ID93/GLA-SE TB Vaccine Candidate

TB Vaccines Global Forum Cape Town, 26 March 2013

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ID93 – Stable Emulsion (SE) 100 nm oil droplets stabilized by emulsifiers in a bulk aqueous phase - Manufactured by high-shear homogenization - Pre-formed emulsion added to antigen before injection -Antigen or additional immunostimulant may be localized in oil phase, aqueous phase, or at the interface

Emulsion components

Oil : squalene Emulsifier: phosphatidylcholine Cosurfactant: Isotonicity agent: buffer: Pluronic F68 glycerol ammonium phosphate, pH 5.1

ID93 Rv3619 Rv1813 Rv3620 Rv2608 Pluronic F68 squalene oil droplet phosphatidylcholine 2

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Enabling Roles of Adjuvants

T cell vaccines

Antibody Response Broadening Antigen Dose Sparing

Immune Response Durability Vaccine Dosage Sparing

Immune Senescence

Vaccine Therapy CONFIDENTIAL

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Adjuvant Platforms in Approved Vaccines

– – –

Alum

•

Alum alone

•

Alum/MPL (AS04) Emulsions

•

MF59, AF03 Virosomes

–

(Liposomes..coming soon?) CONFIDENTIAL

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ID93-virosome particle architecture

Neuraminidase Hemagglutinin GLA integrated into bilayer ID93 is anchored in virosome membrane via lipid anchor The integration occurs at the time of particle assembly 6

Adjuvants in TB Vaccine Candidates

AS01 (M72); MPL, QS21, Liposomal (TLR4) CAF01 (H1) Liposome IC31 (H1,H56,H4) (TLR9) GLA-SE (ID93) (TLR4)

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Next Generation Adjuvant: GLA GLA Based; Synthetic TLR 4 Agonist

Proven Mechanism of Action: Based on MPL Several Formulations Have Been Prepared Clinical Stage (Five Trials Completed; Six More in Progress) Scaled Production, Low COG

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Rational Design of TLR 4 Ligands PO 4 interfaces with TLR-4 chain 1 Acyl interface with TLR-4 chain 2

Synthetic TLR-4 agonist

Lipid “sandwich” in MD2 CONFIDENTIAL

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Optimizing Adjuvant Activity

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Increased Purity= Increased Potency CONFIDENTIAL

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TLR4 Agonists: Designer Adjuvants CONFIDENTIAL

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Significance of GLA Purity, Potency

Lowest Doses of Any TLR Agonist in Clinic (5ug or less) Favorable COG

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TLR Agonist to Adjuvant

Micelle • Nanomicellar GLA Emulsified • GLA-SE Small Particle • GLA/Alum • GLA-LI Liposome

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Adjuvant Formulation Library

GLA R848 • • • • • • • • QS21 • • • CpG • • Aqueous suspension Alum-adsorbed Liposome Niosome Emulsion Aqueous solution Liposome Emulsion Aqueous solution Liposome Emulsion Aqueous solution Emulsion • • • •

GLA + QS21

– Aqueous suspension – Liposome – Emulsion

GLA + R848

– Aqueous suspension – Liposome – Emulsion

GLA + CpG

– Aqueous suspension – Emulsion

GLA + Poly (I:C)

– Aqueous suspension – Emulsion

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Importance of Adjuvant Selection

30000

IFN-



Th1

400 25000 300 20000

TNF

15000 10000 5000 200 100 0 0

ID83+ G LA SE S E 1ug S E G LA G LA 5ug S E 20 ug ID83+ ID83+ ID83+ G LA SE S E 1ug ID83+ ID83+ S E G LA G LA 5ug S E 20 ug

• GLA-SE enhances Th1 responses

Th2

800 700

IL-5

800 700

IL-13

600 600 500 500 400 300 400 300 200 200 100 100 0 0

ID8 3+S LA E S E 1 LA ug ID8 3+G ID8 3+G ID8 3+G S E 5 LA ug S E 2 0ug ID8 3+S LA E S E 1 ug LA S E 5 ug S E 2 0ug LA ID8 3+G ID8 3+G ID8 3+G

while SE promotes Th2 cytokines

Adjuvant Selection: A Matter of Life or Death 100 90 80 70 60 50 40 30 20 10 0 0 50 100 Days post challenge (d) 150

