Document text
The Childhood Immunization Schedule and
Safety: Studies in the Vaccine Safety Datalink
Matthew F. Daley MD
Advisory Committee on Immunization Practices, June 23, 2023
KAISER PERMANENTE INSTITUTE FOR HEALTH RESEARCH
•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 PreventionDisclaimers
Schedule and Safety 2
KAISER PERMANENTE INSTITUTE FOR HEALTH RESEARCH
•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 contextOutline
3 Schedule and Safety*Now referred to as The National Academies of Sciences, Engineering, and Medicine (NASEM)
KAISER PERMANENTE INSTITUTE FOR HEALTH RESEARCH
•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:
oRandomized clinical trials not suitable approach to address research questions about
schedule for ethical reasons
oObservational studies needed in existing surveillance systems (including in VSD)
oMethods for such studies complex; feasibility work needed
oDevelop metrics for exposure to schedule
oFocus on long -term outcomes: allergic, autoimmune, neurologicIOM: The Childhood Immunization Schedule and Safety
4 Schedule and SafetyRef: Institute of Medicine, National Academies Press, 2013. DOI: 10.17226/13563.
KAISER PERMANENTE INSTITUTE FOR HEALTH RESEARCH
•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 concernWhite Paper on Studying Schedule in VSD:
Feasibility, Study Design, Outcomes
5 Schedule and SafetyRef: 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
o
oMisclassification bias: survey parents of under -vaccinated children
Use negative control outcomes (example: injuries)
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 findingsWhite Paper, Additional Conclusions
6 Schedule and SafetyRef: 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.
KAISER PERMANENTE INSTITUTE FOR HEALTH RESEARCH
•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:
oNon-vaccine -targeted infections in emergency department and inpatient settings
from 24 through 47 months of age
oManual medical record review validation of sample of outcomes
•Matching: age, sex, presence of chronic diseaseVSD Study: Antigens and Non -Targeted Infections
7 Schedule and SafetyRef: Glanz MF et al, JAMA. 2018;319(9):906 -913.
KAISER PERMANENTE INSTITUTE FOR HEALTH RESEARCH
•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:
oMatched odds ratio, 0.94; 95% CI, 0.84 to 1.07
•Secondary analyses: consistent with primary findings
•Conclusions:
oNo association between number of antigens young children receive through
vaccines and likelihood of ED or inpatient encounters for infections
oNo evidence schedule “overwhelms” immune systemResults: Antigens and Non -Targeted Infections
8 Schedule and SafetyRef: Glanz MF et al, JAMA. 2018;319(9):906 -913.
KAISER PERMANENTE INSTITUTE FOR HEALTH RESEARCH
•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
o
oCumulative vaccine antigen
Cumulative vaccine aluminum
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
9 Schedule and SafetyRef: Glanz MF et al, Pediatrics. 2021;148(6):e2021051910.
KAISER PERMANENTE INSTITUTE FOR HEALTH RESEARCH
•Main analyses, three different exposures:
oCumulative vaccine antigen non-significant : adjusted hazard ratio 0.98; 95% CI, 0.97 –1.00
oCumulative vaccine aluminum inversely associated : adjusted hazard ratio 0.77; 95% CI, 0.60 –0.99
oAverage 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
oDecreased risk at higher vaccine aluminum exposure: modest effect size;
more study needed to refute or replicate this findingResults: Schedule and Type 1 Diabetes
10 Schedule and SafetyRef: Glanz MF et al, Pediatrics. 2021;148(6):e2021051910.
KAISER PERMANENTE INSTITUTE FOR HEALTH RESEARCH
•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
oOne inpatient or two outpatient diagnoses of asthma PLUS
oOne or more prescriptions for a long -term asthma control medication
•All analyses done separately for children with and without eczemaVSD Study: Aluminum and Asthma
11 Schedule and SafetyRef: 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.
KAISER PERMANENTE INSTITUTE FOR HEALTH RESEARCH
•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
oNo eczema cohort=4.18 mg
12 Schedule and SafetyRef: Daley MF et al, Acad Pediatr . 2023 Jan -Feb;23(1):37 -46. Results: Aluminum and Asthma Study
KAISER PERMANENTE INSTITUTE FOR HEALTH RESEARCH
Crude
Incidence Rate
of Asthma by
Quantity of
Vaccine-
Associated
Aluminum
13
Schedule and SafetyRef: Daley MF et al, Acad Pediatr . 2023 Jan -Feb;23(1):37 -46.
KAISER PERMANENTE INSTITUTE FOR HEALTH RESEARCH
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.
14 Schedule and Safety
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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
15 Schedule and Safety
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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 processInterpretation: Aluminum and Asthma Study
16Ref: 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
KAISER PERMANENTE INSTITUTE FOR HEALTH RESEARCH
Asthma Prevalence among Children <18 years of Age:
United States, 1980 –2020
17 Schedule and Safety0.02.04.06.08.010.012.0
1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016 2018 2020
YearPCV7DTaP
replaces DTPHib
Hep BHep A
(high incidence)
Hep A
(national)DTaP-Hep B-IPV
(PediarixTM)DTaP-IPV-Hib
(Pentacel ®)
PCV13
replaces PCV7Percent
(%)
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
KAISER PERMANENTE INSTITUTE FOR HEALTH RESEARCH
•Denmark national databases (Dr. Anders Hviid presentation at ACIP)
•New study in VSD:
oCohort: 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 riskFurther Investigations, Vaccine Aluminum and Risk of Asthma
18 Schedule and Safety
KAISER PERMANENTE INSTITUTE FOR HEALTH RESEARCH
•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:
oExamine cumulative, repeated exposures to vaccines and vaccine ingredients
oExamine 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 risksThe Schedule and Safety: Broader Context
19 Schedule and Safety
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