The Childhood Immunization Schedule and 

Safety: Studies in the Vaccine Safety Datalink

Matthew F. Daley MD

Advisory Committee on Immunization Practices, June 23, 2023
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• No conflicts of interest to disclose

• The findings in this presentation are those of the speaker and do not 

necessarily represent the official position of the Centers for Disease 

Control and Prevention

Disclaimers

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• 2013 Institute of Medicine* (IOM) Report

• Feasibility work in Vaccine Safety Datalink (VSD)

• Three published VSD studies

oAntigens and non-targeted infections

oSchedule and type 1 diabetes (T1DM)

oAluminum and asthma

• Future investigations

• Schedule and safety: broader context

Outline

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*Now referred to as The National Academies of Sciences, Engineering, and Medicine (NASEM)
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• Subtitle: Stakeholder Concerns, Scientific Evidence, and Future Studies

• Existing evidence supported safety of schedule “as a whole”

• Evidence gaps: each new vaccine added to existing schedule; safety studies 

usually of acute adverse events; long-term health outcomes less well studied 

• Committee conclusions:

o Randomized clinical trials not suitable approach to address research questions about 

schedule for ethical reasons

o Observational studies needed in existing surveillance systems (including in VSD)

o Methods for such studies complex; feasibility work needed

o Develop metrics for exposure to schedule

o Focus on long-term outcomes: allergic, autoimmune, neurologic

IOM: The Childhood Immunization Schedule and Safety

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Ref: Institute of Medicine, National Academies Press, 2013. DOI: 10.17226/13563.
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• VSD: collaboration between CDC and integrated healthcare 

organizations, conducts vaccine safety surveillance and research

• White Paper objectives:

oExposure: define measures of vaccination schedule which could be 

evaluated, with focus on first 24 months of life

oOutcomes: identify plausible adverse events, with emphasis on long-term 

adverse events

oKey design considerations, analytic approaches

• Potential outcomes prioritized based on feasibility, public health 

significance, and public concern

White Paper on Studying Schedule in VSD:

Feasibility, Study Design, Outcomes

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Ref: Glanz JM et al, Vaccine. 2016;34 Suppl 1:A1-A29.
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• High priority outcomes included: allergic disorders (e.g., asthma), 

autoimmune disease (e.g.,T1DM), neurologic (e.g., epilepsy)

• Some public concerns may have limited biologic plausibility

• Attention to bias, unmeasured confounding

o Misclassification bias: survey parents of under-vaccinated children

o Use negative control outcomes (example: injuries)

o Control for differences in health care utilization

• Plan for a long and complex process; any initial positive associations 

will need studies to refute or replicate initial findings

White Paper, Additional Conclusions

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Ref: 1) Glanz JM et al, Vaccine. 2016;34 Suppl 1:A1-A29. 2) Daley MF et al, Vaccine. 2017;35(15):1873-1878. 3) Daley MF et al, Acad Pediatr. 2018;18:754-762. 
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• Public concern: early childhood immunization “overloads” immune system

• Design: Matched case-control

• Exposures: cumulative vaccine antigen exposure, estimated by summing 

number of antigens in each vaccine dose birth through age 23 months

• Outcomes:

o Non-vaccine-targeted infections in emergency department and inpatient settings 

from 24 through 47 months of age

o Manual medical record review validation of sample of outcomes

• Matching: age, sex, presence of chronic disease

VSD Study: Antigens and Non-Targeted Infections

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Ref: Glanz MF et al, JAMA. 2018;319(9):906-913.
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• Among children with versus without non-vaccine-targeted infections 

from 24 through 47 months of age, matched odds ratio for cumulative 

vaccine antigen exposure not significant:

o Matched odds ratio, 0.94; 95% CI, 0.84 to 1.07

• Secondary analyses: consistent with primary findings

• Conclusions:

o No association between number of antigens young children receive through 

vaccines and likelihood of ED or inpatient encounters for infections

o No evidence schedule “overwhelms” immune system

Results: Antigens and Non-Targeted Infections

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Ref: Glanz MF et al, JAMA. 2018;319(9):906-913.
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• Public concern: vaccine antigens and ingredients (including aluminum, used as 

adjuvant) interfere with immune function, increase risk of autoimmune disease

• Design: retrospective cohort

• Exposures:

o Cumulative vaccine antigen

o Cumulative vaccine aluminum

o Average days under-vaccinated

• Outcome: T1DM, identified using diagnosis codes

• Follow up: Mean length of follow up >5 years

• Analyses adjusted for sex, race and ethnicity, maternal age, birth weight, 

gestational age, utilization (number of well-child visits)

VSD Study: Schedule and Type 1 Diabetes

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Ref: Glanz MF et al, Pediatrics. 2021;148(6):e2021051910.
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• Main analyses, three different exposures:

o Cumulative vaccine antigen non-significant: adjusted hazard ratio 0.98; 95% CI, 0.97–1.00

o Cumulative vaccine aluminum inversely associated: adjusted hazard ratio 0.77; 95% CI, 0.60–0.99

o Average days under-vaccinated non-significant: adjusted hazard ratio 1.01; 95% CI, 0.99–1.02 

