Transcript WTBD2004 34 The future of vaccine development

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