.
        MMWR Morb Mortal Wkly Rep. 2018; 67: 149-155
        • Been JV
        • Lugtenberg MJ
        • Smets E
        • et al.
        Preterm birth and childhood wheezing disorders: a systematic review and meta-analysis.
        PLoS Med. 2014; 11e1001596
        • Güngör D
        • Nadaud P
        • LaPergola CC
        • et al.
        Infant milk-feeding practices and food allergies, allergic rhinitis, atopic dermatitis, and asthma throughout the life span: a systematic review.
        Am J Clin Nutr. 2019; 109: 772s-799s
        • Simon TD
        • Haaland W
        • Hawley K
        • et al.
        Development and validation of the Pediatric Medical Complexity Algorithm (PMCA) version 3.0.
        Acad Pediatr. 2018; 18: 577-580
        • Lin DY
        • Wei LJ
        • Ying Z.
        Checking the Cox model with cumulative sums of martingale-based residuals.
        Biometrika. 1993; 80: 557-572
        • Glanz JM
        • Clarke CL
        • Daley MF
        • et al.
        The childhood vaccination schedule and the lack of association with type 1 diabetes.
        Pediatrics. 2021; 148e2021051910
        • Lipsitch M
        • Tchetgen Tchetgen E
        • Cohen T.
        Negative controls: a tool for detecting confounding and bias in observational studies.
        Epidemiology. 2010; 21: 383-388
        • Arnold BF
        • Ercumen A
        • Benjamin-Chung J
        • et al.
        Brief report: negative controls to detect selection bias and measurement bias in epidemiologic studies.
        Epidemiology. 2016; 27: 637-641
        • Mehrabadi A
        • Dodds L
        • MacDonald NE
        • et al.
        Association of maternal influenza vaccination during pregnancy with early childhood health outcomes.
        JAMA. 2021; 325: 2285-2293
        • Willhite CC
        • Karyakina NA
        • Yokel RA
        • et al.
        Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide and its soluble salts.
        Crit Rev Toxicol. 2014; 44: 1-80
        • Shao F
        • Zheng P
        • Yu D
        • et al.
        Follicular helper T cells in type 1 diabetes.
        FASEB J. 2020; 34: 30-40
        • Alessandrini F
        • Musiol S
        • Schneider E
        • et al.
        Mimicking antigen-driven asthma in rodent models-how close can we get?.
        Front Immunol. 2020; 11575936
        • Moorman JE
        • Akinbami LJ
        • Bailey CM
        • et al.
        National surveillance of asthma: United States, 2001-2010.
        Vital Health Stat. 2012; 3: 1-58
        • Moorman JE
        • Rudd RA
        • Johnson CA
        • et al.
        National surveillance for asthma—United States, 1980-2004.
        MMWR Surveill Summ. 2007; 56: 1-54
        • Corkins MR
        • AAP Committee on Nutrition
        Aluminum effects in infants and children.
        Pediatrics. 2019; 144e20193148
        • Mitkus RJ
        • King DB
        • Hess MA
        • et al.
        Updated aluminum pharmacokinetics following infant exposures through diet and vaccination.
        Vaccine. 2011; 29: 9538-9543
        • Karwowski MP
        • Stamoulis C
        • Wenren LM
        • et al.
        Blood and hair aluminum levels, vaccine history, and early infant development: a cross-sectional study.
        Acad Pediatr. 2018; 18: 161-165
        • DeStefano F
        • Gu D
        • Kramarz P
        • et al.
        Childhood vaccinations and risk of asthma.
        Pediatr Infect Dis J. 2002; 21: 498-504
        • Grüber C
        • Illi S
        • Lau S
        • et al.
        Transient suppression of atopy in early childhood is associated with high vaccination coverage.
        Pediatrics. 2003; 111: e282-e288
        • Martignon G
        • Oryszczyn MP
        • Annesi-Maesano I
        Does childhood immunization against infectious diseases protect from the development of atopic disease?.
        Pediatr Allergy Immunol. 2005; 16: 193-200
        • Thomson JA
        • Widjaja C
        • Darmaputra AA
        • et al.
        Early childhood infections and immunisation and the development of allergic disease in particular asthma in a high-risk cohort: a prospective study of allergy-prone children from birth to six years.
        Pediatr Allergy Immunol. 2010; 21: 1076-1085
        • Del Giudice G
        • Rappuoli R
        • Didierlaurent AM.
        Correlates of adjuvanticity: a review on adjuvants in licensed vaccines.
        Semin Immunol. 2018; 39: 14-21