# Presentation: 679563

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

**	****Robert Davis, MD, MPH**
**Director**
**Immunization Safety Office**
**CDC**

## 			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**

**Notes:**
Bullet 2 might be a place to raise possibility of link to the BT syndromic surveillance work.

## Diphtheria		206,939		1921		1	  -99.99

**Measles****	****	****	****894,134****	****	****1941****	****	****86****	****  -99.99**
**Mumps****	****	****	****152,209****	****	****1968****	****	****352****	****  -99.76**
**Pertussis****	****	****265,269****	****	****1934****	****	****6,031****	****  -97.63**
**Polio (wild)****	****	****21,269****	****	****1952****	****	****0****	****-100.00**
**Rubella****	****	****	****57,686****	****	****1969****	****	****238****	****  -99.58**
**Cong. Rubella Synd.****	****20,000+****	****	****(1964-5)****	****	****3****	****  -99.98**
**Tetanus****	****	****	****1,560+****	****	****1948****	****	****33****	****  -97.88**
**Invasive Hib Disease****	****20,000+****	****	****1984****	****	****33****	****  -99.83**
**	****	****	****	**

**       ****Disease                   Pre-vaccine Era*           Year                     1999**        % change**

## Diphtheria		206,939		1921		1	  -99.99

**Measles****	****	****	****894,134****	****	****1941****	****	****86****	****  -99.99**
**Mumps****	****	****	****152,209****	****	****1968****	****	****352****	****  -99.76**
**Pertussis****	****	****265,269****	****	****1934****	****	****6,031****	****  -97.63**
**Polio (wild)****	****	****21,269****	****	****1952****	****	****0****	****-100.00**
**Rubella****	****	****	****57,686****	****	****1969****	****	****238****	****  -99.58**
**Cong. Rubella Synd.****	****20,000+****	****	****(1964-5)****	****	****3****	****  -99.98**
**Tetanus****	****	****	****1,560+****	****	****1948****	****	****33****	****  -97.88**
**Invasive Hib Disease****	****20,000+****	****	****1984****	****	****33****	****  -99.83**
**	****	****	****	**

**       ****Disease                   Pre-vaccine Era*           Year                     1999**        % change**

## Diphtheria		206,939		1921		1	  -99.99

**Measles****	****	****	****894,134****	****	****1941****	****	****86****	****  -99.99**
**Mumps****	****	****	****152,209****	****	****1968****	****	****352****	****  -99.76**
**Pertussis****	****	****265,269****	****	****1934****	****	****6,031****	****  -97.63**
**Polio (wild)****	****	****21,269****	****	****1952****	****	****0****	****-100.00**
**Rubella****	****	****	****57,686****	****	****1969****	****	****238****	****  -99.58**
**Cong. Rubella Synd.****	****20,000+****	****	****(1964-5)****	****	****3****	****  -99.98**
**Tetanus****	****	****	****1,560+****	****	****1948****	****	****33****	****  -97.88**
**Invasive Hib Disease****	****20,000+****	****	****1984****	****	****33****	****  -99.83**
**	****	****	****	**

**       ****Disease                   Pre-vaccine Era*           Year                     1999**        % change**

## Diphtheria		206,939		1921		1	  -99.99

**Diphtheria****	****	****206,939****	****	****1921****	****	****1****	****  -99.99**
**Measles****	****	****	****894,134****	****	****1941****	****	****86****	****  -99.99**
**Mumps****	****	****	****152,209****	****	****1968****	****	****352****	****  -99.76**
**Pertussis****	****	****265,269****	****	****1934****	****	****6,031****	****  -97.63**
**Polio (wild)****	****	****21,269****	****	****1952****	****	****0****	****-100.00**
**Rubella****	****	****	****57,686****	****	****1969****	****	****238****	****  -99.58**
**Cong. Rubella Synd.****	****20,000+****	****	****(1964-5)****	****	****3****	****  -99.98**
**Tetanus****	****	****	****1,560+****	****	****1948****	****	****33****	****  -97.88**
**Invasive Hib Disease****	****20,000+****	****	****1984****	****	****33****	****  -99.83**
**	****	****	****	**

**       ****Disease                   Pre-vaccine Era*           Year                     1999**        % change**

**	****	****	****	**
**	****	****	****	**
**Vaccine Adverse Events****	****0****	****	****	**** ****	****11,827^ ****	****  **

## 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

**Notes:**
Why is vaccine safety important?

A higher standard of safety is expected of vaccines because they are generally given to healthy persons, frequently babies and children, our most vulnerable population.

