Transcript 5_17_10_Coovadia_CORE_Group

Pediatric TB and HIV
The Potential of New TB Vaccines
Dr. Hoosen Coovadia
Nelson Mandela School of Medicine, University of KwaZulu Natal
Board of Directors, Aeras Global TB Vaccine Foundation
Presentation to the CORE Group
May 17, 2010
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Estimated TB Incidence Rate, 2007
Estimated new TB cases (all
forms) per 100 000 population
No estimate
0-24
25-49
50-99
100-299
>= 300
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
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HIV Prevalence Among TB Cases, 2007
Global estimate: about 1.4 million TB/HIV cases and 450,000 TB/HIV deaths a year
HIV prevalence in
TB cases, (%)
No estimate
0–4
5–19
20–49
>= 50
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
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HIV/AIDS and TB:
A Deadly Combination
+
•
•
•
•
One in four HIV
deaths is linked to
TB
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 than
doubled in countries with high HIV prevalence in the
past 15 years
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Drug Resistance
• WHO estimates 490,000 MDR-TB cases emerge every
year, with more than 110,000 deaths
• Extensively drug-resistant (XDR) TB has been identified
in 57 countries as of November 2009
• In 2008, WHO reported that the highest rates of MDR TB
ever recorded, with peaks of up to 22% of new TB cases,
were in some settings of the former Soviet Union. In the
same region, 1 in 10 cases of MDR-TB is XDR-TB
• Treatment for drug-resistant TB is much longer, more
complex and more expensive - with much lower success
rates
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Global Health issues for children
WHO, “World Health 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 and
communities affected by TB
• TB exposure due to inadequate health systems – poor
delivery 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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Pediatric HIV
• 2.1 million children were
living with HIV/AIDS, vast
majority in sub-Saharan
Africa.
• 1000 children get newly
infected with HIV each day.
• Children acquire HIV from
their HIV-infected mothers
during pregnancy, birth or
breastfeeding.
• PMTCT works, but needs broader rollout and accessibility to those
who need it most.
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Maternal TB/HIV important risk factor for
pediatric TB and mortality
• Estimated TB rate:
-10 times higher in HIV-exposed
uninfected children <5 years than in
non-HIV exposed
-30 times higer in HIV-infected
children<5 years than non-HIV
exposed (Mukade 1997)
-1596/100,000 pop. HIV+ infants ≤ 12
mo. vs 65.9/100,000 pop. In HIVinfants ≤ 12 mo. (Hesseling CID 2009)
• Maternal TB/HIV important risk factor for pediatric TB and mortality
(Pillay 2004; Khan 1999; Cotton 2008; Gupta 2007)
Adapted from presentation by Amita Gupta, July 19, 209
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WHO Estimated TB Cases by Age, 2006
Country
Total Cases
Cases in Children < 15 % in Children
Myanmar
Nigeria
Pakistan
The Phillipines
78,489
261,404
244,736
230,217
8,007
32,310
61,905
12,167
10.2
12.4
25.3
5.3
Russian Fed.
South Africa
Thailand
Uganda
Tanzania
Viet Nam
Zimbabwe
Total
183,373
220,486
85,928
75,250
117,489
143,023
76,296
6,678,188
7,778
35,449
2,317
12,099
18,890
7,559
12,267
630,722
4.2
16.1
2.7
16.1
16.1
5.3
16.1
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 TB
disease worldwide
•
BCG is not know to protect against latent TB
•
BCG is not recommended for use in infants
infected with HIV due to increased risk for
severe BCG-related complications
•
Despite wide use, particularly in high burden
countries, BCG has had no apparent impact
on the growing global TB epidemic
•
BCG does reduce risk of severe pediatric
TB disease, so it should continue to be used
until 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 world’s infants is
too risky to give to those born infected with the AIDS
virus, says a new study published by the World Health
Organization. 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
(<1 case/million), in conjunction
with new drugs and diagnostics
• Safe and effective in preventing
TB in children, adolescents and
adults, including people with
HIV (for whom BCG is unsafe)
• Protect against all forms of TB –
including MDR and XDR
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Global TB Vaccine Pipeline
Vaccine Candidate
Pre-Clinical
Phase I
Phase II
Phase IIb Phase III
AERAS402/Crucell Ad35
Crucell N.V./Aeras
MVA85A/AERAS-485
OETC/Aeras
GSK M72
GSK Biologicals/Aeras
Hybrid 1 SSI IC-31
SSI, TBVI, Intercell
HyVac4/AERAS-404
sanofi pasteur/SSI/Intercell/Aeras
VPM 1002
Max Planck/Vakzine Projekt Management GmbH/TBVI
AdAg85A
McMaster University
RUTI
Archivel Farma, S.I.
