0. Hope in the TB Pipeline: Vaccines
Dr. Michael Brennan
Senior Advisor, Global Affairs
J2J Lung Health Media Training
42nd Union World Conference on Lung Health
Lille, France
27 October 2011

1. WHO Global Tuberculosis Control 2011 Report
“Major progress in TB care and control has been achieved since the introduction of the DOTS strategy in the mid-1990s and the launch of its successor, the Stop TB Strategy, in However, progress is constrained by old technologies. To achieve the Stop TB Partnership’s target of eliminating TB by 2050, a transformation in TB prevention, diagnosis and treatment is required.”

2. This presentation will include…
Why the world needs new TB vaccines
Predicted impact of new TB vaccines
Challenges in TB vaccine development
How the Product Development Partnership model is advancing new TB vaccines
Progress in TB vaccine clinical development
Clinical trial field sites conducting TB vaccine studies
Regulatory capacity
Funding needs to develop TB vaccines that will be affordable and available worldwide

3. The Tuberculosis Pandemic Source: World Health Organization (WHO) 2010
Global incidence rate = 128 cases/100,000
1.4 million TB-related deaths
8.8 million new cases of TB
80% of the TB burden is in 22 countries
TB/HIV co-infection and TB drug resistance are key barriers to progress

4. The Need for a New TB Vaccine
BCG developed 90 years ago, not improved upon since
Reduces risk of severe pediatric TB disease, but:
Unreliable protection when given to newborns against adult pulmonary TB, which accounts for most TB worldwide
Wide use, but no apparent impact on the growing global TB epidemic
Not known to protect against latent TB
Not recommended for use in infants infected with HIV

5. The Pathway of TB Infection and Pathogenesis
Transmission
Pulmonary Lung
Disease
10%
90%
Reinfection 5%
Latent
Disease
Dissemination

6. The Pathway of TB Infection and Pathogenesis
Transmission
Pulmonary Lung
Disease
Vaccine
10%
Vaccine
Vaccine
90%
Reinfection
Vaccine
Vaccine 5%
Latent
Disease
Dissemination

7. Meeting the Public Health Need: Target Populations for TB Vaccines
Active Disease
Covered by existing vaccine
Latently Infected
No coverage or impact from existing vaccine
Pre-infection
Infants
Adolescents
Adults
HIV+ All Ages
Target vast, unmet need for new, more effective TB prevention in multiple populations
Potential replacement and/or boost for widely used BCG:
180 countries recommend BCG
100M+ doses per year 7

8. TB Epidemiology: Differences in Disease Populations
in Different Countries Can Impact Vaccine Approach
TB Disease India
Primary Infection 62% %
Re-infection 20% %
Reactivation 18% %
* Adapted from Chris Dye, WHO

9. The Potential of New TB Vaccines
A new, more effective TB vaccine could:
Contribute significantly to global efforts to eliminate TB as a public health threat
Be safer and more 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
Reduce the cost and burden of TB on patients, health care systems and national economies

10. Impact of Immunization on Vaccine Preventable Disease
Smallpox
From: “Understanding Vaccines” USDHHS NIH/NIAID Science Education)

11. Potential Impact of a 50% Effective Vaccine
All age groups
39 & 37%
52%
80%
92%
Abu-Raddad LJ, Sabatelli L, Achterberg JT, Sugimoto JD, Longini IM Jr, Dye C, Halloran ME. Epidemiological benefits of more effective tuberculosis vaccines, drugs and diagnostics. Proc Natl Acad Sci USA. 2009;106(33):

12. Better TB Vaccines: Reasons for Optimism
Most people (80-90%) do not get disease when
infected with Mtb = natural resistance
Evidence of limited BCG vaccine efficacy in children
New TB vaccine candidates provide some protection in animals
New TB vaccines boost immune responses
in early human clinical studies

