Sabin-IPV development, clinical trials & optimization

Transcription

1 Sabin-IPV development, clinical trials & optimization Wilfried Bakker 11 th WHO/UNICEF consultation with OPV/IPV manufacturers

2 Contents Sabin-IPV type 2 immunogenicity Clinical Trials Optimizations update Technology Transfer

3 Is Sabin-IPV type 2 less Immunogenic? VS. 3

4 Type 1 Upper VNT limit 6 wt Polio VNT [Log2] DU/shd 3 Log-cycles (factor 8) VNT increase required for protection Salk-IPV Ref. Sabin-IPV sipv + AlOH3 4 Westdijk et al., 2011, Vaccine

5 Relative potency 5 Westdijk et al., 2011, Vaccine

6 Relative potency type 1 Type 1 6

7 14 12 Type 2 Upper VNT limit 12 wt Polio VNT [Log2] Log-cycles (factor 8) VNT increase required for protection DU/shd Salk-IPV Ref. Sabin-IPV sipv + AlOH3 7 Westdijk et al., 2011, Vaccine

8 Relative potency type 2 Type 2 8

9 Compare the upper VNT limits difference Type Type 2 Upper VNT limit 12 wt Polio VNT [Log2] DU/shd Upper VNT limit 6 Salk-IPV Ref. Sabin-IPV sipv + AlOH3 wt Polio VNT [Log2] DU/shd Salk-IPV Ref. Sabin-IPV sipv + AlOH3 6 6 Log2-cycles = factor 64 9

10 Compare the upper VNT limits difference wt Polio VNT [Log2] Type DU/shd Upper VNT limit 10 Salk-IPV Ref. Sabin-IPV sipv + AlOH3 wt Polio VNT [Log2] Type DU/shd Upper VNT limit 12 Salk-IPV Ref. Sabin-IPV sipv + AlOH3 2 2 Log2-cycles = factor 4 10

11 Comparing apples with peares VS. Standardization is required to estimate of the relative potency for this new Sabin-IPV product 11

12 Is Sabin-IPV type 2 less Immunogenic? Answer : NO, the dosage may even be chosen too high!!! Solution : a Sabin-IPV reference standard is required 12

13 Immunogenicity, formulation for Clinical phase 1 study Sabin-IPV vaccine formulation considerations: 1. Neutralizing antibody titre should be equal or higher than that induced by the international (Salk-IPV) reference 2. At higher D-antigen doses a plateau in neutralizing antibody level is reached Plain formulation (DU / single human dose) Al(OH) 3 formulation (DU / single human dose) High Target Low High Target Low Type Type Type For reference: plain Salk-IPV formulation is (type 1 2 3): DU/shd 13 Westdijk et al., 2011, Vaccine

14 Does Sabin-IPV also induce neutralizing antibodies against wild-type poliovirus strains in humans? 14

15 Clinical Trials recent Milestones & Planning Planned final product filling operations: Milestone : Pre-clinical lots (safety) : Conform requirements, October 2010 Milestone : Phase I/II clinical lots : Q for European study (RIVM/WHO); for local study by RIVM/WHO Phase I/II clinical trial started in Poland: AUG 2011 Europe (Adults & Infants) : ongoing Planned : Cuba (Adults) : 2012 Scientific Advise by the Dutch MEB obtained in JULY 2008 : Sabin-IPV immunogenicity & safety should be equivalent or better than that for Salk-IPV 15 Verdijk et al., 2011, ERV

16 Phase I/II Clinical Trial by RIVM 16 Verdijk et al., 2011, ERV

17 RIVM Phase I - Sabin-IPV in adults 3 goups (n=15/group): Sabin-IPV ( DU) Adjuvanted Sabin-IPV ( DU) IPV Single injection Age

18 RIVM Phase I - Sabin-IPV in adults Preliminary conclusions Immunogenicity: All three polio virus types in both Sabin-IPV groups showed a booster immune response against both Salk and Sabin strains For each polio virus type, the immunogenicity results were comparable with the control group (conventional IPV) Safety: Frequency of local injection site reactions (incl. erythema, induration, swelling and pain) were similar for all three groups Frequency of systemic reactions (incl. fever, vomiting, headache) were comparable in all three groups 18

19 How about the lower in-process yields? 19

20 Initially, no process optimization was done for timing reasons Base case = Clinincal lots (2009) Yield** 18 ml For reference: approx. 2.5 ml bioreactor volume required to make one IPV dose* 20 * Van Wezel et al., 1984, Rev.Inf.Dis. ** Yields expressed in ml bioreactor volume Vaccinology required for Public to make Health one dose

