Opportunities and Obligations: Vaccine Safety in the Genomics Era presentation

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Title: Opportunities and Obligations: Vaccine Safety in the Genomics Era

1

Opportunities and Obligations Vaccine Safety
in the Genomics Era

Robert Davis, MD, MPH Director Immunization
Safety Office CDC
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Opportunities and Obligations Vaccine Safety
in the Genomics Era

History of vaccine safety issues
Vaccine safety infrastructure
New/future field of vaccine genomics
Some examples
Future opportunities

3
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Disease Pre-vaccine Era
Year 1999
change
Diphtheria 206,939 1921 1 -99.99 Measles 89
4,134 1941 86 -99.99 Mumps 152,209 1968 35
2 -99.76 Pertussis 265,269 1934 6,031
-97.63 Polio (wild) 21,269 1952 0 -100.00 Rubel
la 57,686 1969 238 -99.58 Cong. Rubella
Synd. 20,000 (1964-5) 3 -99.98 Tetanus 1,56
0 1948 33 -97.88 Invasive Hib
Disease 20,000 1984 33 -99.83
5
Disease Pre-vaccine Era
Year 1999
change
Diphtheria 206,939 1921 1 -99.99 Measles 89
4,134 1941 86 -99.99 Mumps 152,209 1968 35
2 -99.76 Pertussis 265,269 1934 6,031
-97.63 Polio (wild) 21,269 1952 0 -100.00 Rubel
la 57,686 1969 238 -99.58 Cong. Rubella
Synd. 20,000 (1964-5) 3 -99.98 Tetanus 1,56
0 1948 33 -97.88 Invasive Hib
Disease 20,000 1984 33 -99.83
6
Disease Pre-vaccine Era
Year 1999
change
Diphtheria 206,939 1921 1 -99.99 Measles 89
4,134 1941 86 -99.99 Mumps 152,209 1968 35
2 -99.76 Pertussis 265,269 1934 6,031
-97.63 Polio (wild) 21,269 1952 0 -100.00 Rubel
la 57,686 1969 238 -99.58 Cong. Rubella
Synd. 20,000 (1964-5) 3 -99.98 Tetanus 1,56
0 1948 33 -97.88 Invasive Hib
Disease 20,000 1984 33 -99.83
7
Disease Pre-vaccine Era
Year 1999
change
Diphtheria 206,939 1921 1 -99.99 Measles 89
4,134 1941 86 -99.99 Mumps 152,209 1968 35
2 -99.76 Pertussis 265,269 1934 6,031
-97.63 Polio (wild) 21,269 1952 0 -100.00 Rubel
la 57,686 1969 238 -99.58 Cong. Rubella
Synd. 20,000 (1964-5) 3 -99.98 Tetanus 1,56
0 1948 33 -97.88 Invasive Hib
Disease 20,000 1984 33 -99.83
Vaccine Adverse Events 0 11,827

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But.

No vaccine is 100 percent safe.
As more people are vaccinated, diseases decrease
or even disappear
But real - and perceived - vaccine side effects
increase.
Public concern about the safety of vaccines
Decreased vaccination levels
Disease epidemics
Alternatively, high profile disasters shake
public confidence in vaccine (and drug) safety
Swine flu vaccine campaign GBS
Rotavirus vaccine intussusception
Vioxx myocardial infarction
Lead to increased development costs, regulatory
burden, and increased disease burden

Whooping Cough Notifications and Vaccine
Coverage, England and Wales 1960-93

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Recent research supports safety of vaccine policy

No increased risk for autism after MMR vaccine
No increased risk for autism among children
receiving high doses of thimerosal
No increased risk for multiple sclerosis or optic
neuritis after hepatitis B vaccine
No increased risk for inflammatory bowel disease
after MMR or MCV

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Recent Research

But, many parents think we are asking the wrong
questions
They dont really care about population based
studies _if_ they think they are somehow at
risk
Recent finding Jan 2006 of autism gene from
Utah study
Likely no single gene dictates autism
More likely that each gene - individually -
raises the risk
Parents want to know If my child has one or more
risk genes, will the vaccines trigger autism (or
some other problem)
This is a very good question

Parents want to know If my child has one or more
risk genes, will the vaccines trigger autism (or
some other problem)
This fundamental idea will my genes modify the
effect of an exposure - is the biggest question
today in medication safety as well as in
pharmaceutical development
Are there some drugs that work better/are safer
in some people

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Personalized Genetic Medicine

