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Transcript
Global TB Vaccine Foundation Progress in Developing TB Vaccines Second Stop TB Partners’ Forum New Delhi, India March 25, 2004 Jerald C. Sadoff MD Aeras Mission To develop and insure availability of new effective TB vaccines for all people who need them Aeras Goals • To obtain regulatory approval and insure supply of a new TB vaccine regimen to prevent TB in the next 7-10 years • To introduce 2nd generation vaccines with improved product profiles and efficacy against latent TB in 9-15 years vaccinate Infants vaccinate Adolescents Acute Infection Highly infectious Latent Infection Reactivation in Adolescents and Adults vaccinate Infants Adolescents vaccinate Acute Infection Highly infectious Latent Infection Reactivation in Adolescents & Adults Aeras Strategy • To bring the best current vaccine candidates forward as fast as possible • To insure manufacturing and supply at an affordable price • To eliminate delay between licensure and availability through early factory construction • Every year lost costs 2 million lives Rationale for TB vaccine potential • Human immunology – Humans with IL-12 and INF γ pathway defects highly susceptible to TB • Animal models that mimic human TB can be protected with vaccines • 20 yrs of iterative testing of antigens that healthy infected humans respond to have narrowed the choices Prime Boost Strategy For Protection against Acute Infection and Disease in Infants Candidates for the Priming of Newborns: • BCG • Recombinant BCG • Live attenuated recombinant TB variant Candidates for Boosting Infants and adolescents • Recombinant fusion protein in adjuvant • Vectored vaccines – MVA recombinant – Adenovirus recombinant – oral shigella auxotroph dsRNA expression system • Heat shock associated proteins Recombinant Live Prime • rBCG30 recombinant BCG over expressing Ag85b (Marcus Horowitz) in phase I clinical trials • rBCG Lysteriolysin O (Steffan Kaufman) • Auxotrophic live TB – TB Vac candidate – Bill Jacobs, Barry Bloom – Aeras/Kaufmann Booster Vaccines for infants and Adolescents – Recombinant Fusion Proteins • GSK/IDRI Mtb72f fusion protein in AS01/AS02 (Steve Reed) – in Phase I clinical trials • SSI ESAT-6/Ag85b fusion protein in SSI adjuvant (Peter Anderson) • SSI Ag X/Ag85a fusion protein in SSI adjuvant (Peter Anderson) Booster Vaccines for infants and Adolescents – Vectored Vaccines • Oxford MVA – Expressing Ag85a (Adrian Hill) in Phase I clinical trials • Aeras/Crucell Adenovirus vector expressing TB antigens • Aeras Shigella dsRNA vector expressing TB antigens Vaccines to prevent the latent state or reactivation from the latent state • DosR regulon controls expression of many proteins expressed during the latent state • BCG can be locked in latent state and present DosR regulated proteins • Latent state proteins vaccines as: – Recombinant proteins – Vectors – Adeno, MVA and Shigella – Heat shock associated proteins rBCG30 • Recombinant Tice BCG which overexpresses Ag85b • Protects Guinea pigs better than BCG • Has been produced to cGMP standard at the Korean Institute of Tuberculosis • A modern bio-fermentation process for its final manufacture being developed at Aeras facility at Biovac in S. Africa rBCG30 • Thirty subjects enrolled at two sites in phase I trial – Dr. Dan Hoff - St. Louis University – Dr. Thomas