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 2 nd generation vaccines with improved product profiles and efficacy against latent TB in 9-15 years

Infants Acute Infection Latent Infection Reactivation in Adolescents and Adults Highly infectious vaccinate Adolescents

Infants Acute Infection Latent Infection Reactivation in Adolescents & Adults Highly infectious vaccinate Adolescents

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 over- expresses 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 BALB/c mice were immunized with 10 6 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 Naive BCG p BCG p  ureC BCG p  ureC-llo + Days post-challenge fold (log 10 ) fold (log 10 ) Log 10 cfu in lungs Courtesy of Dr. Stefan Kaufmann, Max Plank Inst. Infect. Dis., Germany

BCG PasteurrBCG p ::llo + rBCG p ::  ureC-llo + Intravenous dose/mouse: BCG p -- 8x10 7 rBCG p ::llo x10 7 rBCG p ::  ureC-llo x10 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

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

Mtb32 C-termMtb39Mtb32 N-term ~14KD ~39KD ~20KD Construction of Mtb72f Mtb32 C-term = Ra12 Mtb32 N-term = Ra35 Mtb39 = tbH9

Corim VI Study (monkeys): 20 weeks post-challenge

Corim VI Study (monkeys): 48 weeks post-challenge

CORIM VI study (monkeys): 99 weeks Post-Challenge BCG/Mtb72f BCG/AS02 AS02

PR 4558A, Group II, 10/30/2001

PR 2799F, Group III, 10/30/2001

PR 2799F, Group III, 12/30/2001

Shigella-rdsRP vector Access cytoplasm Lysis due to  asd Release of rdsRP Invasion Nucleus A live oral vaccine against TB is possible: Delivery of rdsRP by Shigella vectors Synthesis of recombinant segment-S mRNA by RNA-dependent RNA polymerase activity of rdsRP Amplification of mRNA encoding TB antigens by alphavirus amplicon EF2-independent translation of TB antigens Presentation of TB antigens in the context of HLA class I&II Induction of TB-specific CD4 + and CD8 + T cells

Epidemic Dynamics R = R 0 (1-EC) Where: R 0 = 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 1Yr 2Yr 3Yr 4Yr 5Yr 6Yr 7Yr 8 Process Devel Phase III Manufacture Release Phase III Material Release Assay Validation Operaqtional Chaqracterization Immune Response, Disease, Infection Assays Clinical Operational Characterization Infection Detection & Disease Stdy rBCG30-4 Phase I S. Africa PPD-, 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 rBCG30-1 Phase I US PPD- Adults 30 Subjects 110 GP 30 Subjects 90 Subjects (30/Site) 90 Subjects (30/Site) Stdy rBCG30-3 Phase I US PPD+ Adults Koch Phen Guinea Pig Study 30 Subjects Stdy rBCG30-2 Phase I Africa PPD- Adults Go/NoGo Stdy rBCG30/72f-1 Phase II S. Africa + 2 Other Sites Prime Boost 4-Arm Trial Neonates 648 Subjects (216/Site) (1)BCG (2)rBCG30 (3)BCG Prime + Mtb72fBoost (4)rBCG30 Prime + Mtb72f Boost Site Development/Epidemiology/Infrastructure/Training

Fig 3 rBCG30 Prime + 72f Boost Subject to a Later Supplemental Request Yr 1Yr 2Yr 3Yr 4Yr 5Yr 6Yr 7Yr 8 Interim Analysis (POC) (1)BCG (2)rBCG30 (3)BCG Prime + Mtb72fBoost (4)rBCG30 Prime + Mtb72f Boost Final Scale Up – Development & Manufacture 72f Final Scale Up for Manufacturing rBCG30 Pivotal Phase III 3 Arm Study – Adolescents & Adults Interim Analysis (POC) (1)Placebo (2)Mtb72fBoost (3)rBCG30 Prime + Mtb72f Boost 25,000 Subjects Pivotal Phase III 4 Arm Study - Neonates 26,000 Subjects Go/NoGo Initial Safety

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 years