Tania Schink Edeltraut Garbe

BIPS ‒ Institute for Epidemiology and Prevention Research

28th ICPE. 23-26 August 2012, Barcelona

Risk of Febrile Convulsions after MMRV Vaccination in Comparison to MMR- or

MMR+V-Vaccination

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• This study was funded by GalxoSmithCline. The authors had complete autonomy for the process of establishing the protocol, carrying out the analyses and interpreting the results. This also includes the full right to publish the results without limitation.

• EG is running and TS is working for a department that occasionally performs studies for pharmaceutical industries. These companies include Bayer, Celgene, GlaxoSmithKline, Mundipharma, Novartis, Sanofi-Aventis, Sanofi Pasteur MDS, and STADA

• EG has been a consultant to Bayer-Schering, Nycomed, Teva and Novartis.

• EG is a member of the German Standing Vaccination Committee (Ständige Impfkommission, STIKO).

Disclosures

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• Febrile convulsions (FC) are seizures associated with a significant rise in body temperature

• Often attended by loss of consciousness

• Mostly in children between 6 months to 6 years, twice as common in boys as in girls

• 1st FC: hospitalization to exclude epilepsy or meningitis

• Good prognosis

Background: FC

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• Vaccination against measles-mumps-rubella (MMR) for children well established

− often: immunization against varicella on the same day

• August 2006: Launch of quadrivalent vaccine Priorix-Tetra® against measles-mumps-rubella-varicella (MMRV) in Germany

• 1st dose 11.-14. month, 2nd dose 15.- 23. month (> 4 weeks in between)

• Advantages: − less injections and thus less injection complications

− higher coverage of V

Background: MMRV

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• Increased risk of FC observed with quadrivalent vaccine ProQuad® against MMRV:

− Jacobsen et al. (2009): RR = 2.20 (1.04 – 4.65), 5 – 12 days after immunization

− Klein et al. (2010): RR = 1.98 (1.43 – 2.73), 7 – 10 days after immunization

• Metaanalysis based on 10 RCTs in children < 3 years − 7,317 subjects who received MMRV compared to 4,455

subjects who received MMR or MMR and V separately on the dame day (MMR+V)

− Primary analysis: FC between day 5 and 12 regardless of dose: RR = 3.96 (0.78 – 38.87)

− Secondary analysis: FC between day 5 and 12 after 1st dose: RR= 7.18 (0.91 – 327.9)

Background: MMRV

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• Retrospective matched cohort study − MMRV to MMR

− MMRV to MMR+V

• Matching 1:1 for − sex

− age at vaccination (± 1 month),

− calendar month of vaccination (± 1 month)

− SHI

• Study period: 1.1.2006 – 31.12.2008

Methods: Study Design

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• Data source: German Pharmacoepidemiological Research Database (GePaRD)

− > 15 million insurants from 4 statutory health insurances (SHI)

− hospitalizations, ambulatory diagnoses, drug dispensations, outpatient (EBM codes) and inpatient procedures (OPS codes)

− outpatient diagnoses lack exact date (only related to quarter) → not suitable for outcome definition

Methods: Data Source

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• Inclusion criteria − children born between 1.1.2004 - 31.12.2008 − entry into SHI within 180 days of birth − first vaccination with one of the index vaccines: MMRV,

MMR, MMR+V

• Cohort entry: date of first immunization • Cohort exit:

− 91 days after vaccination

− interruption or end of insurance

− end of study period

Methods: Cohort

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• Primary outcome − hospitalization for FC with no plausible other

cause of FC (e.g. infection or neurological condition) coded as main discharge diagnosis (“FC narrow“)

− high specificity, fewer cases, underestimation of attributable risks (ARs)

• Secondary outcome − hospitalization for FC with no neurological

condition coded as main discharge diagnosis (“FC Jacobsen”)

− higher sensitivity, more cases

Methods: Outcome

Specificity Risk

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• Vaccine administrations identified via EBM codes − used for reimbursement of ambulatory treatments including

administration of vaccines

− prescription data could not be considered, as physicians generally use vaccines deposited in their own medical practices (“Sprechstundenbedarf”)

− EBM codes for immunizations vary between Regional Associations of SHI-Accredited Physicians (Kassenärztlichen Vereinigungen, KVs) and change over time

→ Pilot study to assess exposure coding

Methods: Exposure

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• Potential confounders − age and sex

− history of FC

− administration of other vaccines, assessed 30 days before to 30 days after index vaccination

− infectious diseases, assessed as hospitalizations for an infectious disease 15 days before to 30 after index vaccination

− neurological diseases, esp. epilepsy

− SES, SHI as proxy

Methods: Confounder

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• Risk intervals (days after vaccination):

• Statistical analyses − cumulative incidences of FC for MMRV, MMR and MMR+V

for the respective risk periods

− risk ratios and risk differences (attributable risks, ARs)