• Sensitivity analyses, factoring in family history T1DM: similar to 

primary results

• Conclusions:

oVaccine schedule not associated with increased risk of T1DM

o Decreased risk at higher vaccine aluminum exposure: modest effect size; 

more study needed to refute or replicate this finding

Results: Schedule and Type 1 Diabetes

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Ref: Glanz MF et al, Pediatrics. 2021;148(6):e2021051910.
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• Public concern: vaccine ingredients (specifically aluminum, used as adjuvant) 

increase risk of allergic disorders including asthma

• Biologic plausibility: based on animal data, aluminum in vaccines could “skew” 

toward T-helper cell 2 (Th2) response; Th2 cells play role in allergic asthma

• Design: retrospective cohort

• Exposure: cumulative vaccine aluminum received birth through 23 months of age

• Outcome: persistent asthma at 24 through 59 months of age

o One inpatient or two outpatient diagnoses of asthma PLUS

o One or more prescriptions for a long-term asthma control medication

• All analyses done separately for children with and without eczema

VSD Study: Aluminum and Asthma

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Ref: 1) Baylor NW et al, Vaccine. 2002;20 Suppl 3:S18-23. 2) Goullé JP et al, Med Mal Infect. 2020;50:16-21. 3) Hogenesch H. Front Immunol. 2012;3:406. 4) Sastry 

M et al, PLoS One. 2017;12:e0186854. 5) Alessandrini F et al, Front Immunol. 2020;11:575936. 6) Daley MF et al, Acad Pediatr. 2023 Jan-Feb;23(1):37-46. 
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• N=14337 with eczema: 6.0% developed persistent asthma

• N=312654 without eczema: 2.1% developed persistent asthma

• Median vaccine-associated aluminum:

oEczema cohort=4.18 mg

o No eczema cohort=4.18 mg

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Ref: Daley MF et al, Acad Pediatr. 2023 Jan-Feb;23(1):37-46. 

Results: Aluminum and Asthma Study
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Crude 

Incidence Rate 

of Asthma by 

Quantity of 

VaccineAssociated 

Aluminum

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Ref: Daley MF et al, Acad Pediatr. 2023 Jan-Feb;23(1):37-46. 
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Association between Cumulative Vaccine-Associated 

Aluminum and Persistent Asthma

Notes: Cox proportional hazards analyses; separate models for eczema and no eczema cohorts; other covariates included number of outpatient visits; number of ED 

visits; child’s race/ethnicity; medical complexity; VSD site; birth month and year. EGA, estimated gestational age.

Schedule and Safety 14
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Aluminum and Asthma Study: Secondary Analyses

Notes: Cox proportional hazards analyses; separate models for eczema and no eczema cohorts; other covariates included number of outpatient visits; number of ED 

visits; child’s race/ethnicity; medical complexity; VSD site; birth month and year

Schedule and Safety 15
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• Small positive association between cumulative vaccine-associated aluminum 

before 24 months and persistent asthma 24-59 months

• Positive finding for children with and without eczema

• Secondary analyses: positive associations in some but not all analyses

• Study strengths: deliberate process; extensive feedback; large sample; VSD with 

high data quality; sophisticated analyses

• Study limitations: no data on dietary/environmental aluminum exposure (although 

little to none of ingested aluminum absorbed per recent AAP report); no data on 

social determinants of health; unmeasured confounding; antigen effects

• The first step of a multi-step research process

Interpretation: Aluminum and Asthma Study

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Ref: 1) Daley MF et al, Acad Pediatr. 2023 Jan-Feb;23(1):37-46. 2) Corkins MR, AAP Committee on Nutrition. Pediatrics. 2019;144:e20193148.

Schedule and Safety
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Asthma Prevalence among Children <18 years of Age:

United States, 1980–2020

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0.0

2.0

4.0

6.0

8.0

10.0

12.0

1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016 2018 2020

Year

PCV7

DTaP 

replaces DTP

Hib

Hep B

Hep A 

(high incidence)

Hep A 

(national)

DTaP-Hep B-IPV

(PediarixTM)

DTaP-IPV-Hib

(Pentacel®)

PCV13

replaces PCV7

Ref: The data from 1980-1996 and 2001-2020 are from National Health Interview Survey (NHIS): 1) 1980–1996 data are from Akinbami LJ, Schoendorf

KC, Parker J. Am J Epidemiolol. 2003. 2) 2001–2020 data are from https://www.cdc.gov/asthma/nhis/default.htm

Percent 

(%)
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• Denmark national databases (Dr. Anders Hviid presentation at ACIP)

• New study in VSD:

o Cohort: larger cohort, longer follow up time

oExposure: aluminum before 12 months of age

oEczema: treat eczema as covariate

oOutcome: asthma diagnosed at a later age (60 through 84 months of age); 

asthma diagnosed earlier may represent viral-induced wheezing (not asthma)

• Additional consideration of other data sources which could help 

assess relationship between vaccine aluminum exposure and 

subsequent asthma risk

Further Investigations, Vaccine Aluminum and Risk of Asthma

Schedule and Safety 18
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• Totality of available evidence continues to support the safety of the routine childhood 

vaccination schedule

• Existing federal vaccine safety surveillance systems robust and responsive to concerns 

expressed by parents of young children

• Precipitated by 2013 IOM Report on schedule, new field of study is being developed:

o Examine cumulative, repeated exposures to vaccines and vaccine ingredients

o Examine long-term health outcomes

• At time of IOM Report, few studies of the safety of the schedule “as a whole”

• Evidence accumulating around specific testable hypotheses; results which can be 

communicated to parents

• Additional studies related to aluminum and asthma risk planned and ongoing

• Benefits of vaccination strongly outweigh known and potential risks

The Schedule and Safety: Broader Context

Schedule and Safety 19
THANK YOU

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