1. FinOM Efficacy Trial of 7-Valent Pneumococcal Conjugate Vaccine Terhi Kilpi National Public Health Institute (KTL) Finland

2. 2 FinOM Study Group Principal investigator Study coordination Bacteriology Immunology Otorhinolaryngology Biostatistics Data management Virology Study clinic personnel Senior adviser Juhani Eskola, Terhi Kilpi Arto Palmu, Kari S Lankinen Elja Herva, Maija Leinonen Helena Käyhty, Heidi Åhman Pekka Karma Jukka Jokinen, Mika Lahdenkari, Jouko Verho Jaason Haapakoski, Esa Ruokokoski, Marko Grönholm Tapani Hovi Wilhelm Bredenberg, Heljä Savolainen, Ritva Syrjänen P Helena Mäkelä FinOM Vaccine Trial

3. 3 evaluated efficacy of two 7-valent pneumococcal (Pnc) conjugate vaccines for prevention of AOM due to vaccine serotypes in children less than 2 years of age clinical phase from December 1995 to March 1999 2 497 children enrolled (55 % of the birth cohort) in Tampere area

4. 4 Study design All children were randomized to receive PncCRM (Prevnar®, Prevenar®), PncOMPC, or control (HBV) vaccine at 2, 4, 6, and 12 mo Follow-up from 2 to 24 mo at the study clinic All respiratory infections requiring medical attention were evaluated and treated at the study clinic FinOM Vaccine Trial

5. 5 Definition of AOM Symptoms –At least one of the following: fever, earache, irritability, diarrhea, vomiting, acute otorrhea not caused by otitis externa, or other symptoms of respiratory infection Signs –A visually abnormal tympanic membrane (in regard of color, position and/or mobility) suggesting middle ear effusion FinOM Studies

6. 6 Acute Otitis Media (AOM) Myringotomy with aspiration performed in AOM with effusion Middle ear fluid (MEF) sample for bacterial culture, pneumococcal serotyping and pneumolysin PCR AOM episode defined to start at diagnosis and to last for 30 days FinOM Studies

7. 7 Efficacy of PncCRM against AOM Primary –All AOM episodes due to vaccine serotypes Secondary –First and subsequent AOM episodes due to vaccine serotypes Other –All Pnc AOM episodes –All AOM episodes –Recurrent AOM FinOM Vaccine Trial

8. 8 Efficacy of PncCRM against AOM Post Hoc –AOM episodes due to vaccine related serotypes (6A, 9N, 18B, 19A, 23A) –AOM episodes due to serotypes unrelated to vaccine types –AOM episodes due to individual serotypes FinOM Vaccine Trial

9. 9 Disposition of subjects FinOM Vaccine Trial

10. 10 All AOM episodes due to vaccine serotypes FinOM Vaccine Trial Primary analysis Vaccine efficacy: 57% (95% CI: 44% to 67%) Per protocol follow-up from 6.5 to 24 months of age

11. 11 First and subsequent AOM episodes due to vaccine serotypes FinOM Vaccine Trial Per protocol follow-up Secondary analysis *Per person-year

12. 12 Summary of efficacy results FinOM Vaccine Trial Per protocol follow-up from 6.5 to 24 months of age Acute Otitis Media

13. 13 Summary of efficacy results FinOM Vaccine Trial Intention to treat follow-up from 2 to 24 months of age Acute Otitis Media

14. 14 Pneumococcal AOM episodes FinOM Vaccine Trial Per protocol follow-up from 6.5 to 24 months of age Acute Otitis Media

15. 15 PCR counts* in MEF of Pnc Ply PCR positive AOM PCR counts Pnc culture negative Pnc culture positive * GM (95% CI) FinOM Vaccine Trial

16. 16 Individual vaccine serotypes FinOM Vaccine Trial Per protocol follow-up Acute Otitis Media

17. 17 Vaccine, vaccine-related and other serotypes FinOM Vaccine Trial Per protocol follow-up Acute Otitis Media

