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2. Progress in Developing TB Vaccines Second Stop TB Partners Forum New Delhi, India March 25, 2004 Jerald C. Sadoff MD 3. Aeras Mission
4. Aeras Goals
5. Infants vaccinate vaccinate Adolescents Latent Infection Acute Infection Reactivation in Adolescents and AdultsHighly infectious 6. Infants vaccinate vaccinate Adolescents Latent Infection Acute Infection Reactivation in Adolescents & AdultsHighly infectious 7. Aeras Strategy
8. Rationale for TB vaccine potential
9. Prime Boost Strategy For Protection against Acute Infection and Disease in Infants 10. Candidates for the Priming of Newborns:
11. Candidates for Boosting Infants and adolescents
12. Recombinant Live Prime
13. Booster Vaccines for infants and Adolescents Recombinant Fusion Proteins
14. Booster Vaccines for infants and Adolescents Vectored Vaccines
15. Vaccines to prevent the latent state or reactivation from the latent state
16. rBCG30
17. 18. rBCG30
19. Intracellular tropism of intracellular bacteria Courtesy of Dr. Stefan Kaufmann, Max Plank Inst. Infect. Dis., Germany 20. rBCG:: ureC - llo +
21. Protective capacity of rBCG:: ureC - llo +in the murine aerosol model of tuberculosis BALB/c mice were immunized with 10 6CFU BCG or rBCG:: ureC - llo +and challenged 120 days after vaccination.Bacterial load in lungs was determinedpost aerosol-challenge withM. tuberculosisH37Rv. 0 10 20 30 40 50 60 70 80 90 100 2.5 3.5 4.5 5.5 Naive BCG p BCG p ureC BCG p ureC - llo + Days post-challenge Log 10cfu in lungs Courtesy of Dr. Stefan Kaufmann, Max Plank Inst. Infect. Dis., Germany ------2.12-fold (log 10 ) ------1.13-fold (log 10 ) 22. 0 25 50 75 100 125 150 0 10 20 30 40 50 60 70 80 90 100 110 BCG Pasteur rBCG p :: llo + rBCG p :: ureC - llo + Intravenous dose/mouse: BCG p-- 8x10 7 rBCG p ::llo +-- 1x10 7 rBCG p :: ureC-llo +-- 3x10 7 Virulence of BCG p :: ureC - llo +in SCID mice Day post infection Percent survival Courtesy of Dr. Stefan Kaufmann, Max Plank Inst. Infect. Dis., Germany 23. Mtb72f is the lead booster candidate
24. Construction of Mtb72f Mtb32 C-term = Ra12 Mtb32 N-term = Ra35 Mtb39 = tbH9 Mtb32 C-term Mtb39 Mtb32 N-term 192 1 391 195 1 323 ~14KD ~39KD ~20KD 25. Corim VI Study (monkeys):20 weeks post-challenge 26. Corim VI Study (monkeys):48 weeks post-challenge 27. CORIM VI study (monkeys):99 weeks Post-Challenge BCG/Mtb72f BCG/AS02 AS02 28. PR 4558A, Group II, 10/30/2001 29. PR 2799F, Group III, 10/30/2001 30. PR 2799F, Group III, 12/30/2001 31. Shigella -rdsRP vector
Invasion Nucleus A live oral vaccine against TB is possible: Delivery of rdsRP byShigellavectors Synthesis of recombinantsegment-S mRNAby RNA-dependent RNApolymerase activity of rdsRP Amplification of mRNA encoding TB antigens by alphavirus ampliconEF2-independenttranslation of TB antigens Presentation of TB antigens in the context of HLA class I&II Induction of TB-specific CD4 +and CD8 +T cells 32. Epidemic Dynamics
33. Slide courtesy of Chris Dye, WHO, Geneva 34. Fig 2rBCG30 Live TB Vaccine Yr 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr 6 Yr 7 Yr 8 Process Devel Phase III Manufacture Release Phase III Material Release Assay Validation Clinical Operational Characterization Infection Detection & Disease Stdy rBCG30-4Phase I S. AfricaPPD- , 11-12 yr StdyrBCG30-5Phase I S. Africa + 2Other Sites PPD- , 5 yr Stdy rBCG30-6Phase I S. Africa + 2Other SitesInfants 3 Months Stdy rBCG30-1 Phase I US PPD- Adults 30 Subjects 110 GP 30 Subjects 30 Subjects 90 Subjects (30/Site) 90 Subjects (30/Site) Stdy rBCG30-3Phase I USPPD+ Adults Koch Phen Guinea Pig Study 30 Subjects Stdy rBCG30-2Phase I Africa PPD- Adults Stdy rBCG30/72f-1Phase II S. Africa + 2 Other Sites Prime Boost4-Arm Trial Neonates648 Subjects (216/Site)
Site Development/Epidemiology/Infrastructure/Training Operaqtional Chaqracterization Immune Response, Disease, Infection Assays Go/NoGo 35. Fig 3rBCG30 Prime + 72f Boost Subject to a Later Supplemental Request Yr 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr 6 Yr 7 Yr 8 Interim Analysis (POC)
Final Scale Up Development & Manufacture 72f Final Scale Up for Manufacturing rBCG30 Pivotal Phase III 3 Arm Study Adolescents & Adults Interim Analysis (POC)
25,000 Subjects Pivotal Phase III 4 Arm Study - Neonates 26,000 Subjects Initial Safety Initial Safety Go/NoGo 36. Summary