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Progress in Developing New TB Vaccines
Jerald C. Sadoff, MDReversing the Tide: The End of Tuberculosis
Columbia UniversityMarch 7th 2006
2
Potential Impact of 50-90% Effective Vaccines
• Vaccines in combination with antibiotics could control the epidemic
• Pre-exposure or post-exposure vaccines could eliminate about 1/3 of disease and death
• A TB vaccine with pre- and post-exposure efficacy could achieve global control of TB
Ziv et al, Emerging Infectious Diseases, Vol.10, No.9 September 2004
Lietman, T, Blower SM, Clin. Inf Dis.2000:30:S316-22
Lietman, T. Blower SM. Science. 1999:286:1300-01
3
Aeras Global TB Vaccine Foundation
Mission:
To develop new TB vaccines and ensure their availability to all who need them
Goals:
- To obtain regulatory approval and ensure supply of a new TB vaccine regimen within 7-10 years
- To introduce 2nd generation vaccines with improved product profiles and efficacy against latent TB in 9-15 years
4
Aeras
AcademiaCapetown Univ. S. Africa
St. Johns, BangaloreKarolinska, Stockholm
Max Plank, BerlinLeiden Univ.
UCLAU.C. Davis
Vanderbilt Univ.Colorado St. Univ.
Harvard U.European TBVac
Foundations/GovernmentBill & Melinda Gates Foundation
U.S. CDC, NIH, FDADANIDA, Denmark
EDCP, EuropeSTOP TB, WHO
Industry GSK, Rixenstart Belgium
Crucell, HollandSSI, Denmark
ImmunoBiology, UKSerum Institute, India
Thymed, Germany
8
9
Field Site Developed in the Breede River Valley of the Boland-Overberg Region of Western
Cape Province, South Africa
Boland-Overberg Region
Breede RiverValley
Ceres
10
11
India Site
Palamaner Taluk
St. John’s MedicalCollege, Bangalore
Palamaner Taluk• Population of 350,000• Mostly rural • ~ 3 hours from Bangalore• TB incidence rate in adults of 150-200/100,000• St. Johns has long standing relationship with Emauss Leprosy Hospital in Palamner and has conducted large nutritional cohort studies in this community.
12
13
0
10
20
30
40
50
60
0 6 12 18 24 30 36 42 48
Months of Age
Inci
den
ce p
er 1
0,00
0
Incidence observed in BCG Trial w ith active surveillance
Incidence of tuberculosis in 11,667 BCG vaccinated infants with a smear
and/or culture positive for M.tb
Total TB incidence = 3.1%2-year TB incidence = 2.7%
14
Preliminary Conclusions and Approach
Conclusion:
• Field trials of new TB vaccines feasible in this population
Approach:
• Large cohort studies in 9000 infants and 12000 adolescents in S. Africa and India to confirm high incidence
15
Basis for New TB Vaccine Development• Humans are resistant to infection & disease
– Only ~30% of exposed individuals are infected– Only ~10% of infected individuals get disease
• Human resistance related to the immune system– Humans with INFγ and TNF genetic and
pharmacologic pathway defects highly susceptible to TB
16
Potential Uses of Effective TB Vaccine
17
Prime Boost Strategies
14 Weeks
24 Weeks
18
Protection in Eight BCG Trials
Trial and Subjects Duration(years)
Percentprotection
North American Indians (2792 subjects from 1935-1995
9-11 (60) 80 (52)
Chicago : infants 12-23 75
Georgia : school children 20 None
Puerto Rico : population below 20 years 5 ½ - 7 ½ 31
Georgia and Alabama : general pop. 14 14
Great Britain : school children (54,239 subjects age 14-15 from 1950-72
15 78
Mandanapalle, South India: general pop 9-14 31
Chingleput, South India : general population (265,172 subjects)
7 ½ None
Baily, G. V. J., et al, Indian Journal Medical Research 70, September 1979, pp. 349-363.