Personalized medicine personalized drug
delivery under intense study by
NIH/NHGRI/pharmaceutical industry
Efficacy
Beta blockers work better among carriers of
specific genes (which also differ by race)
Safety
Albuterol may not work - and may even be harmful
- among asthmatics with specific genetic
variations

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Personalized Genetic Medicine

Diagnostics
The AmpliChip CYP450 test
first microarray-based pharmacogenomic test in
clinical setting.
provides information on enzyme activity of the
CYPC19 and CYP2D6 genes - genes that play
particularly important roles in the metabolism of
a large number of widely prescribed medications
more accurate dosing safer dosing

Personalized medicine personalized drug
delivery under intense study by
NIH/NHGRI/pharmaceutical industry
Efficacy
Beta blockers work better among carriers of
specific genes (which also differ by race)
Safety
Albuterol appears to work less well, and may even
be harmful, among asthmatics with specific
genetic variations at the pnp gene
Diagnositcs
AmpliChip CYP450 test
For vaccine Personalized approach is to
understand which people are at risk for
Vaccine adverse events
Vaccine failure

Pharmacogenomics vs. Vaccine-genomics

Pharmacogenomics Personalized therapies for
acute/chronic conditions Typically, response to
medication is observed, or can be measured Side
effects and adverse medication events common
medication discontinuation, illness, lawsuits
large incentive for personalizing
delivery Vaccine-genomics Personalized
vaccines to improve safety profile or vaccine
responsiveness Vaccine response rarely measured
in real world. Serious side effects or vaccine
AE very rare. Little economic incentive for
manufacturers to lead way for personalizing
delivery
17
Goals To understand the genetic variations that
predispose children, adolescents or adults to
vaccine adverse events or vaccine failure
18

The typical study approach

Case-control study (rare outcome) Cases
children with seizures following MMR
vaccination Controls children vaccinated with
MMR who did not experience seizures Assess
genetic differences between cases and controls,
using either candidate genes or whole genome
approach Optimally identify a single
polymorphism or group of polymorphisms very
common in cases, uncommon in controls
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How would results be applied?

If able to identify a single polymorphism or
group of polymorphisms very common in cases yet
uncommon in controls (ie high RR for
disease) Assess predictive power of
polymorphism(s) when applied to population How
many people need to be identified excluded from
vaccination to prevent one seizure? Quantify
risks and benefits of excluding children/adults
from vaccination May be different depending on
vaccine, outcome, likelihood of exposure to wild
type disease, presence of herd immunity,
etc Ex MMR and seizures Smallpox
vaccine and myocarditis Study/identify risk
minimization processes Ex tylenol to prevent
febrile seizures vaccinating at different ages
not vaccinating, etc
20

How do we create the system necessary for the
optimal scientific study?

Needs System Basic science background Technolog
y Analytic capability Scientists Efficiencies
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How do we create the system necessary for the
optimal scientific study?

System needs Need to have capacity to
ascertain rare events after vaccination On the
order of 1/1000 to 1/10,000 (or even
rarer) Cannot be done with premarketing or even
postmarketing clinical trials Option 1 VAERS
(Vaccine Adverse Events Reporting
System) Passively reported VAE Option 2
Population based setting Active identification
of VAEs possible Advantage full spectrum of
VAE unbiased ascertainment
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How do we create the system necessary for the
optimal scientific study?

Systems Vaccine Safety Datalink
Began in 1991 as a collaborative project between
CDC and four HMOs
Group Health Cooperative, Seattle, WA
Northwest Kaiser Permanente, Portland, OR
Northern California Kaiser Permanente, Oakland
South California Kaiser Permanente, Los Angeles
Expanded in 2000 to include four more HMOs
Harvard Pilgrim Health Care, Boston, MA
HealthPartners, Minneapolis, MN
Kaiser Permanente Colorado, Denver, CO
Marshfield Clinic, Marshfield, WI
Total over 10 million members

Vaccine Safety Datalink (VSD)

Patient Characteristics (Birth records) (Census)
Health Outcomes (Hospital) (ER) (Clinic)
Vaccination Records
VSD Linked Analysis Database
24

How do we create the system necessary for the
optimal scientific study?

Needs System Basic science background Technolo
gy Analytic capability Scientists Other
Efficiencies
25

How do we create the system necessary for the
optimal scientific study?

Needs Basic science background Understanding
of pathways involved in potential VAEs Basic
disease pathogenesis Inflammation
pathways Immune response pathways Used to
identify potential candidate genes and candidate
gene pathways For many (if not most) of VAEs,
this is currently unknown Distinct from
medication AE related (for ex) to cyp450
pathway
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How do we create the system necessary for the
optimal scientific study?