Not only are vaccines recommended to prevent disease, in many cases, they are required by law for school attendance.

Consequently, the moral duty for first do no harm in public health may exceed that of clinical medicine, because decisions affect the entire population rather than one patient at a time.  For example, if a vaccine was unknowingly contaminated with a virus as the early polio vaccines did , millions of persons could be affected.

Furthermore this lower tolerance for vaccine side effects compared to other medicines means we need to study vaccine reactions occurring as rare as one in a million doses. Such studies are costly, difficult, and less likely to be definitive.

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

## 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

**Notes:**
Why is vaccine safety important?

A higher standard of safety is expected of vaccines because they are generally given to healthy persons, frequently babies and children, our most vulnerable population.

Not only are vaccines recommended to prevent disease, in many cases, they are required by law for school attendance.

Consequently, the moral duty for first do no harm in public health may exceed that of clinical medicine, because decisions affect the entire population rather than one patient at a time.  For example, if a vaccine was unknowingly contaminated with a virus as the early polio vaccines did , millions of persons could be affected.

Furthermore this lower tolerance for vaccine side effects compared to other medicines means we need to study vaccine reactions occurring as rare as one in a million doses. Such studies are costly, difficult, and less likely to be definitive.

## Recent Research 

- But, many parents think we are asking the wrong questions
- They don’t 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

**Notes:**
Why is vaccine safety important?

A higher standard of safety is expected of vaccines because they are generally given to healthy persons, frequently babies and children, our most vulnerable population.

Not only are vaccines recommended to prevent disease, in many cases, they are required by law for school attendance.

Consequently, the moral duty for first do no harm in public health may exceed that of clinical medicine, because decisions affect the entire population rather than one patient at a time.  For example, if a vaccine was unknowingly contaminated with a virus as the early polio vaccines did , millions of persons could be affected.

Furthermore this lower tolerance for vaccine side effects compared to other medicines means we need to study vaccine reactions occurring as rare as one in a million doses. Such studies are costly, difficult, and less likely to be definitive.

- 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’

**Notes:**
Why is vaccine safety important?

A higher standard of safety is expected of vaccines because they are generally given to healthy persons, frequently babies and children, our most vulnerable population.

Not only are vaccines recommended to prevent disease, in many cases, they are required by law for school attendance.

Consequently, the moral duty for first do no harm in public health may exceed that of clinical medicine, because decisions affect the entire population rather than one patient at a time.  For example, if a vaccine was unknowingly contaminated with a virus as the early polio vaccines did , millions of persons could be affected.

Furthermore this lower tolerance for vaccine side effects compared to other medicines means we need to study vaccine reactions occurring as rare as one in a million doses. Such studies are costly, difficult, and less likely to be definitive.

## 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

**Notes:**
Why is vaccine safety important?

A higher standard of safety is expected of vaccines because they are generally given to healthy persons, frequently babies and children, our most vulnerable population.

Not only are vaccines recommended to prevent disease, in many cases, they are required by law for school attendance.

Consequently, the moral duty for first do no harm in public health may exceed that of clinical medicine, because decisions affect the entire population rather than one patient at a time.  For example, if a vaccine was unknowingly contaminated with a virus as the early polio vaccines did , millions of persons could be affected.

Furthermore this lower tolerance for vaccine side effects compared to other medicines means we need to study vaccine reactions occurring as rare as one in a million doses. Such studies are costly, difficult, and less likely to be definitive.

## 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

**Notes:**
Why is vaccine safety important?

A higher standard of safety is expected of vaccines because they are generally given to healthy persons, frequently babies and children, our most vulnerable population.

Not only are vaccines recommended to prevent disease, in many cases, they are required by law for school attendance.

Consequently, the moral duty for first do no harm in public health may exceed that of clinical medicine, because decisions affect the entire population rather than one patient at a time.  For example, if a vaccine was unknowingly contaminated with a virus as the early polio vaccines did , millions of persons could be affected.

Furthermore this lower tolerance for vaccine side effects compared to other medicines means we need to study vaccine reactions occurring as rare as one in a million doses. Such studies are costly, difficult, and less likely to be definitive.

- 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***_

**Notes:**
Why is vaccine safety important?

A higher standard of safety is expected of vaccines because they are generally given to healthy persons, frequently babies and children, our most vulnerable population.

Not only are vaccines recommended to prevent disease, in many cases, they are required by law for school attendance.

