4-4leishrisk vaccine development

7/29/2019 4-4LeishRisk Vaccine Development

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Leishmaniasis: Challenges for Vaccine

Development

Steven G. Reed

Infectious Disease Research Institute

Seattle


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IDRI Goals: Leishmaniasis

To improve existing vaccines for use in therapy

and prevention. Antigen Discovery

Vaccine Development

Manufacturing Process Clinical Testing

To improve existing diagnostics for VL and

PKDL and develop a test(s) to demonstrate cure


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Challenges to Leishmania Vaccine

Development

PROBLEM: How to finance?

Making a vaccine requires industrytype effort, But Activity generally carried out in academic

organizations

Solution requires creative leveraging of public/privatefunds

IDRI Solution: Create PPP, including Non-

Profit Biotech collaborating with industry


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Funding Development of a Leishmaniasis Vaccine


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Development

Problem: How to Access Adjuvant? Academic adjuvants not practical (IL12, P. acnes- IFN)

Most new clinical adjuvants are in hands of industry

Available clinical adjuvants promote too much Th2 (alum, AS02)

Mouse data misleading (i.e. CpG)

IDRI Solution: License MPL

Optimize MPL formulation

Develop synthetic MPL substitute to lower COG


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Next Generation of TLR-4

Agonists

Gluco-pyranosylphospho-Lipid A

Molecules; Enhance PotencyOver MPL


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Geneexpression

(Log2rela

tivetomedia)

GLA-AF

MPL-AF

DC: 4h in vitro activation

Agonist Concentration (ng/ml)

IL-6IL-1IL-12p40

0

20000

40000

60000

80000

100000

120000

1000200408

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5000

10000

15000

20000

1000200408

Mouse

Human

0

10000

20000

30000

40000

1000200408

0

50

100

150

200

250

10002004080

20

40

60

80

100

10002004080

20

40

60

80

100

1000200408


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Development

Problem: How to demonstrate POC

Solution:

Perform clinical trials in multiple indications Prophylactic/Therapeutic approaches


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Leishmaniasis: Rationale for a

Therapeutic Vaccine Animal Models

L. majorin mice L. infantum in dogs

Success of immuno-chemotherapy VL

trials in Brazil, India Clinical experience with ML/CL in

Brazil and Venezuela

PKDL studies in Sudan


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Immunotherapy for Leishmaniasis

Genaro, et al. Clinics in Dermatology, 1996


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PKDL in Sudan


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Leish-111f + MPL-SEClinical Development


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Leish-111f: Recombinant Antigen

Comprised of 3 Linked Subunits

TSA LmSTI1 LeIF (N-term)

BamH I

22KD 62KD 26KD

EcoR I


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Figure 1 - Vaccination against Leishmaniasis using recombinant

leishmanial antigens formulated in MPL-SE

0

0,5

1

1,5

2

2,5

2 3 4 5 6 7 8

Weeks Post Infection

Footpa

dSwelling(mm)

Saline

MPL-SE

TSA (2)

LmSTI1 (2)

TSA-LmSTI1 (2)

LeIF (2)

TSA-LmSTI1-

LeIF (2)

Leish-111f (TSA-LmSTI1-LeIF)

BALB/c - L. major C57BL/6 - L. infantum


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Leish-111f + MPL-SE Vaccine

Leish-111f

Antigen

MPL-SE

Adjuvant

Complete Vaccine


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Therapeutic Indications (In Progress)

Combine vaccine with chemotherapyfor treating:

VL

PKDL

CL

ML

111f S


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Prophylactic Indications (Planned)

Cutaneous leishmaniasis Visceral leishmaniasis (prevent VL,

prevent PKDL)


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Completed Clinical Trials

2003 2004 2005 2006 2007

US Healthy Subjects

Phase 1

Peru ML Patients Phase 1

Brazil CL Patients Phase 1

Colombia Healthy Subjects

Phase 1 MST+/ Phase 2 MST-


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Brazil/Peru Trial - Design

Brazil

Phase 1

Peru

Phase 1

Population CL ML

Vaccine Dose (n)

__ Leish -111f + 25g MPL-SE

5g(9)

10g(9)

20g(9)

5 g (12)

10 g (12)

20 g (12)

Control(n)MPL-SE(8)

Saline (9)Saline (12)

Chemotherapy Antimonial Antimonial

Endpoints

Safety and Tolerability

Immunogenicity

Clinical Evolution


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Brazil CL Therapeutic Trial Results

Clinical Status at Study Day 336

67%

89%100%

78%75%

0

2

4

6

8

10

5 g

Vaccine

10 g

Vaccine

20 g

Vaccine

MPL-SE Saline

N

umberofPa

tients

Relapsed

Cured


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Summary

The Leish-111f + MPL-SE vaccine:

Safe and well tolerated

Immunogenic Does not exacerbate disease

when given with chemotherapy toCL and ML patients

Vaccine Development; Sub-unit


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Vaccine Development; Sub unit

vaccines

Selective:

Use only relevant antigens Use adjuvants with desired qualities

Versatile: Antigens can be used alone,in combination, as fusions

Manufacturing options greatlyincreased


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Wk 0 63 9 13

Immunizations Challenge with

L. infantum

Parasite

burden

C57BL/6 mice

Next Generation Vaccine: SMT plus MPL-SE

Sterol 24-c-methyltransferase (SMT): A


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Sterol 24 c methyltransferase (SMT): A

Potent Leishmaniasis Vaccine Candidate

SMT is involved in the biosynthesis of ergosterol; target of

amphotericin B

Leishmania SMT is highly conserved among species(>96%), and is homologous to those ofTrypanosoma

(66%) and Candida (39%), but no homologous proteinfound in humans.


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Development

PROBLEM: Sustainability

Solution:

Incentives for Pharma Exclusive vs. Non-Exclusive (include diligence

requirements)

Multiple Indications

Vaccine registration in Europe, U.S., etc.


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Summary: The Ideal Leishmania Vaccine

Safe

Induces effective T cell response against

appropriate antigens Induces long-term immunity

Prophylactic and therapeutic activity Effective against more than one form ofleishmaniasis

Cost-effective Reproducible, transferable manufacturing

process

Leishmaniasis Vaccine


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Leishmaniasis Vaccine

Development:Future Directions

Finalize Antigen Selection

BUT Antigen Vaccine MPL-SE is Effective, but, COG is an Issue

Animal Studies, Mice, Hamsters, Dogs(combine with rabies)

Obtain POC in Clinic


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Special Thanks To:

Yasu Goto

Rhea Coler Ajay Bhatia

Jeff Guderian

Sylvie Bertholet Franco Piazza

Alejandro Llanos

Hashim Ghalib

Shyam Sundar

NIAID

Bill and MelindaGates Foundation

4-4leishrisk vaccine development

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