1. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 1 European Regulatory Authorities´ Perspective and View on Proving Safety and Immunogenicity of Combined Vaccines - General Aspects - - Recent experiences -

2. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 2 Multivalent Vaccines Available in the EU (I) DTPw/a - based –DTPa-IPV –DTPa/Hib –DTPa-IPV/Hib –DTPw-IPV/Hib –DTPa-IPV-HepB –DTPa-IPV-HepB/Hib –DTPa-IPV-HepB-Hib Community-MA since October 2000

3. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 3 Multivalent Vaccines Available in the EU (II) –DTPa-IPV-HepB/Hib (Infanrix - Hexa; Glaxo SmithKline) Pharmaceutical Form: Powder and suspension for suspension for injection –DTPa-IPV-HepB-Hib (Hexavac; Aventis Pasteur MSD) Pharmaceutical Form: Suspension for injection in pre-filled syringe

4. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 4 Simplifying Vaccination Schedules (I)

5. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 5 Simplifying Vaccination Schedules (II)

6. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 6 Simplifying Vaccination Schedules (III)

7. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 7 Towards a harmonised vaccination schedule for primary immunisations of infants and young children in the EU? Simplifying Vaccination Schedules (IV)

8. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 8 Other Advantages Provided by Combined Vaccines Increased compliance Increased vaccine coverage Improved vaccination documentation Reduced overall costs of vaccination campaigns Reduced storage requirements

9. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 9 Potential Quality Concerns Identified During Dossier Evaluation Cumulative stability of vaccine intermediates –seed lots –live or inactivated harvests from bacterial or viral cultures –purified harvests consisting of toxins, toxoids, polysaccharides, bacterial or viral suspensions –purified antigens –conjugated polysaccharides –final bulk vaccine –vaccine in the final closed container stored at low temperature awaiting labelling

10. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 10 Intermediate 1 Days Weeks Months Years Intermediate 2 Days Weeks Months Years Intermediate 3 Days Weeks Months Years Intermediate 4 Days Weeks Months Years Intermediate 5 Days Weeks Months Years Final Bulk Days Weeks Months Years Finished Product Years

11. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 11

12. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 12 Cumulative Stability of Vaccine Intermediates (I) Hexavalent vaccines contain 9 or 10 different antigens: –D- component1 –Pa- components2 or 3 –T- component1 –IPV- component3 –Hib component1 –HepB component1 x 2,3 or 4

13. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 13 Cumulative Stability of Vaccine Intermediates (II) CPMP/BWP/4310/00 Concept Paper on the Development of a CPMP Points to Consider on Stability and Traceability Requirements for Vaccine Intermediates

14. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 14 Potential Efficacy Concerns Identified During Dossier Evaluation (I) Combining antigens to formulate a multivalent vaccine is more than just mixing –Changes may occur in the immunogenicity due to interference of vaccine antigens –Reliable potency testing may become increasingly complicated –Do the established surrogates/correlates for protection need reconsideration?

15. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 15 Epidemiological aspects –Altered pathogen circulation Modified strains due to the use of acellular Pertussis components Invasive Hib- disease may be prevented but pathogen circulation is still ongoing due to persistent infections (carrier status) Potential Efficacy Concerns Identified During Dossier Evaluation (II)

16. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 16 The Hib Valence Are reduced anti- PRP titers before booster immunisation a risk for children in their first and second year of life (I)? –Do we need a redefinition of the cut off levels (1.0 µg/ml and 0.15 µg/ml)? –What type and quality of immune response is triggered by conjugated Hib vaccines? –Is there always an anamnestic immune response in very small children at risk even if there are no detectable anti Hib titers before the booster?

17. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 17 Are reduced anti- PRP titres before booster immunisation a risk for children in their first and second year of life (II)? The ethnic factor (Sweden) The different vaccination schedules (UK)

18. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 18 The Acellular Pertussis Valence (I) Does the number of pertussis antigens determine the clinical efficacy of acellular pertussis vaccines? Are acellular pertussis vaccines inferior to whole cell pertussis vaccines? Are anti Pa antibodies surrogates of protection? Do levels of anti Pa titres correlate with sufficient or insufficient protection from disease?

19. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 19 The Acellular Pertussis Valence (II) Is the genetic polymorphism of circulating B. pertussis strains driven by acellular pertussis vaccines with only one or two components? Does this have an epidemiological impact? Are acellular pertussis vaccines responsible for re-emerging pertussis disease?

20. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 20 Long term persistence of Hepatitis B immune protection Three dose schedule (no booster, early booster - 3, 5, 11/12 months -) Four dose schedule (booster vaccination in the second year of life)

21. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 21 Safety Aspects Fever > 39°C Inconsolable crying Severe local reactions Allergic oedema as a serious adverse reaction

22. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 22 Follow- up Measures Long- term stability testing program focussing on the age of the intermediates used Sampling and testing under the auspices of the EDQM?

23. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 23 Post - Marketing Studies Long- term epidemiological surveillance studies to monitor effectiveness of the hexavalent vaccines as well as distribution and circulation of the natural pathogens Large controlled safety studies to compare the reactogenicity profile of the hexavalent vaccines compared to the vaccine generation used before

24. 19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 24 Pharmacovigilance Aspects Pharmacovigilance data from spontaneous reporting will define the rare adverse drug reaction profile of hexavalent vaccines. These rare effects need to be carefully evaluated to eventually amend the SPC and PIL accordingly.