21 Partial optimizations : minor changes Basic clinical lots process No new Phase I Studies anticipated New Phase I Studies Required?* Alternative adjuvants Fully optimized & Animal-Component Free process 21 * Depends on local requirements

22 Partial optimizations : minor changes Basic clinical lots process No new Phase I Studies anticipated 22

23 Scale-down models Allow troubleshooting and process optimization Science based strategy supported by ICH 23

24 Process optimization Increased cell densities 3x more cells for virus culture 24

25 Virus (type 2) culture at increased cell density Virus titer Microcarrier conc Cell density at infection g L cells ml -1 10LOG CCID 50 ml Compared with the virus yield during CTM preparation this is approx. 2 8 fold higher Data on D-antigen yields are not yet available, however at least a 2-fold increased level is anticipated 25

26 Preliminary DSP process step D-antigen Yields [%] Process step Current CTM Optimized Sabin-IPV lab-scale Type Clarification Concentration (n = 5) 93 (n = 4) Chromatography SEC Chromatography IEX Inactivation Diafiltration (optional) Overall D-ag Yield [%]

27 Increased cell densities Yield 3 ml Partially optimized DSP Yield 6 ml Base case = Clinincal lots (2009) Yield** 18 ml For reference: approx. 2.5 ml bioreactor volume required to make one IPV dose* 27 * Van Wezel et al., 1984, Rev.Inf.Dis. ** Yields expressed in ml bioreactor volume Vaccinology required for Public to make Health one dose

28 Technology Transfer of Sabin-IPV technology Workshop on Sabin-IPV: Challenges and Benefits June

29 Hands-on training at RIVM Training on both crucial process steps/ operation units and related QC testing: 1. Answer partner s queries 2. Partner should be able to implement both the process at lab scale and related QC testing 3. Partner should be able to transfer this process internally 4. Make proper choices especially concerning pilot and commercial scale productions: equipment & materials 5. Gain more insight in the process and related QC testing 6. Evaluate further training needs 7. Define further input needed from RIVM 8. Good interaction between RIVM and Partner s Sabin-IPV team 29

30 Design Sabin-IPV training at RIVM 30

31 Hands-on training at RIVM 31

32 New Phase I Studies Required?* Alternative adjuvants Fully optimized & Animal-Component Free process 32 * Depends on local requirements

33 Preliminary DSP process step D-antigen Yields [%] Process step Current CTM Optimized Sabin-IPV lab-scale Type Clarification Concentration Chromatography SEC (n = 5) 93 (n = 4) Chromatography IEX Inactivation Diafiltration (optional) 95* Overall D-ag Yield [%] * * * 33 * n = 2 / n = 3

34 Increased cell densities Yield 3 ml Partially optimized DSP Yield 6 ml Fully optimized DSP (starting from ACF USP) Yield 2 ml Base case = Clinincal lots (2009) Yield** 18 ml Base case = Clinincal lots (2009) Yield** 18 ml For reference: approx. 2.5 ml bioreactor volume required to make one IPV dose* 34 * Van Wezel et al., 1984, Rev.Inf.Dis. ** Yields expressed in ml bioreactor volume Vaccinology required for Public to make Health one dose

35 Increased cell densities Yield 3 ml Increased cell densities & ACF media Yield 1 ml Partially optimized DSP Yield 6 ml Fully optimized DSP (starting from ACF USP) Yield 2 ml Base case = Clinincal lots (2009) Yield** 18 ml Base case = Clinincal lots (2009) Yield** 18 ml For reference: approx. 2.5 ml bioreactor volume required to make one IPV dose* 35 * Van Wezel et al., 1984, Rev.Inf.Dis. ** Yields expressed in ml bioreactor volume Vaccinology required for Public to make Health one dose

36 Acknowledgements / Questions Website: Sabin-IPV@rivm.nl Sabin-IPV project team Wilfried Bakker Project management Eric van Gerven Facilities / Validation Nico van den Heuvel Production Fred van Nimwegen QC Yvonne Thomassen Process Dev. Janny Westdijk Assay Development Bernard Metz Inactivation Studies Ahd Hamidi Technology Transfer Peter van t Veld QA Lars Sundermann QP Monique van Oijen Registration Pauline Verdijk Clinical Strategy Claire Boog Head Vaccinology And many other RIVM/BBio colleagues _ 36