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Pediatric TB and HIVThe Potential of New TB Vaccines
Dr. Hoosen Coovadia
Nelson Mandela School of Medicine, University of KwaZulu NatalBoard of Directors, Aeras Global TB Vaccine Foundation
Presentation to the CORE GroupMay 17, 2010
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Estimated TB Incidence Rate, 2007
Estimated new TB cases (allforms) per 100 000 population
The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World HealthOrganization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.
Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.WHO 2009. All rights reserved
No estimate
0-24
50-99
>= 300
25-49
100-299
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No estimate
04
2049
>= 50
519
HIV prevalence inTB cases, (%)
The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health
Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.WHO 2009. All rights reserved
HIV Prevalence Among TB Cases, 2007
Global estimate: about 1.4 million TB/HIV cases and 450,000 TB/HIV deaths a year
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HIV/AIDS and TB:A Deadly Combination
HIV suppresses the human immune system
TB suppresses the human immune system Each makes the other worse synergistically
The number of new cases of TB has more thandoubled in countries with high HIV prevalence in the
past 15 years
One in four HIV
deaths is linked toTB
+
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Drug Resistance WHO estimates 490,000 MDR-TB cases emerge every
year, with more than 110,000 deaths
E
xtensively drug-resistant (XDR) TB has been identifiedin 57 countries as of November 2009
In 2008, WHO reported that the highest rates of MDR TBever recorded, with peaks of up to 22% of new TB cases,were in some settings of the former Soviet Union. In thesame region, 1 in 10 cases of MDR-TB is XDR-TB
Treatment for drug-resistant TB is much longer, morecomplex and more expensive - with much lower successrates
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Global Health i
ssues
for children
WHO, WorldHealth Statistics, 2010
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Human Rights Issue No vaccine to provide long-term protection from
pulmonary TB
No HIV vaccine
No benefit from biomedical advances for people andcommunities affected by TB
TB exposure due to inadequate health systems poordelivery of INH prophylaxis
TB and HIV diagnostics inadequate for testing children
Poor pediatric tracking programs to measure incidence
Social circumstances lead to exposure poverty,malnutrition
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Maternal TB/HIV important risk factor forpediatric TB and mortality
Estimated TB rate:
-10 times higher in HIV-exposeduninfected children
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WHOEstimated TB Cases by Age, 2006
Country Total Cases Cases in Children < 15 % in Children
Myanmar 78,489 8,007 10.2
Nigeria 261,404 32,310 12.4
Pakistan 244,736 61,905 25.3
The Phillipines 230,217 12,167 5.3
Russian Fed. 183,373 7,778 4.2
South Africa 220,486 35,449 16.1
Thailand 85,928 2,317 2.7
Uganda 75,250 12,099 16.1
Tanzania 117,489 18,890 16.1
Viet Nam 143,023 7,559 5.3
Zimbabwe 76,296 12,267 16.1
Total 6,678,188 630,722 9.4
Adapted from Childhood TB by AHesseling, PMusoke, AGupta, JSadoff
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Existing TB Vaccine Ineffective BCG provides unreliable protection against
pulmonary TB, which accounts for most TBdisease worldwide
BCG is not know to protect against latent TB
BCG is not recommended for use in infantsinfected with HIV due to increased risk forsevere BCG-related complications
Despite wide use, particularly in high burden
countries, BCG has had no apparent impacton the growing global TB epidemic
BCG does reduce risk of severe pediatricTB disease, so it should continue to be useduntil a better TB vaccine is available
BCG introduced in 1921
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Tuberculosis: TB Vaccine Too Dangerous
for Babies With AIDS Virus, Study Says
July 2, 2009 The vaccine against tuberculosis that is
routinely given to 75 percent of the worlds infants is
too risky to give to those born infected with the AIDS
virus, says a new study published by the World HealthOrganization. It recommended that vaccination be
delayed until babies can be tested.
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Goals for Better TB Vaccines Eliminate TB as a public health
threat, in line with global targets(
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Global TB Vaccine Pipeline
Additional research at the discovery/early pre-clinical level: Bhagawan Mahavir Medical Research Center; Cardiff University; EpiVax, Inc.; ImmunoBiology Ltd.; Infectious Disease ResearchInstitute; Institute de Pharamacologie, Puso; Karolinska Institute; Malaysia-Finlay Institute, NIAID; NIH; Osaka University; Shanghai H&G Biotech; Sequella; UCLA; and, Vanderbilt University .
Vaccine Candidate Pre-Clinical Phase I Phase II Phase IIb Phase III
AE
RAS402/Crucell Ad35Crucell N.V./Aeras
MVA85A/AERAS-485OETC/Aeras
GSK M72GSK Biologicals/Aeras
Hybrid 1 SSI IC-31SSI, TBVI, Intercell
HyVac4/AERAS-404sanofi pasteur/SSI/Intercell/Aeras
VPM 1002Max Planck/Vakzine Projekt Management GmbH/TBVI
AdAg85AMcMaster University
RUTIArchivel Farma, S.I.
Hybrid 1 SSI CAF01SSI
AERAS-rBCGAeras
AERAS-CapsidAeras
Other rBCG rMtbAlbert Einstein S. of Med., Institute Pasteur, Univ. of Zaragoza, TBVI
AERAS-other virusAeras
Protein/PolysaccharidesInst. Pasteur de Lille/Inserm, Albert Einstein S. of Med., Aeras, Karolinska Instit.