18. 18 Vaccine-related serotypes FinOM Vaccine Trial Per protocol follow-up Acute Otitis Media

19. 19 PncCRM is efficacious against –culture-confirmed, vaccine serotype specific AOM (VE: 57%) –culture-confirmed AOM due to vaccine-related serotypes (VE: 51%) –culture-confirmed pneumococcal AOM (VE: 34%) FinOM Vaccine Trial Conclusions

20. Extended follow-up FinOM Vaccine Trial

21. 21 Objectives To assess long-term effects of PncCRM on –pneumococcal carriage –antibody persistence –surgery due to OM in the routine practice after the Vaccine Trial FinOM Follow-up Study

22. 22 Methods Single follow-up visit at the age of 4 to 5 years in spring 2001 Collection of data –Parental interview –Pneumatic otoscopy –Medical records –Nasopharyngeal, blood and saliva samples FinOM Follow-up Study

23. 23 Inclusion criteria FinOM Follow-up Study

24. 24 1597 Study flow Start of long-term follow-up Children, N FinOM Vaccine Trial and Follow-up Study 65 dropped out during the trial 1662 756 1490 107 moved out of Tampere Area Age, months Fully evaluated children = Analysis population 1 Eligible children = Analysis population 2 Complete tympanostomy data available Hospital tympanostomy data available

25. 25 Case ascertainment for tube placement Fully evaluated children (Analysis population 1) –Parental interview –Hospital records from Tampere University Hospital, three district hospitals (78%) –Medical records from private physician offices for verification (22%) Eligible children (Analysis population 2) –Hospital records from Tampere University Hospital, three district hospitals FinOM Follow-up Study

26. 26 Tube placement during the Vaccine Trial Included in the study services Close follow-up in the study clinics, active treatment strategy, specific criteria for referral in the SOP Tampere University Hospital Free of charge Within 4 to 8 weeks of referral FinOM Studies

27. 27 Tube placement after the Vaccine Trial Public hospitals –Nominal charge –Waiting time 3 to 4 months –78% Private medical centers and hospitals –Charge 10 x public sector charge –No waiting time –22% FinOM Studies

28. 28 Incidence of tube placement * * National hospital discharge register and national sick insurance reimbursement database / 100 person-years * Age, years

29. 29 1597 Study flow Start of long-term follow-up Children, N FinOM Vaccine Trial and Follow-up Study 65 dropped out during the trial 1662 756 1490 107 moved out of Tampere Area Age, months Fully evaluated children = Analysis population 1 Eligible children = Analysis population 2

30. 30 Tympanostomy tube placement in fully evaluated children* FinOM Vaccine Trial and Follow-up Study Intention to treat follow-up *Per 100 person-years *Analysis population 1

31. 31 Tympanostomy tube placement in all eligible children* Intention to treat follow-up *Per 100 person-years FinOM Vaccine Trial and Follow-up Study *Analysis population 2

32. 32 Cumulative hazard of tympanostomy tube placement Start of long-term follow-up Cumulative hazard FinOM Vaccine Trial and Follow-up Study Fully evaluated children HBV PncCRM

33. 33 Cumulative hazard of tympanostomy tube placement Start of long-term follow-up Cumulative hazard FinOM Vaccine Trial and Follow-up Study All eligible children HBV PncCRM

34. 34 Kinetics of anti-23F Start of long-term follow-up  g/ml FinOM Vaccine Trial and Follow-up Study HBV PncCRM

35. 35 Kinetics of anti-19F Start of long-term follow-up  g/ml FinOM Vaccine Trial and Follow-up Study PncCRM HBV

36. 36 Kinetics of anti-6B Start of long-term follow-up  g/ml FinOM Vaccine Trial and Follow-up Study PncCRM HBV

37. 37 Long-term effect on otitis media and carriage FinOM Follow-up Study P=0.05

38. 38 PncCRM PncCRM reduces tube placement due to OM Vaccine efficacy against OM persists for several years FinOM Follow-up Study Conclusions

39. 39 Thank you