Needs System Basic science background Technolog
y Analytic capability Scientists Other
Efficiencies
27

How do we create the system necessary for the
optimal scientific study?

Needs Technology Analytic capability Technology
Use of 500K chips for SNP analysis becoming
more routine Could partner with producers of
chips (Affy Illumina etc) for cost,
individualized production etc Specimen
collection typically blood samples (buccal
swabs or other in future offer possibility of
remote/streamlined collection of specimens from
case/family) Data tracking one of major
challenges of Human Genome Project Will need
attention in any future endeavors for vaccine
genomics
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How do we create the system necessary for the
optimal scientific study?

Needs Technology Analytic capability 500K
chips give information on 500,000 single
nucleotide polymorphisms Challenges typical
logistic regression analysis has 10-100
covariates (not 500K) 1. Running chips is a
specialized knowledge/capability 2. Need
mainframe computers for data storage and
analysis 3. Need advanced/new biostatistical
algorithms for fitting models 4. Almost
guaranteed to find more false than true
positives 5. Individual SNPs might not be as
important or illuminating as haplotypes
29

How do we create the system necessary for the
optimal scientific study?

Needs Analytic capability 1. Running chips is
a specialized knowledge/skill 2. Need
mainframe computers for data storage and
analysis Need to create this capability (ie
within CDC) or collaborate with academic
partners 3. Need advanced/new biostatistical
algorithms for fitting models Needs specialized
collaborations with biostatistical genetics and
genetic epidemiology
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How do we create the system necessary for the
optimal scientific study?

Needs Analytic capability 4. Almost guaranteed
to find more false than true positives For
candidate genes can use standard approach For
non-candidate genes (a) assess strength and
consistency of association (b) assess biologic
plausibility (if possible) (c) replicate,
replicate, replicate 5. Individual SNPs might
not be as important or illuminating as
haplotypes
31

How do we create the system necessary for the
optimal scientific study?

Needs For identification of cases, selection of
controls, and enrollment Knowledge of
vaccine/schedule/adverse events Collaborative
network with organizations/populations of
interest Historically infectious disease
specialists epidemiologists For basic
science/gene pathways Immunologists/infectious
disease specialists Geneticists For
analysis Collaboration with partners with
capabilities to run samples Biostatisticians/gene
tic epidemiologists to analyze data
32

How do we create the system necessary for the
optimal scientific study?

How do we create the system necessary for the
optimal scientific study? Needs System Basic
science background Technology Analytic
capability Scientists Other Efficiencies
33

How do we create the system necessary for the
optimal scientific study?

Needs Efficiencies Consider moving away from
specific control groups. Option genotype 1000
people from each HMO and use that as a standard
control group for every study Expensive to begin
with, but saves cost savings and more efficient
in the long run
34

How do we create the system necessary for the
optimal scientific study?

How do we create the system necessary for the
optimal scientific study? Presently System
exists in integrated fashion (VSD) Basic science
background/scientific expertise needs
concentration/integration Technology/Analytic
capability available needs coordinated
approach Efficiencies needs evaluation
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Vaccine Safety Case StudyRheumatoid Arthritis
and Hepatitis B Vaccine
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Rheumatoid Arthritis Background

Chronic autoimmune disease
Population prevalence of 1-2 worldwide
Over 7 million affected in U.S.
lt50 5 year survival rate among most severely
affected

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Why study genetics vaccination with regard to
rheumatoid arthritis?

RA HLA DR4 associated with increased
susceptibility to disease
Hepatitis B infection HLA DR3 associated with
altered susceptibility
Reports of RA among HB vaccine recipients HLA-DR
types that either increase RA susceptibility or
HBV response

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Study Question

Are there specific genes that predispose to
Rheumatoid arthritis following hepatitis B
vaccination?

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Study design options

Cohort Are rates of RA increased among vaccine
recipients relative to non-HBV recipients?
Specifically, are rates of RA particularly
increased among persons with specific genetic
polymorphisms (ie of HLA DR4) compared to those
persons without such polymorphisms?
Case-control Is HBV receipt over-represented
among subjects with RA compared to controls?
Specifically, is combination of HBV and certain
polymorphisms over-represented among cases
compared with controls?