As of November 2009
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Aeras Global TB Vaccine Foundation
MissionTo develop new, more effective TBvaccines and ensure their availability toall who need them
Goal A more effective, safe and affordable
TB vaccine by 2016
Method Collaborate with academic, biotech,
pharmaceutical and NGO partners todevelop and test new TB vaccines
Pursing a Prime-Boost strategy bydeveloping a modern replacement forBCG plus booster vaccines
Develops vaccines in its own lab and
manufacturing plant
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Safer in HIV infected infants orothers with immune-suppression
BCG or rBCG boosted with anotherTB vaccine is much better thaneither vaccine alone
Constructed to address each stageof the TB life cycle
Prevent infection and reactivation
A new vaccine candidate with all ofthese properties is expected toenter clinical trials in 2010
Recombinant BCG (rBCG) - A Better BCG
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Summary of Aeras Candidates in Clinical TestingSSI HyVac4 / AERAS-404 Status: Phase I
Recombinant protein vaccine intended to be a booster vaccine
Phase I clinical trials
Current trials in Finland, Sweden, South Africa
GSK M72 Status: Phase II
Recombinant protein vaccine intended to be a booster vaccine
Phase I and II trials conducted in Europe, Africa and Asia, including a Phase I trial in HIV+ in
EuropeCurrent trials in South Africa, the Gambia
AERAS-402 / Crucell Ad35 Status: Phase IIb
Viral vectored vaccine utilizing adenovirus 35; intended to be a booster vaccine
Phase I and II trials conducted in North America and Africa; Phase IIb recently initiated in HIV+ inSouth Africa
Current trials in South Africa
MVA85A / AERAS-485 Status: Phase IIb
Viral vectored vaccine utilizing modified vaccinia Ankara; intended to be a booster vaccine
The most clinically-advanced booster vaccine for tuberculosis with an ongoing proof-of-conceptPhase IIb trial in infants
Previous clinical trials in the UK and Africa, including in HIV+
Awarded orphan drug status by EMEA
Current trial in South Africa
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Aeras Partnerships for Field Research
SATVI/U of Cape TownWorcester, South Africa
Makerere UniversityKampala, Uganda
KEMRI/CDCKisumu, Kenya
St. Johns Research InstitutePalamaner, India
Cambodian Health CommitteeSvay Rieng, Cambodia
Manhica Health Research CentreManhica, Mozambique
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Example of Site Development
South Africa Partnership with South African Tuberculosis Vaccine Initiative (SATVI)
Field site developed in Worcester (~120 km from Cape Town)
Infrastructure developed:
State-of-the-art immunology laboratory Highly skilled staff capable of performing the duties necessary to maintain the
infrastructure and execute clinical research
Clinical and office facilities
Professional Development Program (Siyantinga- Reach for the Stars) program initiated in 2001
Resource Center established in 2005
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Clinical Trials Field Site Development
Large-scale community-based clinicaltrials are conducted in high burdencountries
Aeras partners with local researchinstitutions to establish field sites andconduct clinical research
Build local infrastructure and health
care/research capacity to perform futureGood Clinical Practice (GCP) compliantPhase III clinical trials
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Activities in South Africa
Research Partner - South AfricanTuberculosis Vaccine Initiative (SATVI)
Conducting Phase I, II and IIb studies of
fourvaccine candidates Adult and infant enrollment
Over 230 staff trained since 2004
Most advanced site for large-scale TB
vaccine trials in the world Future infant studies planned of AERAS-
402/Crucell Ad35
Western Cape
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Activities in South Africa
Research Partner University ofCape Town Lung Institute
Phase II clinical trial in adults with
active or previous TB (AERAS-402/Crucell Ad35 )
Cape Town
Future study of TB vaccine
candidate in HIV infected adultsplanned (part of multi-centerMVA85A/AERAS-485 study)
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Activities in South Africa
Research Partner Aurum Institute Enrolling adults with HIV in Phase IIb trial Safety and efficacy of TB vaccine
(MVA85A/AERAS-485)
Klerksdorp, North West (mining area)
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Access and Availability Future access considered at every stage of vaccine
development Manufacturing
Guarantee by partners for sufficient production and affordableprices, or technology transfer
Manufactured by Aeras with partners in developing world Aeras will not consider vaccine candidates that will be costly to
manufacture on a large scale
Pricing Dual pricing for affordable distribution in resource-poor countries Cost plus purchase from partner Aeras provides at cost
Distribution Developing world governments International organizations (GAVI, UNICEF) Developing world partners
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TB Vaccine Development Timeline
Field Site Preparation ($2-4 million per yr, per site)
2.5 Years 3 Years 4 Years
Direct costs to develop one TB vaccine candidate could be as much as$340 million
Phase III licensure trials are complex and the most costly componentInfant trial - between $70 and $140 millionAdolescent and adult trial - between $130 and $265 million
Aeras has a broad pipeline of vaccine candidates, 4 of which are currentlyin clinical trials
With sufficient resources, a new TB vaccine could be ready in 7 10 years.
1 - 2 Years 1 Year
Vaccin
eDiscovery
Pre-
Clinical
Testing
Phase
I
Phase
II
Phase IIb Phase III
Manufacturing ($310 million to build and upgrade facilities; $10 million per year to maintain)
$3 million $18 million $48 million
Licensure
$3.5 million
Costs associated with thedevelopment of a portfolio ofTB vaccine candidates
Costs related to thedevelopment ofone TBvaccine candidate
up to $265million
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Aeras gratefully acknowledgesthesupportof
thefollowing majordonors
Netherlands Ministry of Foreign Affairs
THE MARY LYNNRICHARDSON
FUND
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