Hybrid 1 SSI CAF01
SSI
AERAS-rBCG
Aeras
AERAS-Capsid
Aeras
Other rBCG rMtb
Albert Einstein S. of Med., Institute Pasteur, Univ. of Zaragoza, TBVI
AERAS-other virus
Aeras
Protein/Polysaccharides
Inst. Pasteur de Lille/Inserm, Albert Einstein S. of Med., Aeras, Karolinska Instit.
Additional research at the discovery/early pre-clinical level: Bhagawan Mahavir Medical Research Center; Cardiff University; EpiVax, Inc.; ImmunoBiology Ltd.; Infectious Disease Research
Institute; Institute de Pharamacologie, Puso; Karolinska Institute; Malaysia-Finlay Institute, NIAID; NIH; Osaka University; Shanghai H&G Biotech; Sequella; UCLA; and, Vanderbilt University.
As of November 2009
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Aeras Global TB Vaccine Foundation
Mission
To develop new, more effective TB
vaccines and ensure their availability to
all who need them
Goal
• A more effective, safe and affordable
TB vaccine by 2016
Method
• Collaborate with academic, biotech,
pharmaceutical and NGO partners to
develop and test new TB vaccines
• Pursing a Prime-Boost strategy by
developing a modern replacement for
BCG plus booster vaccines
• Develops vaccines in its own lab and
manufacturing plant
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Induction of Immunity:
Prime –Boost Infants
BCG or rBCG
IM or as an aerosol
Capsids in bacteria or as an aerosol
24 Weeks
14 Weeks
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Recombinant BCG (rBCG) - A Better BCG
• Safer in HIV infected infants or
others with immune-suppression
• BCG or rBCG boosted with another
TB vaccine is much better than
either vaccine alone
• Constructed to address each stage
of the TB life cycle
• Prevent infection and reactivation
• A new vaccine candidate with all of
these properties is expected to
enter clinical trials in 2010
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Summary of Aeras Candidates in Clinical Testing
SSI 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
Europe
•Current 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+ in
South 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-concept
Phase 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
St. John’s Research Institute
Palamaner, India
Makerere University
Kampala, Uganda
SATVI/U of Cape Town
Worcester, South Africa
KEMRI/CDC
Kisumu, Kenya
Cambodian Health Committee
Svay Rieng, Cambodia
Manhica Health Research Centre
Manhica, 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 clinical
trials are conducted in high burden
countries
• Aeras partners with local research
institutions to establish field sites and
conduct clinical research
• Build local infrastructure and health
care/research capacity to perform future
Good Clinical Practice (GCP) compliant
Phase III clinical trials
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Activities in South Africa
Research Partner - South African
Tuberculosis Vaccine Initiative (SATVI)
• Conducting Phase I, II and IIb studies of
four vaccine 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 AERAS402/Crucell Ad35
• Western Cape
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Activities in South Africa
Research Partner – University of
Cape Town Lung Institute
• Phase II clinical trial in adults with
active or previous TB (AERAS402/Crucell Ad35 )
• Cape Town
• Future study of TB vaccine
candidate in HIV infected adults
planned (part of multi-center
MVA85A/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 affordable
prices, 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
Costs associated with the
development of a portfolio of
TB vaccine candidates
Field Site Preparation ($2-4 million per yr, per site)
Manufacturing ($310 million to build and upgrade facilities; $10 million per year to maintain)
Phase IIb
Vaccin
e
Disco
very
PreClinic
al
Testin
1 - 2 Years
g
$3.5 million
Phase
I
Phase III
Licensure
Phase
II
1 Year
2.5 Years
3 Years
4 Years
$3 million
$18 million
$48 million
up to $265
million
Costs related to the
development of one TB
vaccine candidate
•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 component
–Infant trial - between $70 and $140 million
–Adolescent and adult trial - between $130 and $265 million
•Aeras has a broad pipeline of vaccine candidates, 4 of which are currently
in clinical trials
•With sufficient resources, a new TB vaccine could be ready in 7 – 10 years.
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Aeras gratefully acknowledges the support of
the following major donors
THE MARY LYNN
RICHARDSON
FUND
Netherlands Ministry of Foreign Affairs