ID93/GLA-SE TB Vaccine Candidate

1. ID93/GLA-SE TB Vaccine Candidate TB Vaccines Global Forum Cape Town, 26 March 2013 CONFIDENTIAL

2. 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 oil droplet phosphatidylcholine ID93 – Stable Emulsion (SE) ID93 Rv3619 Rv1813 Rv3620 Rv2608 Pluronic F68 squalene 2

4. Enabling Roles of Adjuvants • T cell vaccines • Antibody Response Broadening • Antigen Dose Sparing • Immune Response Durability • Vaccine Dosage Sparing • Immune Senescence • Vaccine Therapy CONFIDENTIAL

5. Adjuvant Platforms in Approved Vaccines Alum Alum alone Alum/MPL (AS04) Emulsions MF59, AF03 Virosomes (Liposomes..coming soon?) CONFIDENTIAL

6. 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

7. Adjuvants in TB Vaccine Candidates • AS01 (M72); MPL, QS21, Liposomal (TLR4) • CAF01 (H1) Liposome • IC31 (H1,H56,H4) (TLR9) • GLA-SE (ID93) (TLR4) CONFIDENTIAL

8. 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 CONFIDENTIAL

9. Rational Design of TLR 4 Ligands PO4 interfaces with TLR-4 chain 1 Acyl interface with TLR-4 chain 2 Synthetic TLR-4 agonist Lipid “sandwich” in MD2 CONFIDENTIAL

10. Optimizing Adjuvant Activity CONFIDENTIAL

11. Increased Purity= Increased Potency CONFIDENTIAL

12. TLR4 Agonists: Designer Adjuvants CONFIDENTIAL

13. Significance of GLA Purity, Potency • Lowest Doses of Any TLR Agonist in Clinic (5ug or less) • Favorable COG CONFIDENTIAL

14. TLR Agonist to Adjuvant CONFIDENTIAL

15. Adjuvant Formulation Library • GLA • Aqueous suspension • Alum-adsorbed • Liposome • Niosome • Emulsion • R848 • Aqueous solution • Liposome • Emulsion • QS21 • Aqueous solution • Liposome • Emulsion • CpG • 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 CONFIDENTIAL

16. Importance of Adjuvant Selection while SE promotes Th2 cytokines • GLA-SE enhances Th1 responses Th2 Th1

17. Adjuvant Selection: A Matter of Life or Death 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.

18. Do We Need A New TB Vaccine? • Boosting BCG • Therapeutic Vaccination CONFIDENTIAL

19. ID93/GLA-SE, ID83/GLA-SE:Protection in BCG primed Guinea Pigs

20. Do We Need A New TB Vaccine? • Boosting BCG • Therapeutic Vaccination CONFIDENTIAL

21. TB: Infection Prime-Vaccine Boost 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.

22. 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) CONFIDENTIAL

23. 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

24. Vaccine Optimization • Future Directions: • Adjuvant Formulation, TLR Combinations • ID Delivery CONFIDENTIAL

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

26. TB Protection: TLRL Synergy

27. 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

28. Dendritic Cells in Human Skin Langerhans cells • CD1a • Langerin (CD207) • Birbeck granules • E-cadherin CD1a Dermal dendritic cells • CD1b • DC-SIGN (CD209) • FXIIIa DC-SIGN

29. Intra-dermal Delivery Microneedles Combined with Adjuvant

30. 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 CONFIDENTIAL

31. Funding Development BMGF NIAID BARDA DARPA ALM Murdock Trust CONFIDENTIAL

32. 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