1. 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

2. Estimated TB Incidence Rate, 2007
Estimated new TB cases (all forms) per population
No estimate
0-24
25-49
50-99
>= 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 All rights reserved

3.  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
HIV prevalence in TB cases, (%)
No estimate
0–4
5–19
20–49
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 All rights reserved
>= 50

4. 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

5. 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
A new TB vaccine that would prevent all forms of TB would help prevent and reduce the spread of MDR and XDR-TB

6. Global Health issues for children
WHO, “World Health Statistics, 2010”

7. 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

8. 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.

9. 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 HIV-infants ≤ 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

10. WHO Estimated 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
Tanzania
117,489
18,890
Viet Nam
143,023
7,559
Zimbabwe
76,296
12,267
Total
6,678,188
630,722
9.4
Adapted from “Childhood TB” by AHesseling, PMusoke, AGupta, JSadoff

11. 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
Global health authorities, including the WHO and the Stop TB Partnership, agree that TB will not be eliminated without new technologies, including a new, more effective vaccine.

12. 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.

13. 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
In conjunction with new drugs and diagnostics
TB will not be eliminated without a new TB vaccine
Vaccines can prevent onset and reduce transmission of disease

14. 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 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

15. 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

16. Induction of Immunity: Prime –Boost Infants
BCG or rBCG
IM or as an aerosol
Capsids in bacteria or as an aerosol
24 Weeks
BCG or rBCG, EPI, concominant studies
14 Weeks

17. 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
May eliminate need for HIV screening of infants prior to rBCG

18. 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
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
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
Aeras has 4 candidates that are currently being tested in clinical trials
These candidates are in various stages of clinical development, from Phase I to Phase IIb and have been tested in a variety of regions – Europe, North America and Africa – and a variety of populations – including adults, infants and people living with HIV
Based on data to date:
All vaccine candidates found to have acceptable safety profiles
All candidates induced CD4+ and/or CD8+ T-cell responses to TB antigens
Immunogenicity results of booster candidates after BCG-priming are encouraging for post-BCG prime-boost strategy
With sufficient resources, a new TB vaccine could be available as early as 2016

19. Aeras Partnerships for Field Research
St. John’s Research Institute
Palamaner, India
Cambodian Health Committee
Svay Rieng, Cambodia
Makerere University
Kampala, Uganda
KEMRI/CDC
Kisumu, Kenya
Manhica Health Research Centre
Manhica, Mozambique
SATVI/U of Cape Town
Worcester, South Africa 19

20. 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

21. 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 21

22. 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 AERAS-402/Crucell Ad35
Western Cape

23. Activities in South Africa
Research Partner – University of Cape 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 adults planned (part of multi-center MVA85A/AERAS-485 study)

24. 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)

25. 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

26. 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)
Vaccine Discovery
Pre-Clinical Testing
Phase I
Phase II
Phase IIb
Phase III
Licensure
1 - 2 Years
1 Year
2.5 Years
3 Years
4 Years
Costs related to the development of one TB vaccine candidate
$3.5 million
$3 million
$18 million
up to $265 million
$48 million
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.

27. Aeras gratefully acknowledges the support of the following major donors
THE MARY LYNN RICHARDSON FUND
Netherlands Ministry of Foreign Affairs