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BCG Replacements:Recombinant BCG & TB ready for Phase I
• rBCG30 over-expressing TB antigen 85B: Horwitz at UCLA which is not acceptable to regulatory authorities as a final product
• rBCGs escaping the endosome: Kaufmann at Max Planck Institute
• Aeras 403 rBCG – Aeras recombinant BCG combines Horwitz and Kaufmann discoveries
• Recombinant attenuated TB: Bill Jacobs at Albert Einstein University
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% Ag85B-specific IFN- Producing CD8+ T cells (Hanekom Assay)(Means ± SEs)
Tice rBCG30
Group
-0.1
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Day 0 Day 56 Day 112 Day 252
p=.05
*
*Wilcoxon matched pairs test (compared w ith Day 0)
Preliminary data from 17/30 subjects in trial
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Intracellular tropism of intracellular bacteria
Courtesy of Dr. Stefan Kaufmann, Max Plank Inst. Infect. Dis., Germany
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pAF112
oriM
PAg85B Ag85A Ag85B Ag 10.4
rBCG Aeras 403 Strain Construction
BCG Danish 1331
Pfo integrationPlasmid for endosome
escape
AFV102
Phsp60sacB
OriE
PkanKanR
ureCL-flank
PAg85B
Ag85Bleader peptide
pfo
ureCR-flank
MCS
ENpAF102
AFV112 Aeras 403
Over-expressionPlasmid
oriE
PRv3130
24
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rBCG Vaccine - Aeras 403
• New Fermentation and foam drying process developed which produces very high yield of room temperature stable vaccine
• Aeras factory can produce the worlds needs for bulk vaccine- 150-300 million doses/year
• Aeras bulk vaccine will be shipped to developing world manufacturers for foam drying, packaging and distribution
• Phase I clinical trials scheduled for August 06
27
Prime Boost Strategies
14 Weeks
24 Weeks
28
Candidates for boosting infants and adolescents in or about to start Phase I
• Recombinant fusion proteins in adjuvant– M72 fusion GSK/Aeras
– Ag85B::ESAT6 SSI/TBVAC
– Ag85B::10.4 fusion SSI/Aeras
• Vectored vaccines– rMVA-Ag85A Oxford
– rAd35-Ag85A-Ag85B-TB10.4 fusionAeras/Crucell
– Oral Shigella dsRNA capsids Aeras
29
rBCG prime with rAd35 Aeras 403 BoosterFold rise in CD8+T cells
0
1
2
3
4
5
6
85a 85b 10.4
BCGAFRO-1
30
Prime Boost Strategies
14 Weeks
24 Weeks
31
EM of procapsids in S. flexneri MPC51
32
Completion of second strand triggers mRNA synthesis and secretion
Nucleocapsid (NC)
L
M
S
P2 catalyzes synthesis of mRNA, which is passively secreted back through P4 hexamers on capsid surface for translation
mRNA
Shigella-rdsRP vector
• Access cytoplasm• Lysis due to murI• Release of rdsRP
Invasion
Nucleus
Delivery of rdsRP by Shigella vectors
to host antigen presenting cells
Synthesis of recombinant segment-S and segment-M mRNA by RNA-dependent RNA polymerase activity of rdsRP
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
34
rdsRP encoded antigen mRNA expression by HeLa cells
HeLa cell 14 hr post-invasion by MPC51 carrying rdsRP LSMtb4 (85A-85B-10.4 encoded on rSeg-M) Probed with anti-85A IgY
35
Mouse Dose Response/Immunogenicity Study
Cellular immune responses of BALB/c mice vaccinated intranasally with varying doses of the Shigella-vectored nucleocapsid LSMtb4 (expresses Ag85A-85B-10.4 fusion) or Ad35 TBS administered IM
IFN+ CD4 Ag85A
LSMtb
4 (1
0e5
cfu)
LSMtb
4 (5
x10e
4 cf
u)
LSMtb
4 (1
0e4
cfu)
Ad35TBS (1
0e9
pfu)
0.00
0.25
0.50
0.75
1.00
x-fo
ld i
ncr
ease
ab
ove
bac
kgro
un
d TNF+ CD8 Ag85A
LSMtb
4 (1
0e5
cfu)
LSMtb
4 (5
x10e
4 cf
u)
LSMtb
4 (1
0e4
cfu)
Ad35TBS (1
0e9
pfu)
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
x-fo
ld i
ncr
ease
ab
ove
bac
kgro
un
d
36
Vaccine Development Timelines
2004
Preclinical AerasAeras 404 (oral)
2005
2006
2007 2008
Phase I and IIAeras 403/402
2009 2010
Field Site Preparation & Epidemiology
Preclin. Aeras 402 & Aeras 403
Phase III Aeras 403 Prime Aeras 402 Boost Infants &
Adolescents
AerasCrucell
Aeras
2013
20122011 2014
Phase I and IIAeras 403/404
Phase III Aeras 403 Prime Aeras 404 Boost Infants &
Adolescents
Aeras 402 = Crucell Ad35 vectored TB vaccineAeras 403 = rBCG with overexpression & endosome escapeAeras 404 = capsids In shigella for oral delivery
37
Summary
• A moderately effective vaccine + drug control could virtually eliminate the TB 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
• The potential of rBCG prime given at birth followed by viral vector, capsid or protein boost to induce high levels of cellular immunity make this a very attractive vaccine regimen for TB, malaria and HIV
38
Contact Information
Jerald C. Sadoff, MD
President & Chief Executive Officer
Aeras Global TB Vaccine Foundation
7500 Old Georgetown Road, Suite 800
Bethesda, MD 20814
+1-301-547-2912
39
Jerald Sadoff led or contributed to the development of these vaccines
• Licensed– Hepatitis A –Vaqta– H. Influenza conjugate –Liquid Pedvax– Varicella- 4 degree stable Varivax– Combination Hep B & H. Influenza – Comvax– Combination D, T, aP, Polio, H. Influ, Hep B –Hexavac– Measles, Mumps, Rubella, Varicella – MMRV– Rotavirus – Rotatech– Zoster – Zostovac– HPV – (license 06)– Cholera (Killed Whole cell +B -SBL)
• In phase IIB or III– Malaria (Army-GSK-RTSS)– HIV (Merck)– Cholera –Peru 14– Shigella conjugate (NIH)
• In phase I– TB rBCG & M72