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Flow chart for case identification, sample
collection, and data analysis.All persons ages
15 to 59 with continuous HMO membership from
1/1/95 to 12/31/99Computer Definition of
Possible RA CasesChart Review of Possible RA
CasesRheumatologist Review of Selected Cases
todetermine if chart review is adequate to
satisfy1987 ACR criteria for RA Data
analysis (initial Kaiser retrospective
study)Obtain permission from NCK personal
physicians to contact RA patientsPts. Invited
to Enroll in RA-HBV Genetic StudiesPts.
Consented for Study, Blood DrawnBlood Shipped,
Fed Express, o/n to AtlantaHLA and Hepatitis
Antibody TestingData Analysis(genetic
case-only substudy)
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In a separate study of RA, Celera Diagnostics
identified replicated 22 SNPs in RA
patient samples includes R620W missense SNP in
PTPN22 VSD study has assessed the frequency
of these gene SNPs among cases in addition to
the HLA DR4 polymorphisms listed previously
Begovich et al. 2004 AJHG 75330
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Power calculations for gene-environment study of
RA, hepatitis B vaccination, and
HLA-polymorphismsIfGenetic risk (HLA-DR4) OR
5 (conservative)Environmental risk (HBV) OR
2 (likely over-estimate)AndIf DR4 prevalence
is 15 (NCK population of caucasians, NA and
AA)Will have 80 power, alpha 0.05 to detect
interaction of 10 HB coverage Sample size
needed 2
200 5
100 10
50
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Opportunities and Obligations Vaccine Safety in
the Genomics Era

Screen VSD data-sets yearly Identify
subjects/collect specimens on cases q yr
febrile seizures severe limb swelling q 5 yrs
arthritis prolonged crying q 10 yrs
encephalopathy GBS anaphylaxis w/high profile
situations ie intussusceptionGBS Run
genome-scans (500K chips or higher) on cases
Compare with standard age, HMO, race matched
controls
45

Opportunities and Obligations Vaccine Safety in
the Genomics Era

Vision for the Future Screen VSD data-sets
yearly Identify subjects/collect specimens
on cases q yr febrile seizures severe limb
swelling q 5 yrs arthritis prolonged crying
q 10 yrs encephalopathy GBS
anaphylaxis w/high profile situations ie
intussusceptionGBS Run genome-scans (500K chips
or higher) on cases Compare with standard age,
HMO, race matched controls Assess findings for
_candidate_ genes Generate new set(s) of
potential candidate genes/pathways for next
iteration
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Opportunities and Obligations Vaccine Safety in
the Genomics Era Conclusions

Study of vaccine genomics just beginning to get
underway
Evaluations of gene-environment interactions
(HLA-HBV and RA MMR and FH epilepsy and febrile
seizures) can be wrapped into large database
infrastructure (US VSD Scandinavian
population-based studies)
Other studies not discussed today (ie HLA control
of antibody response to specific vaccination) can
be accomplished within the venue of prelicensure
clinical trials

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Opportunities and Obligations Vaccine Safety in
the Genomics Era Challenges on the horizon

New vaccines
Rotavirus
HPV
Acellular pertussis
MMR-V, and many more
Increased focus on adolescents and adults
(meningococcal varicella etc)
Different diseases/potential adverse events (ie
autoimmune)
Increasingly packed schedule
Relatively unknown safety profile

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Opportunities and Obligations Vaccine Safety in
the Genomics Era Vision into the Future

CDC has a critical role for integrating genomics
into vaccine safety
Infrastructure (collaborations)
Only CDC with VSD and VAERS able to identify
subjects with rare AEs
Scientists with the expertise in understanding
adverse events
Forge collaborations with genomics community
Begin to understand how genetic variation
underlies VAE
Understand how to identify people at increased
risk, and devise alternate immunization
strategies

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Is there evidence from the literature that
interactions between vaccination and subgroups
exist?MMR Vaccination and Febrile Seizures.
Evaluation of Susceptible Subgroups and Long-term
Prognosis JAMA Vol. 292 No. 3, July 21, 2004
Vestergaard, Hviid, Madsen et al
51

It is known that the risk for febrile seizures is
increased after MMR vaccination.
Is this increase even higher among particular
people
personal or family history of seizures
perinatal factors
socioeconomic status.
The latter 2 are environment, but the first
(family history) gives some glimpse of genetic
risk factors that might interact with environment
(MMR vaccination)

52
Setting

Population-based cohort study of all children
born in Denmark 1/1/91 12/31/98 and who
survived to 3 months of age total of 537,171
children
Unique personal ID allowed link to mother and
father
(similar database construction underway within
VSD)

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Vaccination

National Board of Health maintains registry of
MMR vaccinations administered in Denmark
Collected info on vaccinations given 1/1/91
12/31/99
Jeryl-Lynn strain used/studied
(recommended) Age of vaccine 15 months
Exact date of vaccine not available imputed day
of week as Wednesday.

