Update: GPEI Program to Develop Affordable IPV · • Concept proven in animals • Simpler...

Update: GPEI Program to Develop Affordable

IPV

WHO/UNICEF Consultation Geneva, 25 October 2012

• Endorsed tOPV-bOPV switch

• Expressed alarm over current IPV price, lack of medium & long term IPV price(s), limited supply options, and cost-benefit.

• Requested WHO to work with partners & manufacturers to enhance IPV affordability & availability.

• Requested Polio Endgame Strategy & Budget 2014-18

Background: WHA Resolution in 2012

GPEI Approaches to Affordable IPV

Fractional Dose with Intradermal IPV

Alum Adjuvant

sIPV Development

Alternate IPV Strains

IPV Demonstration Project

SHORT TERM

Develop and license an affordable IPV option before bOPV switch (2015)

LONG TERM

Develop a safer and affordable IPV before OPV cessation (2018)

FEASIBILITY Demonstrate that IPV introduction is feasible and beneficial (i.e., reduction of VDPV emergence)

PRODUCT DEVELOPMENT

FEASIBILITY DEMONSTRATION

Options Pro Con Target Price

wIPV (IM full dose)

• Well-established product • No need for regulatory

approval

• Current price is too expensive for developing countries

• 1-1.5 dollar/dose (through competition and high volume)

Fractional IPV (ID 1/5 dose with needle and syringe or device)

• No adjuvant needed • Potentially, no needle for

administration

• More complicated regulatory and development process than IM

• Potential concern over lower GMT induced

• Lower acceptability by countries

• <50 cents/dose (inc. device and cartridge)

Adjuvant wIPV (IM 1/5 dose)

• Well-established product and adjuvant (aluminum)

• Concept proven in animals • Simpler development and

regulatory process than ID

• Clinical study needed (2-3 years)

• <50 cents/dose (Single dose vial)

Options for “Affordable IPV” (Short Term)

Alum Adjuvant IPV


Alum Adjuvant IPV

sIPV Development



LONG TERM

FEASIBILITY

PRODUCT DEVELOPMENT


SHORT TERM

Type 3

2

3

4

5

6

7

8

9

10

11

1.8

D units

0.6

D units

(-) (-) EM1 SE Alum (-) EM1 SE Alum (-) EM1 SE Alum EM1

0.2

D units0.06

D units

0.02

D units

0.3

D units

Neu

trali

zin

g

an

tib

od

y t

iters

Lo

g2

Type 1

2

3

4

5

6

7

8

9

10

11

1.8

D units

0.6

D units

(-) (-) EM1 SE Alum (-) EM1 SE Alum (-) EM1 SE Alum EM1

0.2

D units

0.06

D units

0.02

D units0.3

D units

Neu

trali

zin

g

an

tib

od

y t

iters

Lo

g2

Type 2

2

3

4

5

6

7

8

9

10

11

1.8

D units

0.6

D units

(-) (-) EM1 SE Alum (-) EM1 SE Alum (-) EM1 SE Alum (EM1)

0.2

D units

0.06

D units

0.02

D units

0.3

D units

Neu

trali

zin

g

an

tib

od

y t

iters

Lo

g2

Rat Potency Test Showed Potential of Alum-IPV

• The average titer was

higher in all adjuvant

groups (1/2, 1/6, 1/30)

than full-dose (without

adjuvant)

Alum Adjuvant IPV: Accelerated Development Timeline (For Boosting)

Activities 0 Months

2 6 10 14 18 22

Prep.

Phase II/III

4 8 12 16 20 24 Arm/subjects

•Prepare clinical trial (e.g., protocol, ERC, regulatory)

• Infants (350/arm)

•Release of vaccine (e.g., rat/rabbit Tox, rat potency)

Phase I

• Infants – 10-20/arm

•Adult – 10/arm

★ DSMB

Licensure •Preparation

28 30

32 34 38 36

•Review (NRA/WHO) ★ Approval

Safety •Safety with infants (Post-marketing)

★ DSMB



Alum Adjuvant

sIPV Development



SHORT TERM

LONG TERM

FEASIBILITY

PRODUCT DEVELOPMENT


SHORT TERM

Priority in ID IPV Development

Objectives

1. Obtain label change of IPV to include 1/5 fractional

dose with ID administration for supplemental dose

in RI and SIAs

• Generate clinical data

• Discuss IPV label change with NRAs

2. Develop and license ID device appropriate for

developing countries

ID IPV Development: Past Studies

Study Objectives Outcome

Fractional dose of IPV in Oman

To evaluate strategies for making the vaccine affordable for use in developing countries.

Fractional ID doses of IPV at 2, 4, and 6 months induced similar levels of seroconversion but significantly lower titers than IM (N Engl J Med 2010;362:2351-9)

Controlled study of fractional doses of IPV administered intradermally with a needle in the Philippines

To compare a fractional inactivated poliovirus vaccine (IPV) dose administered intradermally (ID) to a full dose administered intramuscularly (IM)

ID produced immune response, no inferior to the IM after immunization 6,10 and 14 weeks (Int J Infect Dis. 2012 16:e110-6.)