Consequently, the moral duty for first do no harm in public health may exceed that of clinical medicine, because decisions affect the entire population rather than one patient at a time.  For example, if a vaccine was unknowingly contaminated with a virus as the early polio vaccines did , millions of persons could be affected.

Furthermore this lower tolerance for vaccine side effects compared to other medicines means we need to study vaccine reactions occurring as rare as one in a million doses. Such studies are costly, difficult, and less likely to be definitive.

## 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**

## Goals:

**To understand the genetic variations that predispose children, adolescents or adults to vaccine adverse events or vaccine failure**

## 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**

## 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**

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

**Needs:**
**System**
**Basic science background**
**Technology**
**Analytic capability**
**Scientists**
**Efficiencies**

## 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**

## 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)

- Vaccination
- Records

- Health
- Outcomes
- (Hospital)
- (ER)
- (Clinic)

- Patient
- Characteristics
- (Birth records)
- (Census)

- VSD Linked
- Analysis Database

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

**Needs:**
**System**
**Basic science background**
**Technology**
**Analytic capability**
**Scientists**
**Other: Efficiencies**

## 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**
**	**

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

**Needs:**
**System**
**Basic science background**
**Technology**
**Analytic capability**
**Scientists**
**Other: Efficiencies**

## 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**

## 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**

## 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**
**	**

## 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**

## 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/genetic epidemiologists to analyze data**
**	**
**	**

## 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**

## 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 **

## 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**

## Vaccine Safety Case Study:Rheumatoid Arthritis and Hepatitis B Vaccine 

## Chronic autoimmune disease
Population prevalence of 1-2% worldwide
Over 7 million affected in U.S.
<50% 5 year survival rate among most severely affected

- Population prevalence of 1-2% worldwide
- Over 7 million affected in U.S.
- <50% 5 year survival rate among most severely affected

**Rheumatoid Arthritis: Background**

## 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

- 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

**Why study genetics & vaccination with regard to rheumatoid arthritis?**

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

**Study Question**

## 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?

- 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?

**Study design options:**

## 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 12/31/99|Computer Definition of Possible RA Cases|Chart Review of Possible RA Cases|Rheumatologist Review of Selected Cases todetermine if chart review is adequate to satisfy1987 ACR criteria for RA|       Data analysis (initial Kaiser retrospective study)Obtain permission from NCK personal physicians to contact RA patients|Pts. Invited to Enroll in RA-HBV Genetic Studies|Pts. Consented for Study, Blood Drawn|Blood Shipped, Fed Express, o/n to Atlanta|HLA and Hepatitis Antibody Testing|Data Analysis(genetic case-only substudy)

## 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 75:330

## Slide 42

## Power calculations for gene-environment study of RA, hepatitis B vaccination, and HLA-polymorphismsIf:Genetic risk (HLA-DR4) OR  = 5 (conservative)Environmental risk (HBV) OR = 2 (likely over-estimate)And:If 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	 		

## 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 intussusception;GBS**
**Run genome-scans (500K chips or higher) on cases **
**	****Compare with standard age, HMO, race matched controls**
**	**
** **

## 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 intussusception;GBS**
**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**
** **
** **

## 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

## 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

**Notes:**
Why is vaccine safety important?

A higher standard of safety is expected of vaccines because they are generally given to healthy persons, frequently babies and children, our most vulnerable population.

Not only are vaccines recommended to prevent disease, in many cases, they are required by law for school attendance.

Consequently, the moral duty for first do no harm in public health may exceed that of clinical medicine, because decisions affect the entire population rather than one patient at a time.  For example, if a vaccine was unknowingly contaminated with a virus as the early polio vaccines did , millions of persons could be affected.

Furthermore this lower tolerance for vaccine side effects compared to other medicines means we need to study vaccine reactions occurring as rare as one in a million doses. Such studies are costly, difficult, and less likely to be definitive.

## 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

**Notes:**
Why is vaccine safety important?

A higher standard of safety is expected of vaccines because they are generally given to healthy persons, frequently babies and children, our most vulnerable population.

Not only are vaccines recommended to prevent disease, in many cases, they are required by law for school attendance.

Consequently, the moral duty for first do no harm in public health may exceed that of clinical medicine, because decisions affect the entire population rather than one patient at a time.  For example, if a vaccine was unknowingly contaminated with a virus as the early polio vaccines did , millions of persons could be affected.

Furthermore this lower tolerance for vaccine side effects compared to other medicines means we need to study vaccine reactions occurring as rare as one in a million doses. Such studies are costly, difficult, and less likely to be definitive.