54
Outcome ascertainment

Incidence of first febrile seizure, recurrent
febrile seizures, and subsequent epilepsy,
gathered from National Hospital Registry which
includes inpatient, outpatient and emergency
department visits.
For febrile seizures, excluded children with
history of non-febrile seizures, cerebral palsy,
head trauma, intracranial tumors, meningitis and
encephalitis (this clarifies the phenotype of
febrile seizure).
Used ICD-10 coding schema

55
Evaluation of high risk strata (effect
modifiers)

Personal history of febrile seizures
Family history
Birth characteristics and sociodemographic factors

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Statistical Analysis

Poisson regression. Entered at 3 mo of age.
Censored at first diagnosis of FS, epilepsy,
death, emigration, enceph/mening/head injury, or
age 5 years or 12/31/99
MMR vaccination analyzed as time varying
covariate

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Subgroup analysis tested for statistical
interaction

Question Is the RR for children with family
history (FH) of epilepsy higher than RR for
children without family history of epilepsy
Risk after MMR vaccination among children with
FH
Risk not after MMR vacc among children with FH
Vs
Risk after MMR vaccination among children
without FH
Risk not after MMR vacc among children without
FH

58
Results

439,251 children (82) received MMR vaccination
17,986 children developed febrile seizures at
least once
RR for FS in the 2 wks after MMR vaccination
2.75 (95 CI 2.55-2.97)
RR did not vary significantly in the subgroups of
children
family history of seizures
perinatal factors
socioeconomic status

59
Subgroup analysis, continued

RR was higher among the subgroup of children with
family history of epilepsy
RR of 4 following vaccination among subjects
with family history
RR of 2.7 after vaccination among subjects
with family history

60
However, story is different when evaluated using
risk difference metric

Among children with family history of epilepsy,
vaccination adds 3.4 additional seizures per 1000
persons vaccinated
(Due to higher RR (4) acting on a lower
baseline risk among non-vaccinated children
(compared to children with personal history of
FS)

61
Significant findings

When viewed on a multiplicative scale, there is
only interaction noted among children with a
family history of epilepsy (RR of 4 following
vaccination among those with family history of
epilepsy vs RR of 2.7 among those without family
history of epilepsy)
However, viewed on an additive scale, the message
is much different
1.6 additional seizures per 1000 children overall
19.5 additional seizures per 1000 among children
with personal history
3.4 additional seizures per 1000 among children
with FH epilepsy
Additive scale is influenced by baseline risk,
and give a more clinically relevant picture of
the risk to the particular person

62
Example of rapid response to emerging public
health question

New conjugate meningococcal vaccination licensed
in January 2005
Recommended for universal use among adolescents
in February 2005
Distribution commenced in March 2005.
By December, 2005, 7 reports of Guillain-Barre
Syndrome within six weeks following Menactra
administration had been received by the VAERS
passive reporting system.
All cases were among 17-19 year olds, and
occurred 11-31 days following vaccination.
Quickly mobilized VSD and studied 110,000
vaccinees.
Comparison with background rates indicated that
the number of reported cases was expected
MMWR publication notified public and medical
community
But did not result in additional reports
Result
Vaccine remained on market

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Vision into the Future

Three major goals
1) Establish broad input into the research agenda
for Immunization Safety Office
External advisory panel comprised of wide range
of stakeholders including federal agencies, major
medical organizations, FDA, CMS, NIH, DoD,
parental groups to help shape vaccine safety
research plan
2) Active surveillance of new vaccines
Weekly updates from VSD and potentially other
MCOs
Real-time assessments of vaccine safety

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Vision into the Future

3) Bring vaccine safety research into the
genomics era
Personalized medicine personalized drug
delivery under intense study by
NIH/NHGRI/pharmaceutical industry
Understand which people/subgroups are at
increased risk for
Vaccine adverse events
Vaccine failure

65
The Road to a Public Health Approach to
Pharmacogenomics will be a long and raucous
journey
66
Immunization Safety Office