Immunogenicity of supplemental doses of poliovirus vaccine for children aged 6-9 months in Moradabad, India

To compare seroconversion after a single dose IPV/OPV for seronegative infants at age 6-9 months

Seroconversion of one dose IPV was lower in ID (59%) than IM (100%), due to problems with injector (Lancet Infect Dis 2012; 12: 128–35)

Fractional doses of IPV administered intradermally by needle-free device in Cuba

To compare the immunogenicity and reactogenicity of fractional-dose ID IPV using jet injector device with full doses IM

Fractional ID doses of IPV at 6, 10 and 14 weeks of age resulted in suboptimal immunogenicity, compared with IM (J Infect Dis. 2010;201:1344-52)

• Two studies with promising results on ID IPV

• Only study with a device issue

• One study used a sub-optimal schedule for IPV (too early and close intervals)

Preliminary Data Suggests 90% Immune Response (Seroconversion and Priming) with Single ID Dose

P1 P2 P3 Randomized controlled trial Field work in Camaguey Province, Cuba IPV from Netherlands Vaccine Institute Enrolling 160 infants per arm Serum at 4m, 8m, 8m+7d and 8m+30d IPV at 4- and 8 m fractional vs full-dose Seroconversion (single and two-dose) Priming (8m and 8m+7d)

Study design Preliminary Results

ID IPV Development: Follow up Studies

Study Objectives Status

Device comparison study in Cuba

To assess immune response among three needle free ID devices (i.e., Bioject 2000, Bioject ID Pen, Pharmajet Tropis)

Likely to start in December 2012

EPI Study in India To assess different EPI schedules (with or without IPV with BCG syringe) for anticipated switch from tOPV to bOPV with or without affordable IPV options

Likely to start enrollment in Q2 2013

EPI Study in Jordan To assess the non-inferiority of fractional-dose (ID Pen) measles vaccine and IPV (1/5 of full dose) compared to full-dose vaccine

Likely to start enrollment in Q1 2013

EPI study in Bangladesh (CDC, ICDDR, B)

To compare seroconversion rates of possible EPI schedules for the end-game (tOPV or bOPV with no IPV, IM IPV or ID IPV with Nano-Pass device)

Likely to start implementation in Q4 2012- Q1 2013

Phase I/IIa study of sIPV with ID delivery (Kunming Institute, BMGF)

To assess safety and immunogenicity of ID sIPV administration with different delivery devices in monkeys, followed by infants

Likely to start implementation in Q2 2013

• These studies would provide immunogenicity and safety of IPV administration with different devices in mid-2013 • Data will also support the label change of IPV (to include ID administration)

Support of ID Device Development

Bioject

1.WHO/PATH supported the development of ID-

pen (spring-powered device), based on their

Bioject 2000 (which is commercially available)

2.WHO/PATH also supports the evaluation of ID-

Pen with IPV in Cuba as well as with BCG in

South Africa

Pharmajet

1.WHO pre-qualified their jet injector (Stratis)

2.WHO/PATH supports clinical evaluation of their

ID device (Tropis) in Cuba

Discussions with NRA and Manufacturers

IPV label change 1. Discussion with GSK/Be NRA and SP/ANSM initiated in October

2011 to define regulatory requirements (e.g. additional clinical data)

2. Cuban trial protocol shared with the two NRAs in June 12: comments awaited

3. Amendment of the protocols if/when appropriate

Device Pre-qualification 1.Discussion with 2 device companies initiated in October 2011 2.Lesson learned from FDA/CBER statement issued in October 2011 for influenza vaccine 3.PQ of pharmajet device (Stratis) has been granted

Development of sIPV

sIPV Development



SHORT TERM

FEASIBILITY

PRODUCT DEVELOPMENT


LONG TERM


Alum Adjuvant

Indonesia Pre-clinical

Country Current status

Expected approval

Phase III

China

TBD

2013

Standalone

Product

Standalone

•BioFarma

Manufacture

•Kunming Institute

Technology transfer from JPRI

Collaboration

With NVI (in the past)

Proof of Concept of sIPV has been proven by some manufacturers

Licensed Licensed Phase II

2013/14

DTaP-IPV

DTaP-IPV

DTaP-IPV

•Biken

•Kaketsuken

•Takeda

JPRI supplies IPV JPRI supplies IPV Technology transfer

from JPRI

Japan

sIPV Development: WHO/RIVM Collaboration

TT

• GMP production and pre-clinical tests

• Phase I in adult (Poland and Cuba)

• Phase I/II in infants (Poland)

• Selected four partners for the technology transfer

Key Challenges in sIPV Development: Type II Production Yield

Virus Type

X

Type I

Type II

Type III

USP harvest (DU/ml)

DSP recovery (%)

After production (DU/ml)

