Sabin-IPV development, clinical trials & optimization · Sabin-IPV development, clinical trials & optimization WilfriedBakker 11 th WHO/UNICEF consultation withOPV/IPV manufacturers

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

25 October 2012

Vaccinology for Public Health

3

Is Sabin-IPV type 2 less Immunogenic ?

VS.

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4

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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5


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]



3 Log-cycles (factor 8) VNTincrease required for protection


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8

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]


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]




6 Log2-cycles = factor 64

∆6

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10

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]


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]




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


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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




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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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Fully optimized DSP(starting from ACF USP)

Yield ≈ 2 mL




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Increased cell densities& ACF mediaYield ≈ 1 mL

Fully optimized DSP(starting from ACF USP)

Yield ≈ 2 mL




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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

Documents

Sabin-IPV development, clinical trials & optimization · Sabin-IPV development, clinical trials & optimization WilfriedBakker 11 th WHO/UNICEF consultation withOPV/IPV manufacturers