Vaccine Safety Datalink (VSD) project
Collaborative project with comprehensive medical
and immunization histories of over 7.5 million
people.
Studies health problems among vaccinated people
compared with unvaccinated people.
Currently using in-depth evaluations to study the
safety of thimerosal in vaccines, and risk for
autism following vaccination.
Vaccine Adverse Event Reporting System (VAERS)
An early-warning passive surveillance system to
detect problems related to vaccines.
Clinical Immunization Safety Assessment (CISA)
Network
Provides in-depth, standardized clinical
evaluations for individuals with unusual or
severe vaccine adverse events to understand
virologic, immunologic and genetic markers for
post-vaccination adverse events.
Brighton Collaboration
A global collaboration to standardize case
definitions and the study of vaccine reactions,
providing a common vocabulary for vaccine
safety research,
Vaccine Acceptance and Risk Perception (VARP)
Scientific study of interventions that increase
vaccine acceptance
Vaccine Technology
Development of safer vaccines and delivery
(needle-free jet injectors)

Importance of Vaccine Safety

Higher standard of safety expected of vaccines
"First do no harm" (primum non nocere)
Moral duty public health clinical medicine
Vaccinees generally healthy (vs. ill for drugs)
Vaccinations universally recommended or mandated
Lower risk tolerance search for rare reactions
vaccine lt 1/100,000 vs. drug 1/1 - 1/1000
Studies of rare events
More costly and difficult
Less likely to be definitive
Has, up until now, largely ignored issues of
subgroup susceptibility

Lines of Evidence Suggesting Causality

Temporal association
illness follows exposure
cases cluster within definable time after
vaccination
Biologic plausibility
animal models
tissue culture or other models
Specificity
unique clinical picture
unique laboratory result
Epidemiologic evidence
risk of illness gt expected by chance

IOM Vaccine Safety Report, 1991-94 Conclusions

Pert Rub DT/Td/T Meas Mump
Polio Hep B Hib Categ 1 Autism

Neuropathy Transverse No

Residual myelitis
(IPV) Evidence
seizure
Thrombocytopenia

Anaphylaxis
Categ 3 Infantile spasms
Encephalopathy
Early onset Hib Favors
Hypsarrythmia Infantile spasm (DT)

(conjugate) Rejection Reye syndrome
SIDS (DT)

SIDS
Categ 4 Acute Chronic GBS
Anaphylaxis GBS (OPV)
Early onset
Favors encepha- arthritis

Hib 18m Accept
lopathy

(unconjugated
Shock

PRP)
Categ 5 Anaphylaxis Acute Anaphylaxis
Thrombocytopenia Polio (OPV) Anaphylaxis
Establish Protracted arthritis
Anaphylaxis (MMR) Death (OPV) Causal
Crying
Death
70

Traditional Vaccine Safety Studies Pre-Licensure

Laboratory
Animals
Humans
Phases I gross toxicity (N 10)
Phase II dosing range/ reactogenicity (N
10-100)
Phase III efficacy ( preliminary safety) (N
1000-10,000)
Advantages
Close, detailed follow-up
Randomized, placebo-controls gt causality
assessment easy
Disadvantage
Poorly detected reactions rare, delayed onset,
subpopulations
No standard case definition for "safety"

Traditional Vaccine Safety Studies Post-Licensure

Traditional tools
passive surveillance (spontaneous reporting
system)
ad hoc controlled epidemiologic studies
New tools
Phase IV trials "linked" to licensure of new
vaccine
Large-Linked Database (LLDB) in HMO population
N 10,000
pre-organized LLDB's
ongoing safety monitoring
controlled epidemiologic studies
"enhanced" passive surveillance as "registry"

72
Traditional Passive Surveillance (e.g., VAERS)

Strengths
National in scope
Timeliness
Relative low cost
Weaknesses
Under-, biased reporting
Complexity
multiple "exposures" "outcomes"
detect "new" change "known" AE's
mix of causal and coincidental events
Generally unable to assess causality

Institute of Medicine (IOM) Reports on Vaccine
Safety

"Many gaps and limitations" in current knowledge
research capacity
Infrastructure for vaccine safety surveillance
inadequate
Needed Population laboratory under active
surveillance

74
Vaccine Safety Datalink

Began in 1991 as a collaborative project between
CDC and four HMOs
Group Health Cooperative, Seattle, WA
Northwest Kaiser Permanente, Portland, OR
Northern California Kaiser Permanente, Oakland
South California Kaiser Permanente, Los Angeles
HealthPartners, Minneapolis
Harvard Pilgrim Health Plan, Boston
Kaiser Colorado, Denver
Marshfield Clinic, Wisconsin
Total over 6 million members