− adjusted odds ratios by multivariable logistic regression

Methods: Analysis

0 – 4 5 – 12 13 – 30

0 – 30

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Results: Flow Chart

584,745 newborns from 1.1.2004 to 31.12.2008

477,622 fulfilling inclusion criteria

82,656 (30%) MMRV

149,259 (55%) MMR

39,203 (15%) MMR+V

271,118 (57%) receiving index vaccinations

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Results: MMRV – MMR Cohort

MMRV N = 74,734

MMR N = 74,734

Sex (male, %) 38,104 (51.0%) 38,104 (51.0%)

Age (mean ± STD) 13.7 ± 4.7 months 13.8 ± 4.6 months

History of FC 578 (0.77%) 571 (0.76%)

History of epilepsy 569 (0.76%) 567 (0.76%)

Infection before vaccination 127 (0.17%) 110 (0.15%)

Cases FC Narrow 14 1.9/10,000 children

3 0.4/10,000 children

Cases FC Jacobsen 45 6.0/10,000 children

19 2.6/10,000 children

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Results: MMRV – MMR+V Cohort

MMRV N = 32,180

MMR+V N = 32,180

Sex (male, %) 16,546 (51.4%) 16,546 (51.4%)

Age (mean +/- STD) 13.0 +/- 3.4 months 12.9 +/- 3.4 months

History of FC 221 (0.69%) 188 (0.58%)

History of epilepsy 243 (0.76%) 263 (0.82%)

Infection before vaccination 65 (0.20%) 50 (0.16%)

Cases FC Narrow 5 1.6/10,000 children

1 0.3/10,000 children

Cases FC Jacobsen 21 6.5/10,000 children

14 4.4/10,000 children

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MMRV vs. MMR+V

5.3 (0.4 – 70.0) 3.5 (0.7 – 19.0) 1.5 (0.3 – 8.7)

0 – 4 5 – 12 13 – 30

MMRV vs. MMR

0.8 (0.3 – 2.5) 4.1 (1.3 – 12.7) 0.5 (0.2 – 1.4)

Results: Odds Ratios – FC Narrow

0 – 4 5 – 12 13 – 30

0 – 30

0 – 30

1.3 (0.7 – 2.4)

3.9 (1.0-14.5)

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0 – 4 5 – 12 13 – 30

0 – 4 5 – 12 13 – 30

MMRV vs. MMR

0.5 (0.2 – 1.3) 2.3 (1.4 – 3.9) 1.1 (0.7 – 1.8)

Results: Odds Ratios – FC Jacobsen

MMRV vs. MMR+V

1.1 (0.3 – 3.5) 1.5 (0.8 – 2.9) 1.6 (0.8 – 3.2)

0 – 30

0 – 30

1.4 (1.0 – 1.9)

1.5 (1.0 – 2.4)

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• Coverage of index vaccinations comparable with literature

• Small proportion of “implausible” vaccinations and unspecific coding

Discussion: Exposure

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• Pilot study: • incidences comparable with literature, • characteristics of hospitalizations for FC, coding pattern,

age- and sex distribution as expected

• Secondary outcome FC Jacobsen and other secondary outcomes as sensitivity analyses

• Only hospital diagnoses of FC, since outpatient diagnoses lack exact date (only related to quarter)

• Not all potential confounders available in desired detail

Discussion: Outcome

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• 4-5-fold increased risk of FC 5 - 12 days after 1st dose MMRV vaccination compared to MMR- or MMR+V-vaccination

• Results comparable with metaanalysis and US studies

• AR in the risk interval 5 - 12 days: − 3.5/10,000 immunizations → 1 case per 2,857 immunizations

compared to MMR

− 2.2/10,000 immunizations → 1 case per 4,545 immunizations compared to MMR+V

• Risk has to be weighted against the benefit of a high coverage of immunization against V and the increased risk of complications for two separate injections

Conclusion

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Thank you!

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0 – 4 5 – 12 13 – 30

MMRV vs. MMR

0.8 (0.2 – 3.0) 4.7 (1.3 – 16.2) 0.4 (0.1 – 1.4)

Results: Risk Ratios – FC Narrow

MMRV vs. MMR+V

. ( . – . ) 5.0 (0.6 – 42.8) 2.0 (0.2 – 22.1) 0 – 4 5 – 12 13 – 30

0 – 30

0 – 30

1.3 (0.7 – 2.4)

4.5 (1.0-20.8)

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0 – 4 5 – 12 13 – 30

0 – 4 5 – 12 13 – 30

MMRV vs. MMR

0.5 (0.2 – 1.4) 2.4 (1.3 – 4.1) 1.1 (0.7 – 1.8)

Results: Risk Ratios – FC Jacobsen

MMRV vs. MMR+V

1.3 (0.3 – 4.7) 1.5 (0.8 – 3.0) 1.5 (0.7 – 3.1)

0 – 30

0 – 30

1.4 (1.0 – 1.9)

1.5 (0.9 – 2.3)