global tb vaccine foundation. progress in developing tb vaccines second stop tb partners’ forum...
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Global TB Vaccine Foundation
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Progress in Developing TB Vaccines
Second Stop TB Partners’ ForumNew Delhi, IndiaMarch 25, 2004
Jerald C. Sadoff MD
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Aeras Mission
To develop and insure availability of new effective TB vaccines for all people who need them
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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
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Infants
LatentInfection
AcuteInfection
Reactivation inAdolescentsand Adults
Highly infectious
vaccinate
vaccinateAdolescents
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Infants
LatentInfection
AcuteInfection
Reactivation inAdolescents
& Adults
Highly infectious
vaccinate
vaccinateAdolescents
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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
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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
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Prime Boost Strategy
For Protection against Acute Infection and Disease in Infants
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Candidates for the Priming of Newborns:
• BCG
• Recombinant BCG
• Live attenuated recombinant TB variant
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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
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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
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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)
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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
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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
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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
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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
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Intracellular tropism of intracellular bacteria
Courtesy of Dr. Stefan Kaufmann, Max Plank Inst. Infect. Dis., Germany
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rBCG::ureC-llo+
• Max Planck Inst. – Stefan Kaufmann
• Escapes endosome through expression of Lysteriolysin O and Urease C which punch holes
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Protective capacity of rBCG::ureC-llo+ in the murine aerosol model of tuberculosis
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.
0 10 20 30 40 50 60 70 80 90 100
2.5
3.5
4.5
5.5
NaiveBCGp
BCGp ureCBCGp ureC-llo+
Days post-challenge
------ 2.12-fold (log10)------ 1.13-fold (log10)
Lo
g10
cfu
in
lu
ng
s
Courtesy of Dr. Stefan Kaufmann, Max Plank Inst. Infect. Dis., Germany
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0 25 50 75 100 125 1500
10
20
30
40
50
60
70
80
90
100
110
BCG Pasteur rBCGp::llo+rBCGp::ureC-llo+
Intravenous dose/mouse:BCGp -- 8x107
rBCGp::llo+ -- 1x107
rBCGp::ureC-llo+ -- 3x107
Virulence of BCGp::ureC-llo+ in SCID mice
Day post infection
Per
cen
t su
rviv
al
Courtesy of Dr. Stefan Kaufmann, Max Plank Inst. Infect. Dis., Germany
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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
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Mtb32 C-term Mtb39 Mtb32 N-term
192
1 391
1951323
~14KD ~39KD ~20KD
Construction of Mtb72fConstruction of Mtb72f
Mtb32 C-term = Ra12
Mtb32 N-term = Ra35
Mtb39 = tbH9
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Corim VI Study (monkeys): Corim VI Study (monkeys): 20 weeks post-challenge20 weeks post-challenge
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Corim VI Study (monkeys): Corim VI Study (monkeys): 48 weeks post-challenge48 weeks post-challenge
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CORIM VI study (monkeys): CORIM VI study (monkeys): 99 weeks Post-Challenge99 weeks Post-Challenge
BCG/Mtb72f
BCG/AS02
AS02
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PR 4558A, Group II, 10/30/2001PR 4558A, Group II, 10/30/2001
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PR 2799F, Group III, 10/30/2001PR 2799F, Group III, 10/30/2001
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PR 2799F, Group III, 12/30/2001PR 2799F, Group III, 12/30/2001
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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 encodingTB antigens by alphavirus amplicon
EF2-independent translation of TB antigens
Presentation of TB antigensin the context of HLA class I&II
Induction of TB-specificCD4+ and CD8+ T cells
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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 vaccineE= vaccine efficacy = 1- Incidence vacinees
Incidence controlsIf R< 1 Epidemic is eliminated
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Slide courtesy of Chris Dye, WHO, Geneva
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Fig 2 rBCG30 Live TB VaccineFig 2 rBCG30 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
Operaqtional Chaqracterization Immune Response, Disease, Infection Assays
Clinical Operational Characterization Infection Detection & Disease
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 rBCG30-1 Phase I US PPD- Adults 30 Subjects
110 GP
30 Subjects
30 Subjects
90 Subjects(30/Site)
90 Subjects(30/Site)
Stdy rBCG30-3 Phase I US PPD+ Adults
Koch PhenGuinea 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
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Fig 3 rBCG30 Prime + 72f BoostFig 3 rBCG30 Prime + 72f BoostSubject to a Later Supplemental RequestSubject to a Later Supplemental Request
Yr 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr 6 Yr 7 Yr 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
Initial Safety
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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