75
Advantages of HMOs for Health Research

Identifiable (large) population
incidence rates and attributable risks
Computerized data bases
Cost data
Integrated systems
Infrastructure

76
VSD Analytic Approach

Screening analyses (automated data)
preliminary assessment of vaccine-outcome
associations
In-depth studies (chart reviews, interviews)
validate outcomes (and dates)
verify vaccination history (and dates)
additional risk factor or clinical information

77
Selected Findings from VSD Studies

No increased risk of chronic arthropathy among
women receiving rubella vaccine
No increased risk of aseptic meningitis after
Jeryl-Lynn mumps vaccine (in U.S. MMR)
Risk of clinical events after 2nd MMR greater at
10-12 than at 4-6 years of age

78
Selected Current VSD Studies

Neonatal and infant mortality
Wheezing and asthma
Timing of vaccination and type 1 diabetes
MMR vaccine and IBD
Hepatitis vaccination and risk of MS
Possible sequelae of thimerosal in vaccines
Rotavirus vaccine and intussusception

79
Diversity of Research Projects

VSD database and infrastructure allow a wide
range of studies in addition to vaccine safety
vaccination coverage
cost studies of different policies or strategies
clinical trials
descriptive epidemiology

80
Research in MCOs Caveats

Identifiable (large) population
enrollment and disenrollment
Computerized data bases
not developed for research
Dynamic
Cost data
may not be generalizable
Integrated systems
not true of many health plans
Infrastructure
not in place in all health plans
research infrastructure often not present

81
Research in Managed Care Organizations
Conclusions

Managed care is the dominant health care delivery
system in the U.S.
MCOs provide great opportunities for
population-based health research
Immunization research in MCOs allows timely and
efficient monitoring of vaccine safety

82
The Public Health Approach to Pharmacogenomics

Goal Personalized delivery of therapeutics that
accounts for the genetic variation of the patient

83
The Public Health Approach to Pharmacogenomics

Goal Personalized delivery of therapeutics that
accounts for the genetic variation of the patient
Thesis
Gene-based diagnostic tests are very powerful
Have distinctive risk/benefit profiles
May have unintended effects
Therefore, the default for gene-based diagnostic
tests and for pharmacogenetics should be
RCTS
Good observational studies
A requirement linked to licensure

84
The Public Health Approach to determine the real
world effectiveness of pharmacogenomics and
monitor its applications

Proper Public Health Use of Genetic Tests and
Pharmacogenomics
How do we get from here to here?
Identification of Appropriate use of
gene-disease genetic testing
association
Not all outcomes research means the same thing
Evidence Integrating Surveillance
Of Evidence
Effectiveness

85
The Public Health Approach to determine the real
world effectiveness of pharmacogenomics and
monitor its applications

Evidence Integrating Surveillance
Of Evidence
Effectiveness
What is evidence?
The basic science approach
Variations in cyp450 polymorphisms are common
Medications for cardiovascular disease and
depression are among the most comonly used, and
are a significant cost driver
Use of these medications may produce adverse
effects and/or difficulties in obtaining proper
therapeutic index.
Polymorphisms of the cyp450 pathway plays a role
in responsivenes
The basic science approach addresses the evidence
about how cyp450 and medications interact to
affect responsiveness

86
The Public Health Approach to determine the real
world effectiveness of pharmacogenomics and
monitor its applications

Evidence Integrating Surveillance
Of Evidence
Effectiveness
What is evidence?
The public health approach
Polymorphisms of the cyp450 pathway plays a role
in responsiveness
Do these polymorphisms affect measurable clinical
outcomes?
Increased morbidity/mortality?
Increased costs of health care?
Decreased quality of life?
The public health approach asks
Given that cyp450 pathway and medications work
together to affect responsiveness, does it
matter?
Is there a better way to deliver rx for some
people?

