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Sabin-IPV development,clinical trials & optimization
Wilfried Bakker
11th WHO/UNICEF consultationwith OPV/IPV manufacturers
25 October 2012
Contents
Sabin-IPV type 2 immunogenicity
Clinical Trials
Optimizations update
Technology Transfer
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Is Sabin-IPV type 2 less Immunogenic ?
VS.
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Type 1
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
0.0 10.0 20.0 30.0 40.0 50.0
DU/shd
wt
Po
lio V
NT
[L
og
2]
Salk-IPV Ref.Sabin-IPVsIPV + AlOH3
Upper VNT limit ≈ 6
3 Log-cycles (factor 8) VNTincrease required for protection
Westdijk et al., 2011, Vaccine
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Westdijk et al., 2011, Vaccine
Relative potency
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Relative potency type 1
Type 1
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Type 2
0
2
4
6
8
10
12
14
0.0 10.0 20.0 30.0 40.0 50.0
DU/shd
wt
Po
lio V
NT
[L
og
2]
Salk-IPV Ref.Sabin-IPVsIPV + AlOH3
Upper VNT limit ≈ 12
3 Log-cycles (factor 8) VNTincrease required for protection
Westdijk et al., 2011, Vaccine
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Relative potency type 2
Type 2
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Compare the upper VNT limits difference
Type 2
0
2
4
6
8
10
12
14
0.0 10.0 20.0 30.0 40.0 50.0
DU/shdw
t P
olio
VN
T [
Lo
g2]
Salk-IPV Ref.Sabin-IPVsIPV + AlOH3
Type 1
0
2
4
6
8
10
12
14
0.0 10.0 20.0 30.0 40.0 50.0
DU/shd
wt
Po
lio V
NT
[L
og
2]
Salk-IPV Ref.Sabin-IPVsIPV + AlOH3
Upper VNT limit ≈ 6
Upper VNT limit ≈ 12
6 Log2-cycles = factor 64
∆6
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Type 3
0
2
4
6
8
10
12
14
0 10 20 30 40 50
DU/shd
wt
Po
lio V
NT
[L
og
2]
Salk-IPV Ref.Sabin-IPVsIPV + AlOH3
Compare the upper VNT limits difference
Type 2
0
2
4
6
8
10
12
14
0.0 10.0 20.0 30.0 40.0 50.0
DU/shdw
t P
olio
VN
T [
Lo
g2]
Salk-IPV Ref.Sabin-IPVsIPV + AlOH3
Upper VNT limit ≈ 10
Upper VNT limit ≈ 12
2 Log2-cycles = factor 4
∆2
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Comparing apples with peares
Standardization is required to estimate of the relative potency forthis new Sabin-IPV product
VS.
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Is Sabin-IPV type 2 less Immunogenic ?
Answer : NO,the dosage may even be chosen too high !!!
Solution : a Sabin-IPV reference standardis required
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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 1 20 10 5 10 5 2.5 Type 2 32 16 8 16 8 4 Type 3 64 32 16 32 16 8
For reference: plain Salk-IPV formulation is (type 1 – 2 – 3): 40 – 8 – 32 DU/shd
Westdijk et al., 2011, Vaccine
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Does Sabin-IPV also induce neutralizing antibodiesagainst wild-type poliovirus strains in humans?
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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 : Q2 2011
– 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
Verdijk et al., 2011, ERV
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Phase I/II Clinical Trial by RIVM
Verdijk et al., 2011, ERV
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RIVM Phase I - Sabin-IPV in adults
● 3 goups (n=15/group):
– Sabin-IPV (20-32-64 DU)
– Adjuvanted Sabin-IPV (10-16-32 DU)
– IPV
● Single injection
● Age 18-49
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● 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
RIVM Phase I - Sabin-IPV in adultsPreliminary conclusions
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How about the lower in-process yields ?