Dose required (DU/viral)

Vial per volume (vial/ml)

Overall: 18.4* (ml/vial)

= ÷ =

Volume required (ml/vial)

120

25

56

40

4

26

48

1

15

10

16

32

4.8

0.1

0.5

0.2

16.0

2.2

* ~3 ml/vial in Salk

Salk (Literature) 2.5

Sabin (SC, non-optimized)

a. Upstream (DU/ml) b. Downstream yield (%) c. Required antigen (DU/dose) d. Fermenter space (ml/dose)

Type I 120 40% 10 0.2

Type II 25 4% 16 16.0

Type III 56 26% 32 2.2

(Total) 18.4

Sabin (Partially Optimized; Serum-containing media) = current optimization work for WHO & selected TT partners

a. Upstream (DU/ml) b. Downstream yield (%) c. Required antigen (DU/dose) d. Fermenter space (ml/dose)

Type I 240 40% 10 0.1

Type II 50 15% 16 2.1

Type III 112 31% 32 0.9

(Total) 3.2

Sabin (Optimized; ACF) = including fully optimized DSP beyond currently validated ranges

a. Upstream (DU/ml) b. Downstream % c. Required antigen (DU/dose) d. Fermenter space (ml/dose)

Type I 400 55% 10 0.0

Type II 90 39% 16 0.5

Type III 140 48% 32 0.5

(Total) 1.0

Process Optimization Project To Address Production Yield

• Adjuvant may allow further 2-4 dose reduction

• Exact antigen requirements need to be confirmed through clinical study


sIPV Development



SHORT TERM

FEASIBILITY

PRODUCT DEVELOPMENT


LONG TERM


Alum Adjuvant

Alternate IPV strain: Current Status

• The PRC stimulated the development of alternate IPV seeds:

– Provided funding to six approaches in 2009-10

– PRC recommended a head-to-head evaluation with specific criteria, and selected RIVM, the Netherlands, as a partner after WHO RFP process in January 2012

– Recommended the first strain candidate (by NIBSC) for evaluation in April 2012

– Will evaluate 3 more strains in Sep 2012 and April 2013 PRC (planned)

• RIVM will conducts an assessment of growth characteristics and safety of different strains over the next 2-3 years

Expected Timing of Alternate Seed Strain Availability for Independent Evaluation

Institute Type I Type II Type III

CDC Q1 2013 Q1 2013 Q1 2013

UCSF Q4 2012 Q4 2012 Q4 2012

NIBSC (Wild

Capsid)

Q1 2011 (already

available)

Q1 2011 (already

available)

Q1 2011 (already

available)

NIBSC (Sabin

Capsid)

Q1 2011 (already

available)

Q1 2011 (already

available)

Q1 2011 (already

available)

SUNY Q3 2012 (already

available)

Q3 2012 (already

available)

Q3 2012 (already

available)



Alum Adjuvant

sIPV Development



SHORT TERM

LONG TERM

PRODUCT DEVELOPMENT


FEASIBILITY

FEASIBILITY

IPV Demonstration Project - Indonesia

MAIN OBJECTIVE

To verify that OPV vaccine virus disappears from the environment after OPV cessation and to demonstrate operational feasibility and immunological equivalence of replacing OPV with IPV in a tropical setting of a developing country

Age of children From birth to 9 months

Duration of study Switch from OPV to IPV in Sept 2007 Planned to end DEC 2012

Study Size Entire Yogyakarta Province (3 mil, birth cohort 50 k)

Area of study All health care system in Yogyakarta province

Status Finalizing in DEC 2012

Potential Additional Study Sri Lanka, Cape Verde

Summary of Results from Yogyakarta

1. To describe environmental behavior of OPV virus before and after vaccine switch

• Sabin virus disappeared from environment within 3 weeks of OPV cessation

• No cVDPV emergence or circulation over the last 5 years, suggesting IPV has provide sufficient humoral and mucosal immunity to stop VDPV

2. To compare coverage with polio vaccine before and after switch

• No significant difference in polio vaccine coverage detected

3. To evaluate vaccine switch and assess operational feasibility of IPV use

• No major problems found with switch or use of IPV

4. To compare sero-prevalence of polio antibodies before and after switch

• Post switch sero-prevalence survey pending

Conclusions

• Development and introduction of affordable IPV is a prerequisite for the end-game strategy and one of top priorities identified by the WHA

• GPEI is pursuing multiple approaches to address this challenge: • Facilitate development of different affordable and safer options • Conduct IPV demonstration projects to assess challenges and

feasibility to include IPV in their routine schedule

• Sufficient evidence is available that affordable IPV through adjuvant and/or ID administration is technically feasible. They can likely be available in 2-3 years

• The methodology to produce Sabin IPV at a lower cost is proven at lab-scale. The work is underway to demonstrate it at a commercial scale within 18-24 months

Update: GPEI Program to Develop Affordable IPV · • Concept proven in animals • Simpler...

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