87
The Public Health Approach to determine the real
world effectiveness of pharmacogenomics and
monitor its applications

Evidence Integrating Surveillance
Of Evidence
Effectiveness
The public health approach
In addition to wanting to know what happens at
the overall population level, the PH approach
also wants to know what happens in these
subpopulations
With drug interactions i.e. CV and other
medications
Elderly i.e. diminished cardiac function
Pediatrics i.e. different disease?
Different ethnic groups i.e. gene-gene-drug
interactions

88
The Public Health Approach to determine the real
world effectiveness of pharmacogenomics and
monitor its applications

Evidence Integrating Surveillance
Of Evidence
Effectiveness
The public health approach
How would we go about collecting information on
measurable clinical outcomes (morbidity/mortality)
in a diverse population (elderly, children,
different ethnicities)?
Observational studies
Randomized clinical trials (RCTs)
Large practical trials (PCTs)

89
Public Health Approach to the real world
effectiveness of pharmacogenomics

Evidence Integrating Surveillance
Of Evidence
Effectiveness
Observational (cohort or case-control) studies
Cyp450
Depression
(Rate of) good outcome (Rate of) bad outcome
() anti-dep a b
() anti-dep - c d
Cyp450 --
Depression
(Rate of) good outcome (Rate of) bad outcome
() anti-dep a b
() anti-dep - c d

90
Public Health Approach to the real world
effectiveness of pharmacogenomics

Observational (cohort or case-control) studies
Cyp450
Depression
(Rate of) good outcome (Rate of) bad outcome
() anti-dep a b
() anti-dep - c d
Cyp450 --
Depression
(Rate of) good outcome (Rate of) bad outcome
() anti-dep a b
() anti-dep - c d
Advantage Data is easily available
(relatively)
Comparison by gene group is relatively
unbiased
Disadvantage Sample size limitations when
stratifying additionally by elderly, by
children, by other medications, by ethnic groups,
etc.

91
Public Health Approach to the real world
effectiveness of pharmacogenomics

Evidence Integrating Surveillance
Of Evidence
Effectiveness
Randomized Clinical Trials allow you to enroll
based on gene status
cyp450 Asthma
(Rate of) good outcome (Rate of) bad outcome
() anti-depl a b
() anti-dep - c d
cyp450 -- Asthma
(Rate of) good outcome (Rate of) bad outcome
() anti-depl a b
() anti-dep - c d

92
Public Health Approach to the real world
effectiveness of pharmacogenomics

Evidence Integrating Surveillance
Of Evidence
Effectiveness
Randomized Clinical Trials allow enrollment based
on gene status
Problems with generalizability and sample size
requirements has led to concept of Large
Practical Clinical Trials
Objective To enroll many (gt100,000) people in
trial randomized at patient (or clinic/provider)
level
Will allow for head to head comparisons of
commonly used medications
For pharmacogenomics, can study not only
does statin A work better than statin B, but
also
are there haplotypic groups whereby statin A
works best for haplotypic group A, while statin
B works best for haplotypic group B?

93
Public Health Approach to the real world
effectiveness of pharmacogenomics

Evidence Integrating Surveillance
Of Evidence
Effectiveness
Large Practical Clinical Trials
Head to head comparisons of commonly used
medications
Can study not only does statin A work better
than statin B, but also
are there haplotypic groups whereby statin A
works best for haplotypic group A, while statin
B works best for haplotypic group B?
Utilizing the natural experiments among large
numbers
Can also study these genetic differences in drug
effectiveness among risk groups (elderly,
pediatrics, etc)
Can look at interactions with other genes, other
medications
Advantage studies looks at drug, gene and system
effects
Diadvantage very expensive to do properly, even
with observational data

94
Public Health Approach to the real world
effectiveness of pharmacogenomics

Evidence Integrating Surveillance
Of Evidence
Effectiveness
RCTs or quasi-experimental designs
What type of system is necessary to get evidence
integrated into practice?
NEEDS
Network of Researchers Organizations IRBs Data
Clinical researchers MCOs
Health care researchers BCBS/United Standards EMR
development
Biostatisticians Medicare/aid
VA

95
Public Health Approach to the real world
effectiveness of pharmacogenomics

Evidence Integrating Surveillance
Of Evidence
Effectiveness
Safety
Vaccine model
VAERS reporting
VSD (population denominator based
collaborative project)
Future registry
buccal swabs for DNA
candidate gene generation
Pharmaceutical model
AERS reporting
CERT and other population based collaborative
projects
Future? registry
buccal swabs for DNA

96
Vision into the Future Vaccine safety research
in the Era of Genomics

CDC has a critical role for integrating genomics
into vaccine safety
Infrastructure (collaborations)
Only CDC with VSD and VAERS able to identify
subjects with rare AEs
Scientists with the expertise in understanding
adverse events
Forge collaborations with genomics community
Begin to understand how genetic variation
underlies VAE
Understand how to identify people at increased
risk, and devise alternate immunization
strategies

97
How do we create the system necessary for the
optimal scientific study? Needs System Basic
science background Technology Analytic
capability Scientists Efficiencies

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