# Presentation: 483605

## Cutting edge safety systems- The Danish example -

**Mads Melbye**
**Statens Serum Institut, **
**Copenhagen, Denmark**

## Agenda

- Unique opportunities for postlicensure research in Denmark
- In 2001, initiative to study postlicensure epidemiology of childhood vaccination
- Recent postlicensure studies of effectiveness and safety

## Unique possibilities for

**Unique possibilities for**
**for epidemiological **
**research in Denmark**

## The Danish registries are unique

**The Danish registries are unique**
** ****an investment worth billions of Danish kroner**
** ****Follow the individual from birth to grave**
** ****follow diseases through generations (gene/environment)**
** ****millions of individuals **
** ****results are robust**

**CRS-number**

**Birth characteristics**
**Diseases**
**Prescribed medication**
**Vaccinations**
**Childcare facilities**
**School performance**
**Family, place of living**
**Education, employment**
**Biological specimens**

## Two important recent contributions

**Two important recent contributions**

## The new initiative 1

- Financial support to establish sections at Statistics Denmark (socio-economic, demographic) and the National Board of Health (diseases, health care parameters) that only facilitate registry research
- Low costs for data
- Cut delivery time to below 2 months
- On-line assess to Statistics Denmark from research milieu
- Data linkages made available to other researchers for free (internet)

## New initiative 2

- Stored biological specimens defined as a registry – means rules for registry research aply (”persondataloven”)
- Opt out register
- Biological specimens involved – aplication to scientific ethics committee
- Unless important to the individual’s health – informed consent not always requested.

## Initiative to study postlicensure epidemiology of childhood vaccination in 2001

## Childhood Vaccination in Denmark 

**Danish childhood vaccination program**
-  **Voluntary**
** ****Free of charge to the vaccinees**
** ****Statens Serum Institut mandated by law to supply the vaccines to the childhood program – all children vaccines from same manufacturer **

**Vaccines today**
-  **DTaP-IPV / Hib, 3,5, and 12 m**
** ****MMR, 15 m, and 12 yr**
** ****DTaP-IPV booster, 5 yr**
**Major changes in 1990s**
-  **Introduction of Hib, 1993**
** ****Whole cell P -> Acell. P, 1997**
** ****OPV -> IPV, 2003 **

## Childhood vaccination database

- Family doctor

- Bill with details

- National Health  Insurance,
- National Board of Health

- Payment to MD

- All registrations

- +

- Information from
- other registries

- National
- Vaccination Register
- 1990-2007
- (the only in the world)
- Type, dose, date, crs-number

## Exposure

**CRS-Number**

**Childhood**
**Vaccination**
**Database**

**Hospital**
**Discharge**
**Registry**

**Psychiatric**
**Registry**

**Birth**
**Registry**

**CPR Registry – **
**Demography**

** ****Statistics**
** ****Denmark –**
** ****Socio-economic**

**Exposure**

**Outcome**

**Potential confounders**

**School**
**performance**

## Epidemiological Study Designs 

** ****Randomized Clinical Trial**
** ****Cohort study - individual-level**
** ****(Self-controlled case-series method)**
** ****Case-control **
** **
**Cohort study - population-level**
** ****Ecological designs **
** ****Other case-series methods **

**No evidence with  respect**
**to causality**

**Weak evidence with **
**respect to causality**

**Evidence with respect to**
**causality**

**Notes:**
Differentgial misclassification ,- spurious associations, non-differential misclassification –mask associations

## Short examples of postlicensure studies

**Effectiveness**
**Herd immunity**
**Booster strategy considerations**
**Safety**

## Cohort Design and Methodology

**Cohort Design and Methodology**

-  N = 500,000  -  1,000,000 children

|  | Cases | Person-years at risk |
| --- | --- | --- |
| Unvaccinated |  |  |
| Vac |  |  |
|    1.dose |  |  |
|    2.dose | 1 | 31⁄2 |
|    3.dose |  |  |

**   ****Poisson regression**

|  | Rate ratio | 95% CI
 |
| --- | --- | --- |
| Unvaccinated | 1 | Referent |
| Vac |  |  |
|    1.dose |  |  |
|    2.dose |  |  |
|    3.dose |  |  |

- OR DEATH,
- EMIGRATION,
- END OF
- FOLLOW-UP,
- WHICHEVER
- FIRST

## Impact of Hib vaccination

- PRP-T Vaccine introduced May 1993
- 542,100 children followed from birth or 1 January, 2001, whichever occurred last
- 2,664,040 person-years of follow-up
- Meningitis (Hib, other) from National Hospital Discharge Registry
- 141 Hib meningitis cases (94 before, 47 after vaccination introduced)
- Risk/confounding factors:  BW, gestational age,
- 	birth complications, birth order, season, gender

## Hib Vaccine Effectiveness

|  | # cases | Person 
years | Vaccine effectiveness against Hib meningitis (95% CI) |
| --- | --- | --- | --- |
| Hib vaccination |  |  |  |
| one dose | 2 | 499,296 | 97.7 (90.8-99.5) |
|  two doses | 2 | 549,149 | 98.9 (95.7-99.7) |
|    three doses | 1 | 770,250 | 99.3 (94.9-99.9) |

## Relative risk of Hib meningitis in unvaccinated children after introduction of Hib vaccination

## Impact of pre-school booster vaccination on pertissus in 0-1 year-old children

- Cohort of all children born in Denmark, 1977-2001
- Place of residence to identify household members and their vaccination history
- Rate ratios of pertussis hospitalisations according to number, age, and vac status of household mmbers
- Estimated the preventable proportion of hospitalisations among 0-1 year-old-children according to age at booster (4-6 years), booster uptake, and efficacy of the booster against transmission