Saline BCG ID93/SE ID93/GLA-SE ID93/GLA-SE confers protection against

Mtb

in guinea pigs. Guinea pigs were injected with saline or were immunized with BCG, ID93/SE, or ID93/GLA-SE. The data is represented as percentage survival of guinea pigs over time following infection with

Mtb

. Log-rank test was used for statistical comparisons of median guinea pig survival among the experimental groups.

p

values  0.05 were considered significant.

Do We Need A New TB Vaccine?

Boosting BCG

Therapeutic Vaccination

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ID93/GLA-SE, ID83/GLA-SE: Protection in BCG primed Guinea Pigs 100 75 50 25 0 0

* *

100 200 Days 300 400 500

Saline BCG' Saline Boost BCG' ID83+GLA-SE BCG' ID93+GLA-SE 19

Do We Need A New TB Vaccine?

Boosting BCG

Therapeutic Vaccination

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TB: Infection Prime Vaccine Boost 100 80 60 40 20 0 0 50 100 150 200 Days p.i.

250

Rx+ID93+GLA-SE (DTT) Rx+ID93+GLA-SE (PTT) Rx d15-105 Saline

300 350 400

Mice were infected with LDA of Mtb. Fifteen days later mice were treated for 90 days with a combination of antibiotics. A subset of mice in each group were immunized three times, three weeks apart with the candidate fusion vaccine one day after chemotherapy was completed. Protection was assessed by monitoring animal survival.

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ID93/GLA-SE: Summary, Status Protection Mouse Models

Prophylactic Therapeutic

Protection in Disease Models

Guinea Pigs NHP

Clinical Trials

1. U. S. Phase I (Ongoing) 2ug vs. 5ug GLA-SE; 2 vs. 10 ug Ag 2. S.A. Phase I (Planned)

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• • • •

Therapeutic Vaccination: Lessons Learned

Safe in Infected, Diseased Individuals • Applications for Post Exposure Prophylaxis and Therapy Human Leishmaniasis: Strong Immune Responses, but Weak Responses to Vaccine Antigens Prior to Vaccination Strong Ag-Specific Responses Induced Post-Vaccine

Immune Response Can Be Re-Directed With Protein/Adjuvant CONFIDENTIAL

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Vaccine Optimization

Future Directions: Adjuvant Formulation, TLR Combinations ID Delivery

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TLR Agonist Synergy (TLR4/TLR7/8): Human DC CONFIDENTIAL

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TB Protection: TLRL Synergy

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Intra-dermal Delivery

Sanofi has demonstrated advantages of ID delivery (Fluzone) BCG Delivered ID Targeting dermal dendritic cells (DDC) TLR 4 expressed on DDC No adjuvants for ID delivery have been developed GLA formulations are safe and effective ID adjuvants

Clinical Trial of ID GLA Ongoing

Dendritic Cells in Human Skin

CD1a

• • • • Langerhans cells CD1a Langerin (CD207) Birbeck granules E-cadherin • • • Dermal dendritic cells CD1b DC-SIGN (CD209) FXIIIa

DC-SIGN

Microneedles Combined with Adjuvant

Intra-dermal Delivery

Cross Cutting Lessons to Accelerate Clinical Development

• • • Common Platforms Useful For Multiple Vaccine Candidates • Adjuvant/Formulation Selection is Critical

More Adjuvant is Not Better

• MPL; 40ug vs. 10ug • GLA Formulations: 2ug < 5ug > 20ug Lowering Development Hurdles • Build on Known Adjuvants When Possible • Use Minimal Amounts

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Funding Development

BMGF NIAID BARDA DARPA Murdock Trust ALM

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Acknowledgments

• IDRI Rhea Coler Sylvie Bertholet Susan Baldwin Mark Orr Tom Vedvick Chris Fox Darrick Carter Greg Ireton • WHO Martin Friede www.pbs.org/nationalparks