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Base case = Clinincal lots (2009)Yield** ≈ 18 mL
For reference: approx. 2.5 mL bioreactor volume required to make one IPV dose*
* Van Wezel et al., 1984, Rev.Inf.Dis.** Yields expressed in mL bioreactor volume required to make one dose
Initially, no process optimizationwas done for timing reasons
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Partial optimizations :minor changes
Fully optimized &Animal-ComponentFree process
Alternativeadjuvants
Basic clinical lots process No newPhase IStudiesanticipated
NewPhase IStudiesRequired?*
* Depends on local requirements
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Partial optimizations :minor changes
Basic clinical lots process No newPhase IStudiesanticipated
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Scale-down models
● Allow troubleshooting and process optimization
● Science based strategy supported by ICH
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Process optimization – Increased cell densities
3x more cellsfor virus culture
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Virus (type 2) culture at increased cell density
• 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
Microcarrier conc g L-1
Cell density at infection ×106 cells mL-1
Virus titer 10LOG CCID50 mL-1
3 3 8.2
6 4 8.7
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Process step
Type 1 2 3 1 2 3
Clarification
Concentration
Chromatography SEC 69 51 79
Chromatography IEX 94 32 94
Inactivation 87 50 55
Diafiltration (optional)
Overall D-ag Yield [%] 40 4 26 44 12 - 15 31
−
90 101 (n = 5)
72 93 (n = 4)
Current CTM Optimized Sabin-IPV lab-scale
Preliminary DSP process step D-antigen Yields [%]
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Increased cell densitiesYield ≈ 3 mL
Partially optimized DSPYield ≈ 6 mL
Base case = Clinincal lots (2009)Yield** ≈ 18 mL
For reference: approx. 2.5 mL bioreactor volume required to make one IPV dose*
* Van Wezel et al., 1984, Rev.Inf.Dis.** Yields expressed in mL bioreactor volume required to make one dose
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Workshop on “Sabin-IPV: Challenges and Benefits”28-30 June 2010
Technology Transfer of Sabin-IPV technology
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Hands-on training at RIVM
Training on both crucial process steps/ operation units and related QC testing:
1. Answer partner’s queries2. 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 needs7. Define further input needed from RIVM8. Good interaction between RIVM and
Partner’s Sabin-IPV team
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Design Sabin-IPV training at RIVM
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Hands-on training at RIVM
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Fully optimized &Animal-ComponentFree process
Alternativeadjuvants
NewPhase IStudiesRequired?*
* Depends on local requirements
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Process step
Type 1 2 3 1 2 3
Clarification
Concentration
Chromatography SEC 69 51 79 77 70 63
Chromatography IEX 94 32 94 93 82 99
Inactivation 87 50 55 86 77 88
Diafiltration (optional)
Overall D-ag Yield [%] 40 4 26 55 39 48
95*−
72 93 (n = 4)
Current CTM Optimized Sabin-IPV lab-scale
90 101 (n = 5)
Preliminary DSP process step D-antigen Yields [%]
*
*
*
* n = 2 / n = 3
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Increased cell densitiesYield ≈ 3 mL
Partially optimized DSPYield ≈ 6 mL
Base case = Clinincal lots (2009)Yield** ≈ 18 mL
Fully optimized DSP(starting from ACF USP)
Yield ≈ 2 mL
Base case = Clinincal lots (2009)Yield** ≈ 18 mL
For reference: approx. 2.5 mL bioreactor volume required to make one IPV dose*
* Van Wezel et al., 1984, Rev.Inf.Dis.** Yields expressed in mL bioreactor volume required to make one dose
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Increased cell densitiesYield ≈ 3 mL
Partially optimized DSPYield ≈ 6 mL
Base case = Clinincal lots (2009)Yield** ≈ 18 mL
Increased cell densities& ACF mediaYield ≈ 1 mL
Fully optimized DSP(starting from ACF USP)
Yield ≈ 2 mL
Base case = Clinincal lots (2009)Yield** ≈ 18 mL
For reference: approx. 2.5 mL bioreactor volume required to make one IPV dose*
* Van Wezel et al., 1984, Rev.Inf.Dis.** Yields expressed in mL bioreactor volume required to make one dose
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Acknowledgements / Questions
Website:www.Sabin-IPV.nl
E-mail:[email protected]
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