## RR for pertussis hospitalisation in children born 1990-2001

|  | Rate Ratio | 95% CI |
| --- | --- | --- |
| Living without other children | 1 |  |
| Living with one other child fully vaccinated (age) |  |  |
|     0-1 year | 0.94 | 0.53-1.69 |
|     2 years | 1.57 | 1.16-2.14 |
|     3 years | 2.13 | 1.60-2.83 |
|     4 years | 2.02 | 1.38-2.94 |
|     5 years | 2.84 | 1.79-4.51 |
|     6-8 years | 2.99 | 1.81-4.92 |
|     9-11 years | 1.45 | 0.20-10.39 |

## RR for pertussis hospitalisation before 2 years of age and living with one other child

**Booster vaccination**
- Preventable proportion
- of hospitalisations:
- 7%-33%
- Most realistic scenario:
- 18%

## MMR and Autism

**MMR and Autism**

-  Wakefield and others: ”MMR increases risk of autism”

-  Cohort of all Danish children born between 1991-98
-  N = 537,303, 2.1 mill. Person-years of follow-up
-  738 cases of Autistic Spectrum Disorders (316 w/autism)

_**Autistic Disorder**_,
- MMR +/-
- RR: **0.92 (**0.68 – 1.24)

_**Other Spectrum Disorders**_,
- MMR +/-
- RR: **0.83** (0.65 – 1.07)

- No association between: age at time of vaccination,
- time since vaccination, date at vaccination,
- and autism or other spectrum disorders

## Childhood Vaccination and Non-targeted Infections

**Childhood Vaccination and Non-targeted Infections**

-  To many antigens overwhelms the immunesystem
-  Vaccination increases risk of non-targeted inf.

-  N = 805,206, 2,9 mill person-years of follow-up
-  84,317 cases of infectious disease hospitalizations

- - **No increased risk of non-targeted infections after              vaccination**

## Diarrhea 

**Diarrhea **

- Adjusted for age, calendar period and other vaccinations

**Vaccination**

- Yes / No

- Trend (within)

## Flue vaccine 

- New regulative: Flue vaccinations electronically recorded to enable effectiveness and safety sudies

## Acknowledgement

- Anders Hviid
- Jan Wohlfart
- Michael Stellfeld
- Kreesten Madsen
- Mogens Vestergaard

## Some referencesContact: mme@ssi.dk

**Association between thimerosal-containing vaccine and autism**.
- JAMA 2003;290:1763-6.
**Childhood vaccination and type 1 diabetes**.
- N Engl J Med 2004;350:1398-404.
**Childhood vaccination and nontargeted infectious disease hospitalization**. JAMA 2005;294:699-705.
**A population-based study of measles, mumps, and rubella vaccination and autism**. N Engl J Med 2002;347:1477-82.
**MMR vaccination and febrile seizures: evaluation of susceptible subgroups and long-term prognosis**. JAMA 2004;292:351-7.
**Postlicensure epidemiology of childhood vaccination: the **
**Danish experience**. Expert Rev Vaccines 2006 October;5(5):641-9.

**Some references****Contact: mme@ssi.dk**

## Cohort of 101,000 pregnant women and offsprings

**Science, 11 juli 2003**

- Ongoing follow-up
- of children at
- age 7 years

## Rate ratio for pertussis hospitalisation in children born 1977-2001

|  | Rate Ratio | 95% CI |
| --- | --- | --- |
| Not living with other children | 1 |  |
| Living with one other child | 2.37 | 2.12-2.65 |
| Living with two other children | 3.89 | 3.41-4.43 |
| Living with three other children | 4.21 | 3.47-5.10 |
| Living with four other children | 4.52 | 3.24-6.29 |
| Living with five+ other children | 5.98 | 4.14-8.64 |

## Thimerosal and Autism

-  Thimerosal, a vaccine preservative, contains mercury.
-  Mercury is neurotoxic.
-  1990s, US: More and more TCVs.
-  TCVs increases risk of Autism.

-  N = 470,000
-  1,227 cases of Autistic Spectrum Disorders

_**Autistic Disorder**_,
- TCV +/-
- RR: **0.85 (**0.60 – 1.20)

_**Other Spectrum Disorders**_,
- TCV +/-
- RR: **1.12 (**0.88 – 1.43)

## MMR and Febrile Seizures

**MMR and Febrile Seizures**

-  Fever occurs in 7% of MMR vaccinated children
-  ”MMR increases risk of Febrile Seizures”

-  N = 540,000
-  17,986 cases of Febrile Seizures

_**2 weeks following MMR**_
- RR: **2.75 (**2.55 – 2.97)

_**Susceptible subgroups**_
- None identified.

_**Risk of reccurence**_
- MMR +/-
- RR: **1.19 (**1.01-1.10)

_**FS and Epilepsy**_
- MMR +/-
- RR: **0.70 (**0.33-1.50)

## Childhood Vaccination and Type 1 Diabetes

**Childhood Vaccination and Type 1 Diabetes**

-  Temporal associations
-  Infections, immuno-modulation.
-  Vaccination increases risk of Type 1 Diabetes

-  N = 740,000
-  681 cases of Type 1 Diabetes

- - **No increased risk of T1D**
**- No clustering of T1D in periods following vaccination.**
**- No increased risk of T1D among children with at least one T1D sibling**