1. Marketing Authorisation & Yearly Licence of Influenza Vaccines - „Mock-up” & Pre-Pandemic Influenza Vaccines Zsuzsanna Pauliny MD zsuzsanna.pauliny@oek.antsz.hu Kálmán Bartha PhD bartha.kalman@oek.antsz.hu National Centre for Epidemiology Budapest, Hungary Viral vaccines in the medical practice 8 June 2010, Cluj-Napoca

2. 2 Marketing Authorisation of Influenza Vaccines - Guidelines New influenza vaccines Nfg on the clinical evaluation of vaccines (CHMP/VEG/164653/05) Annual update of influenza vaccines (Yearly licence) Nfg on harmonisation of requirements (CHMP/BWP/214/96) Summary of Product Caracteristics (SPC) for trivalent influenza vaccines are similar

3. 3 PA/PH/OMCL (08) 16 R OCABR: CELL CULTURED INFLUENZA VACCINE (SURFACE ANTIGEN, INACTIVATED) OCABR: INFLUENZA VACCINE (SURFACE ANTIGEN, INACTIVATED, VIROSOME) OCABR of a Pandemic influenza Vaccine Batch release of Influenza vaccines

4. 4 Yearly Licence to Assess efficacy before licensure Immunological assays 1. 1. Haemagglutinaton Inhibition (HI) test Lower cut-off HI titre <1:10 (=0) Turkey red blood cells are recommended to use in this assay 2. Single Radial Immunodiffusion (SRID) test 3. Single Radial Haemolysis (SRH) test Lower cut-off SRH <4mm 2 (=0)

5. 5 Single Radial Immunodiffusion (SRID) Single Radial Immunodiffusion, abbreviated SRID. Also known as Mancini method. A technique for quantitating soluble proteins that involves placing the solution to be measured into a well cut into an agar or agarose gel containing antiserum specific for the protein. As the solution to be measured diffuses out of the well, it complexes with the antiserum and forms a ring, the size of which is proportional to the quantity of soluble protein in the well.

6. 6 Single Radial Haemolisis (SRH) Viral antigens coupled to RBC suspended in agarose + complement Test serum in wells If antibody positive → lysis of antigen-coated RBC → haemolitic zone Area of zone in mm is proportional to amount of antibody

7. 7 Vaccination effect measured by serology Pre- vs post-vaccination Seroconversion rate (SCR) GMT increase or Seroconversion Factor (SCF) Post-vaccination Seroprotection rate (SPR)

8. 8 Pre- vs post-vaccination Seroconversion rate (SCR) Defined as a proportion of subjects who were either seronegative prior to vaccination and have a post-vaccination titer of ≥ 1:40 or who were seropositive prior to vaccination and have at least a 4-fold increase in titer postvaccination. Seroconversion in HI test: Pre-vaccination: < 10 / post ≥ 40 or at least a 4-fold increase in titre Seroconversion in SRH test: Pre-vaccination: < 4 mm 2 / post ≥ 25 mm 2 or at least a 50% increase in area

9. 9 Pre- vs post-vaccination Seroconversion factor (SCF) or GMT main increase Defined as the ratio of the post vaccination geometric main titre (GMT) divided by the pre-vaccination GMT.

10. 10 Post-vaccination Seroprotection rate (SPR) Immunological correlates of protection: Defined as the proportion of subjects in each group having a post-vaccination titre of ≥ 1:40 HI titre ≥ 1:40 SRH ≥ 25 mm 2

11. 11 Yearly licence / Annual seasonal updates Clinical requirements Seasonal trivalent vaccines Contain 15 μg HA per strain (=45 μg) Clinical trials to verify immunogenicity (and tolerance): Two groups: 18-60 yrs and >60 yrs At least 50 subjects per age group Note: Paediatric population NOT included – no immunological criteria established for children.

12. 12 At least one of the following criteria has to be met: 18-60 years > 60 years Geometric increase in HA titre or in the area of SRD/SRH > 2.5 > 2.5 > 2.0 Seroconversion rate (SCR) > 40% > 40% > 30% Seroprotection rate (HI titre ≥ 40 or SRH ≥ 25 mm2) > 70% > 70% > 60%

13. 13 How to be prepared to pandemic? Major expected issues on pandemic vaccines Population immunologically naif Short time for vaccine development Short time for scientific and regulatory assesment What threshold for efficacy at pre-licensure Size of database for evidency of safety Wide demand for prevention to be met, antigen sparing policy recommended by WHO

14. 14 Proof of Principle Approach In pre-pandemic period mock-up vaccines formulated and produced in the same way as the planned pandemic vaccines Mock-up vaccines contain subtypes of influenza A to which tha majority of population is naϊve. (eg H5N1) Safety and immunogenicity data generated in advance to ant pandemic with „mock-up vaccines”. Data extrapolated to the same construct containing the pandemic strain. Licensure of mock-up vaccines granted in advance to the pandemic.

15. 15 The „Mock-up” (core dossier) principle are based on: The immune response to a specific mock-up vaccine (containing a strain to which subjects were immunologically naϊve) is expected to predict responses to the same vaccine constract, containing an alternative strain. The safety data generated with a specific mock-up vaccine in clinical studies is expected to predict the safety profile observed with the same vaccines construct. The „Mock-up” pandemic influenza vaccine (core dossier) is a vaccine that mimics any future pandemic influenza vaccine in terms of its composition construct (antigen amount, excipients and adjuvant system, if used), manufacturing and control.

16. 16 Guidelines Pandemic vaccines Mock-up pandemic vaccines Guideline on the dossier structure and content for pandemic influenza vaccines (CMP/VEG/4714/03) Core SPC for pandemic influenza vaccine (CMP/VEG/193031/04) Pre-pandemic influenza vaccines Guideline on influenza vaccines prepared from viruses with the potencial to cause a pandemic and intended for use outside the core dossier context (CHMP/VWP/263499/06)

17. 17 Defined points in Guidelines Inclusion of adjuvant has to be justified All three CHMP serological criteria (GMT, Seroprotection, Seroconversion) are to be met Safety studies of limited size (hundreds) in adults and elderly at pre-licensure level for pandemic use Safety studies of full size (thousands) at pre- licensure level for pre-pandemic use Step-wise approach to study in children after licensure Detailed Risk Management Plan prepared at pre- licensure level and implemented during use. Extended populations to be monitored.

18. 18 Summing up Vaccines are „biologicals” – it means, from a regulatory wiev, that - official control for „batch release” is necessary for all of the produced batches – contrary to other medicines In addition Influenza vaccines are different from other vaccines – it means the yearly new composition of virus strains – yearly licence (small clinical trial) is needed in every year (independently but only after! the batch release) to control the efficacy and safety of the new antigen composition The only what we know on pandemic virus – it will be new, coming unexpectedly and majority of the population will be immunologically naive for the virus, it means vulnerable for the disease – prepairing for pandemic we need a modell vaccine („Mock-up” principle)