Littlejohn – Winston Salem N.C. • Vaccine shown safe and well tolerated to date in these volunteers Intracellular tropism of intracellular bacteria Courtesy of Dr. Stefan Kaufmann, Max Plank Inst. Infect. Dis., Germany rBCG::ureC-llo+ • Max Planck Inst. – Stefan Kaufmann • Escapes endosome through expression of Lysteriolysin O and Urease C which punch holes Protective capacity of rBCG::ureC-llo+ in the murine aerosol model of tuberculosis Log10 cfu in lungs 5.5 Naive BCGp BCGp ureC BCGp ureC-llo+ 4.5 ------ 2.12-fold (log10) ------ 1.13-fold (log10) 3.5 2.5 0 10 20 30 40 50 60 70 80 90 100 Days post-challenge BALB/c mice were immunized with 106 CFU BCG or rBCG::ureC-llo+ and challenged 120 days after vaccination. Bacterial load in lungs was determined post aerosol-challenge with M. tuberculosis H37Rv. Courtesy of Dr. Stefan Kaufmann, Max Plank Inst. Infect. Dis., Germany Virulence of BCGp::ureC-llo+ in SCID mice 110 100 90 Percent survival 80 rBCGp::llo+ BCG Pasteur 70 rBCGp::ureC-llo+ 60 50 40 30 20 10 0 0 25 50 75 Day post infection Intravenous dose/mouse: BCGp -- 8x107 rBCGp::llo+ -- 1x107 rBCGp::ureC-llo+ -- 3x107 Courtesy of Dr. Stefan Kaufmann, Max Plank Inst. Infect. Dis., Germany 100 125 150 Mtb72f is the lead booster candidate • Produced in partnership with GSK-BIO and IDRI (Steve Reed) • Given with adjuvant AS01 • Phase I in 30 adult volunteers nearing completion • Acceptable safety and tolerability Construction of Mtb72f 192 323 195 1 ~14KD ~39KD ~20KD Mtb32 C-term Mtb39 Mtb32 N-term 1 Mtb32 C-term = Ra12 Mtb32 N-term = Ra35 Mtb39 = tbH9 391 Corim VI Study (monkeys): 20 weeks post-challenge Grp PR# Wt (kg) 1 S6857-F 2925-D C179-G 2798-G 2728-G 243-L 3407-D 2322-G 4558-A 4405-C S0569-BC 3958-C 2799-F 3799-D 3950-D 2197-G 2.25 2.60 2.21 2.55 36.2 36.7 37.2 37.3 0 0 0 0 2.20 2.68 2.40 2.32 2.28 2.00 2.50 2.98 2.18 2.25 2.90 38.4 38.6 38.4 37.8 37.9 38.2 37.7 37.4 39.3 37.9 37.2 0 3 2 0 0 0 0 0 0 0 0 4117-D 2783-F 1528-AE 2.95 2.11 2.60 37.8 37.9 36.9 0 1 0 2 3 4 Temp (C) ESR mm/hr Chest x-ray Neg. Bronchopn, bil, stable since 27 Sept. 2000 Pn, w/atelectasis, If lung Bronchopn, bil, stable since 2 Oct. 2000 Died: Oct. 23, 2000 (D139) Neg. Pn, bil w/ conso of rt upper & middle lobes Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Increase markings both hilar areas, stable since 9/27/00 Bronchopn, bil Neg. Bronchopn, bil, sl progrsn AS02 BCG / AS02 BCG / Mtb72f BCG / Ra12+TbH9 +Ra35 (mixed) Grp 1 2 3 4 Corim VI Study (monkeys): 48 weeks post-challenge PR# Wt (kg) Temp ESR (C) mm/h r S6857-F 2925-D C179-G 2798-G 2728-G 2322-G 4558-A 2.65 2.41 2.68 2.66 38.5 36.3 38.7 38.8 0 5 0 0 2.36 38.5 2.66 38.0 3 0 4405-C 243-L 3407-D S0569-BC 3958-C 2799-F 3799-D 3950-D 2197-G 4117-D 2783-F 1528-AE 2.77 38.0 2.52 38.1 0 0 2.46 2.73 3.39 2.22 2.78 3.20 3.32 2.36 3.14 0 0 0 0 0 0 0 2 0 38.8 38.0 38.3 38.1 38.1 37.8 37.2 37.7 37.4 Chest x-ray (onset) Neg. Bronchopn, bil, improving Pn, w/atelectasis, LL, improved, stable 6 mths Bronchopn, bil, improved, stable 6 mths Died: Oct. 23, 2000 (D139) Pn, rt, progrsv Widening of superior mediastinum & increased density of lf hilum Neg. Neg. Died: Jan. 17, 2001 (D225) Bronchopn, bil, improving Neg. Bronchopn, bil, resolving Neg. Neg. Increase hilar markings, bil, stable 8 mths Bronchopn, bil, stable 7 mths Neg. (disappearance of susp. Haziness) Bronchopn, bil, sl progrsn AS02 BCG / AS02 BCG / Mtb72f BCG+Ra12+TbH9 +Ra35 (mixed) CORIM VI study (monkeys): 99 weeks Post-Challenge Wt Temp ESR (kg) (C) (mm/hr) 2.99 3.13 3.24 37.2 37.3 37.9 1 1 0 3.12 2.42 37.8 37.9 0 0 2.61 2.95 4.03 2.34 3.04 3.43 4.46 2.54 37.6 38.1 38.0 37.9 38.2 37.8 37.5 38.5 0 0 0 3 1 0 0 5 Chest x-ray Neg. Pn, w/ atelectasis, LL Bronchopn, bil, Died: Oct. 31, 2001 (D512) Died: Oct. 23, 2000 (D139) Neg. Bronchopn, rt, stable 2 mos. Died: Apr. 25, 2002 (D688) Died: Nov. 3, 2001 (D515) Died: Jan. 17, 2001 (D225) Neg. chest (resolved) Neg. Neg. chest (resolved) Neg. Neg. chest (resolved) Bronchopn, bil, stable 5 mos. Bronchopn, bil, stable 19 mos. Neg. AS02 BCG/AS02 BCG/Mtb72f PR 4558A, Group II, 10/30/2001 PR 2799F, Group III, 10/30/2001 PR 2799F, Group III, 12/30/2001 A live oral vaccine against TB is possible: Delivery of rdsRP by Shigella vectors Induction of TB-specific CD4+ and CD8+ T cells Shigella-rdsRP vector Presentation of TB antigens in the context of HLA class I&II Invasion Nucleus • Access cytoplasm • Lysis due to asd • Release of rdsRP EF2-independent translation of TB antigens Amplification of mRNA encoding TB antigens by alphavirus amplicon Synthesis of recombinant segment-S mRNA by RNA-dependent RNA polymerase activity of rdsRP Epidemic Dynamics R = R0 (1-EC) Where: R0 = the number of infectious TB cases caused by 1 TB case C = % of population covered by the vaccine E= vaccine efficacy = 1- Incidence vacinees Incidence controls If R< 1 Epidemic is eliminated Slide courtesy of Chris Dye, WHO, Geneva Fig 2 rBCG30 Live TB Vaccine Yr 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr 6 Yr 7 Yr 8 Site Development/Epidemiology/Infrastructure/Training Operaqtional Chaqracterization Immune Response, Disease, Infection Assays Clinical Operational Characterization Infection Detection & Disease Stdy rBCG30-1 Phase I US PPD- Adults Koch Phen Guinea Pig Study 110 GP Stdy rBCG30-2 Phase I Africa PPD- Adults Stdy rBCG30-3 Phase I US PPD+ Adults Stdy rBCG30-4 Phase I S. Africa PPD- , 11-12 yr Stdy rBCG30-5 Phase I S. Africa + 2 Other Sites PPD- , 5 yr Stdy rBCG30-6 Phase I S. Africa + 2 Other Sites Infants 3 Months Stdy rBCG30/72f-1 Phase II S. Africa + 2 Other Sites Prime Boost 4-Arm Trial Neonates (1) BCG Process (2) rBCG30 Devel Phase Manufacture Release Phase III Material (3) BCG Prime + Mtb72fBoost III (4) rBCG30 Prime + Mtb72f Boost Release Assay Validation 30 Subjects 30 Subjects 30 Subjects 30 Subjects 90 Subjects (30/Site) 90 Subjects (30/Site) 648 Subjects (216/Site) Go/NoGo Fig 3 rBCG30 Prime + 72f Boost Subject to a Later Supplemental Request Yr 1 Yr 2 Yr 3 25,000 Subjects Yr 4 Yr 6 Pivotal Phase III 4 Arm Study - Neonates Initial Safety 26,000 Subjects Yr 5 Interim Analysis (POC) Yr 7 (1) (2) (3) (4) Yr 8 BCG rBCG30 BCG Prime + Mtb72fBoost rBCG30 Prime + Mtb72f Boost Pivotal Phase III 3 Arm Study – Adolescents & Adults Initial Safety Interim Analysis (POC) Final Scale Up – Development & Manufacture 72f Final Scale Up for Manufacturing rBCG30 (1) Placebo (2) Mtb72fBoost (3) rBCG30 Prime + Mtb72f Boost Go/NoGo Summary • A moderately effective vaccine + drug control could eliminate the epidemic • Based on 20 years of research a prime boost vaccine strategy has great potential • This new vaccine regimen could be licensed and available in 7-10 years • A new vaccine to prevent reactivation possible in 10-12 years