# Presentation: 169147

## Vaccine Safety in the Genomics Era

**	**Robert Davis, MD, MPH
- Director of Research
- Center for Health Research, SE

## Vaccine Safety & Genomics

- Why are these two concepts being discussed together at a meeting about post-marketing surveillance?
- After all, vaccines are the ultimate mechanism for public health prevention
- While genomics represents the ultimate mechanism for individualized, personal medicine

**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.

## Vaccine safety and Genomics 

- Personalized medicine & personalized drug delivery under intense study by NIH and industry
- Drugs have different effect by genotype:
- Beta blockers for CHF
- Beta agonists for asthma/RAD
- Metformin for diabetes
- Cyp450 variation and heparin response
- HMGCR gene variant and response to statins
- Large incentive for investment
- Physicians – better therapy
- Legal – reduced adverse events
- Industry – personalized medicine/market share
- Academia – NIGMS; NHGRI; NHLBI, NIDDK, etc

**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.

## Vaccine Safety and Genomics

- Conversely, ‘personalized vaccine delivery’ not under intense study by CDC, NIH or industry.  Why not?
- Patients, doctors and legal system will expect it
- Public vaccine policy will not be able to ignore individual variation in response to newly developed vaccines
- Major reason has to do with frequency of VAE

## Vaccine Safety and Genomics

- Whereas CHF and MI (for ex) are relatively common, and the frequency of genetic variants that affect CHF or asthma therapy may be >10%, the major vaccine problems to affect vaccine delivery are extremely rare:
- GBS and swine flu vaccniation: ~national investigation
- Intussusception and RVV: ~multi-state investigation
- Myocarditis and smallpox vaccination: ~DoD investigation
- GBS after MCV4: ~ required creation of MCO consortium ~100 million lives

## Vaccine Safety and Genomics

- Additionally, there are questionable alignment of incentives for investment
- While:
- Physicians – better reassurance for patients
- Legal – reduced adverse events
- But:
- AEs too rare for most pre-marketing and even post-marketing study of genetic predisposition – low incentive for industry
- Low incentive for NIH funding due to rarity of AE (exception smallpox & anthrax vaccine)

## Vaccine Safety and Genomics   

- 	Leads to:
- Present situation of recurrent major VAE disasters that substantially affect vaccine policy in US/worldwide and lead to increased development costs; patient/doctor dissatisfaction and public suspicion
- Public, legal and medical expectation for identifying persons at increased risk and preventing VAE, along with capability to do so (= drug development)
- Extreme rarity of VAE, and lack of incentive alignment,
- Conclusion that federal agencies (CDC; FDA) with *national surveillance capabilities* will need to play a critical role in identifying these serious, but rare events.

**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.

## Vaccine Safety and Genomics

- FDA and CDC, with VSD and VAERS, are the governmental entities able to identify sufficient numbers of subjects with rare AEs

## How possible is this under the current systems?

**Passive System:**
**	****VAERS (Vaccine Adverse Events Reporting System)**
**	****	****	****Passively reported VAE**
**	****	****	****Contact of reporting system common**
**	****	****	****Contact of patient is possible**
**	****	****	****No current routine collection of biologic specimens ****	****	**
**Active system:**
**	****Vaccine Safety Datalink****	**
**	****Can perform active and timely identification for selected ****	****VAEs**
**	****Would potentially ascertain the full range of disease**
**	****Contact of patient possible**
**	****No routine collection of biologic specimens**

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

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

**VAERS****	****	****	****	****	****	****	****	****	****	****	****	****	****VSD**
**	****	****	****	****	****	****	****	****	****	****	****	****     ****or Consortium**
**	****	****	****	****	****	****	****	****GBS**
**	****	****	****	****	****	****	****	****Myocarditis**
**	****	****	****	****	****	****	****	****Intussusception**
**	****	****	****	****	****	****	****	****Other VAE **
**	****	****	****	****	****	****	****	****	****	****(BP; sz...)**

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

**Patients with these VAE (GBS, myocarditis) would be routinely and systematically identified, contacted and approached for biologic samples (ie saliva by mail)**
**Data would be deidentified and could be made available for analysis by competitive process**
**	**
**If specific genes or haplotypes are identified that substantially increase risk for VAE**
**	****Could incorporate into future screening process**
**	****Could offer alternative vaccination or disease prevention ****	****strategies**
***Given long lag time for data collection for rare conditions, studies now may take 5-10 years to pay off***

## Vaccine Safety in the Genomics Era
Vision for the Future:

**Vision for the Future:**

**Screen VAERs reports and 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**
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