## Slide 49

## 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

## 

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)

**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)**

## 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)

## 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.

## 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

## Evaluation of high risk strata (effect modifiers):

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

## 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

## 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

## 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

## 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

## 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)

## 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

## 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
- Planning for further studied underway

**Notes:**
Why is vaccine safety important?

A higher standard of safety is expected of vaccines because they are generally given to healthy persons, frequently babies and children, our most vulnerable population.

Not only are vaccines recommended to prevent disease, in many cases, they are required by law for school attendance.

Consequently, the moral duty for first do no harm in public health may exceed that of clinical medicine, because decisions affect the entire population rather than one patient at a time.  For example, if a vaccine was unknowingly contaminated with a virus as the early polio vaccines did , millions of persons could be affected.

Furthermore this lower tolerance for vaccine side effects compared to other medicines means we need to study vaccine reactions occurring as rare as one in a million doses. Such studies are costly, difficult, and less likely to be definitive.

## 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

**Notes:**
Why is vaccine safety important?

A higher standard of safety is expected of vaccines because they are generally given to healthy persons, frequently babies and children, our most vulnerable population.

Not only are vaccines recommended to prevent disease, in many cases, they are required by law for school attendance.

Consequently, the moral duty for first do no harm in public health may exceed that of clinical medicine, because decisions affect the entire population rather than one patient at a time.  For example, if a vaccine was unknowingly contaminated with a virus as the early polio vaccines did , millions of persons could be affected.

Furthermore this lower tolerance for vaccine side effects compared to other medicines means we need to study vaccine reactions occurring as rare as one in a million doses. Such studies are costly, difficult, and less likely to be definitive.

## 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

**Notes:**
Why is vaccine safety important?

A higher standard of safety is expected of vaccines because they are generally given to healthy persons, frequently babies and children, our most vulnerable population.

Not only are vaccines recommended to prevent disease, in many cases, they are required by law for school attendance.

Consequently, the moral duty for first do no harm in public health may exceed that of clinical medicine, because decisions affect the entire population rather than one patient at a time.  For example, if a vaccine was unknowingly contaminated with a virus as the early polio vaccines did , millions of persons could be affected.

Furthermore this lower tolerance for vaccine side effects compared to other medicines means we need to study vaccine reactions occurring as rare as one in a million doses. Such studies are costly, difficult, and less likely to be definitive.

## The Road to a Public Health Approach to Pharmacogenomics will be a long and raucous journey

**Notes:**
If you bring up the link to syndromic surveillance at this point, I’d make the point that the programs being constructed, e.g., by us, will facilitate rapid assessment of outcomes, which would need to be married to rapid ascertainment of immunizations.  I WONDER IF I SHOULD DELETE THIS SLIDE delete

## 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)

**Notes:**
Why is vaccine safety important?

A higher standard of safety is expected of vaccines because they are generally given to healthy persons, frequently babies and children, our most vulnerable population.

Not only are vaccines recommended to prevent disease, in many cases, they are required by law for school attendance.

Consequently, the moral duty for first do no harm in public health may exceed that of clinical medicine, because decisions affect the entire population rather than one patient at a time.  For example, if a vaccine was unknowingly contaminated with a virus as the early polio vaccines did , millions of persons could be affected.

Furthermore this lower tolerance for vaccine side effects compared to other medicines means we need to study vaccine reactions occurring as rare as one in a million doses. Such studies are costly, difficult, and less likely to be definitive.

## 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 < 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 > 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

## 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 => 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"

## 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

**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**

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

## Institute of Medicine (IOM) Reports on Vaccine Safety

**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**

## 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

## Advantages of HMOs for Health Research

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

## 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

## 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

## 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

## 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

## 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

## Research in Managed Care Organizations: Conclusions

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

## The Public Health Approach to Pharmacogenomics

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

**Notes:**
If you bring up the link to syndromic surveillance at this point, I’d make the point that the programs being constructed, e.g., by us, will facilitate rapid assessment of outcomes, which would need to be married to rapid ascertainment of immunizations.  I WONDER IF I SHOULD DELETE THIS SLIDE delete

## 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**

**Notes:**
If you bring up the link to syndromic surveillance at this point, I’d make the point that the programs being constructed, e.g., by us, will facilitate rapid assessment of outcomes, which would need to be married to rapid ascertainment of immunizations.  I WONDER IF I SHOULD DELETE THIS SLIDE delete

