global tb vaccine foundation. progress in developing tb vaccines second stop tb partners’ forum...
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Global TB Vaccine Foundation
Progress in Developing TB Vaccines
Second Stop TB Partners’ ForumNew Delhi, IndiaMarch 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
Infants
LatentInfection
AcuteInfection
Reactivation inAdolescentsand Adults
Highly infectious
vaccinate
vaccinateAdolescents
Infants
LatentInfection
AcuteInfection
Reactivation inAdolescents
& Adults
Highly infectious
vaccinate
vaccinateAdolescents
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 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
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
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-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
Corim VI Study (monkeys): Corim VI Study (monkeys): 20 weeks post-challenge20 weeks post-challenge
Corim VI Study (monkeys): Corim VI Study (monkeys): 48 weeks post-challenge48 weeks post-challenge
CORIM VI study (monkeys): CORIM VI study (monkeys): 99 weeks Post-Challenge99 weeks Post-Challenge
BCG/Mtb72f
BCG/AS02
AS02
PR 4558A, Group II, 10/30/2001PR 4558A, Group II, 10/30/2001
PR 2799F, Group III, 10/30/2001PR 2799F, Group III, 10/30/2001
PR 2799F, Group III, 12/30/2001PR 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 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
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
Slide courtesy of Chris Dye, WHO, Geneva
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
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
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