## 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****	****	****	****	****	**** **
**	**

**Notes:**
If you bring up the link to syndromic surveillance at this point, I’d make the point that the programs being constructed, e.g., by us, will facilitate rapid assessment of outcomes, which would need to be married to rapid ascertainment of immunizations.  I WONDER IF I SHOULD DELETE THIS SLIDE delete

## 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**
**	**

**Notes:**
If you bring up the link to syndromic surveillance at this point, I’d make the point that the programs being constructed, e.g., by us, will facilitate rapid assessment of outcomes, which would need to be married to rapid ascertainment of immunizations.  I WONDER IF I SHOULD DELETE THIS SLIDE delete

## 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?**
**	**

**Notes:**
If you bring up the link to syndromic surveillance at this point, I’d make the point that the programs being constructed, e.g., by us, will facilitate rapid assessment of outcomes, which would need to be married to rapid ascertainment of immunizations.  I WONDER IF I SHOULD DELETE THIS SLIDE delete

## 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**
**	**

**Notes:**
If you bring up the link to syndromic surveillance at this point, I’d make the point that the programs being constructed, e.g., by us, will facilitate rapid assessment of outcomes, which would need to be married to rapid ascertainment of immunizations.  I WONDER IF I SHOULD DELETE THIS SLIDE delete

## 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)**
**	**

**Notes:**
If you bring up the link to syndromic surveillance at this point, I’d make the point that the programs being constructed, e.g., by us, will facilitate rapid assessment of outcomes, which would need to be married to rapid ascertainment of immunizations.  I WONDER IF I SHOULD DELETE THIS SLIDE delete

## 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**
**	**

**Notes:**
If you bring up the link to syndromic surveillance at this point, I’d make the point that the programs being constructed, e.g., by us, will facilitate rapid assessment of outcomes, which would need to be married to rapid ascertainment of immunizations.  I WONDER IF I SHOULD DELETE THIS SLIDE delete

## 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. **
**	**

**Notes:**
If you bring up the link to syndromic surveillance at this point, I’d make the point that the programs being constructed, e.g., by us, will facilitate rapid assessment of outcomes, which would need to be married to rapid ascertainment of immunizations.  I WONDER IF I SHOULD DELETE THIS SLIDE delete

## 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**
**	**

**Notes:**
If you bring up the link to syndromic surveillance at this point, I’d make the point that the programs being constructed, e.g., by us, will facilitate rapid assessment of outcomes, which would need to be married to rapid ascertainment of immunizations.  I WONDER IF I SHOULD DELETE THIS SLIDE delete

## 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 (>100,000) 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****”?**
**	**
**	**
**	**

**Notes:**
If you bring up the link to syndromic surveillance at this point, I’d make the point that the programs being constructed, e.g., by us, will facilitate rapid assessment of outcomes, which would need to be married to rapid ascertainment of immunizations.  I WONDER IF I SHOULD DELETE THIS SLIDE delete

## 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****	****	**
**	**

**Notes:**
If you bring up the link to syndromic surveillance at this point, I’d make the point that the programs being constructed, e.g., by us, will facilitate rapid assessment of outcomes, which would need to be married to rapid ascertainment of immunizations.  I WONDER IF I SHOULD DELETE THIS SLIDE delete

## 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**
**	**

**Notes:**
If you bring up the link to syndromic surveillance at this point, I’d make the point that the programs being constructed, e.g., by us, will facilitate rapid assessment of outcomes, which would need to be married to rapid ascertainment of immunizations.  I WONDER IF I SHOULD DELETE THIS SLIDE delete

## 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**
**	****	****	****candidate gene generation**
**	**

**Notes:**
If you bring up the link to syndromic surveillance at this point, I’d make the point that the programs being constructed, e.g., by us, will facilitate rapid assessment of outcomes, which would need to be married to rapid ascertainment of immunizations.  I WONDER IF I SHOULD DELETE THIS SLIDE delete

## 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

**Notes:**
Why is vaccine safety important?

A higher standard of safety is expected of vaccines because they are generally given to healthy persons, frequently babies and children, our most vulnerable population.

Not only are vaccines recommended to prevent disease, in many cases, they are required by law for school attendance.

Consequently, the moral duty for first do no harm in public health may exceed that of clinical medicine, because decisions affect the entire population rather than one patient at a time.  For example, if a vaccine was unknowingly contaminated with a virus as the early polio vaccines did , millions of persons could be affected.

Furthermore this lower tolerance for vaccine side effects compared to other medicines means we need to study vaccine reactions occurring as rare as one in a million doses. Such studies are costly, difficult, and less likely to be definitive.

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