13. Critical Needs in TB Vaccine Field
Advance the pipeline of TB vaccine candidates
Work with partners to market affordable, safe and
effective TB vaccines for all who need them
Evaluate surrogate immune assays and animal models
that predict vaccine induced protection
Develop clinical trial site infrastructure and conduct
clinical trials
Manufacture good manufacturing practice (GMP) lots of TB vaccines
Develop regulatory strategies that advance the testing
and licensure of TB vaccines

15. Aeras’ Mission and the PDP Model
Founded in 2003 with offices in Rockville, Maryland and Cape Town, South Africa
Non-profit biotechnology organization created as a product development partnership
Public-Private Partnerships with industry, academia, governments, NGOs and others to catalyze product development
Mission:
Develop effective TB vaccines/biologics to prevent TB across all age groups in an affordable and sustainable manner.

16. Aeras Africa Office Cape Town, South Africa
Established in 2008 to focus on Site Development and Epidemiology
Started Clinical Trials Management throughout Africa in 2010
13 staff members
Expertise in
Clinical Trials Management
Clinical Data Management and Biostatistics
Laboratory Capacity Development
Clinical Training
Advocacy
Focus on African collaboration in vaccine development

17. Pre-clinical Development at Aeras
Goal: Choose best vaccine portfolio & facilitate pre-clinical development
Antigen selection
Platform development
Product selection
Process development
Good Laboratory Practice (GLP)/regulatory testing
Animal modeling and immunology
Assay development

18. Technical Operations at Aeras
Fully integrated biopharmaceutical manufacturing facility
Upstream (fermentation)
6,000 sq ft completed in 2006
Downstream (Purification and fill/finish)
9,000 sq ft. completed in 2009
Biosafety Level-2 compliant
Meets US and European regulatory standards
Staff expertise in technical operations, quality assurance, and quality control

19. New Paradigm: Partnership & Collaboration
Foundations
Government
NGOs
Civil Society
Pharma &
Biotech
Industry
Academia
Aeras

20. TuBerculosis Vaccine Initiative (TBVI)
European efforts to develop more effective, safe vaccines against tuberculosis that will be globally accessible and affordable.  
R&D support and advocacy
Focus:
Discovery
Preclinical
Phase I/IIa - early clinical stages

21. TB Vaccine Development A Decade of Progress but much more to do!
2000
2002
2009
2011
No new preventive TB vaccines in clinical trials
1st preventive
vaccine enters clinical
trials (MVA85A)
1st Phase IIb proof-of-concept of preventive vaccine initiated
15 vaccines have entered clinical trials, 12 currently in clinical trials
2000
202
2009
2011
15 novel TB vaccine candidates have been in clinical trials in the last decade but no “winner” yet
Robust pipeline of 2nd generation candidates, novel vaccine constructs and new delivery platforms continue to be explored

22. Currently 12 novel TB Vaccines are in Clinical Trials
Phase II
Phase III
Phase IIb
Phase I
AERAS-422 Aeras
AdAg85A McMaster University
Hybrid-I+CAF01 SSI
Hyvac 4/ AERAS-404 SSI, Sanofi-Pasteur, Aeras, Intercell\
SSI H56-IC31 SSI, Aeras, Intercell, TBVI
M72+AS01 GSK, Aeras
RUTI Archivel Farma
VPM Max Planck, Vakzine Projekt Mgmt, TBVI
Hybrid-1+IC31 SSI, TBVI, EDCTP, Intercell
MVA85A/ AERAS-485 Oxford-Emergent Tuberculosis Consortium (OETC), Aeras
AERAS-402/ Crucell Ad35 Crucell, Aeras
Mw [M. indicus pranii (MIP)]
Dept of Biotechnology (India), M/s. Cadila
Prime
Boost
Post-infection
Immunotherapy
TB Vaccine Types
Viral-vectored: MVA85A, AERAS-402, AdAg85A
Protein/adjuvant: M72, Hybrid-1, Hyvac 4, H56
rBCG: VPM 1002, AERAS-422
Killed WC or Extract: Mw, RUTI
Source: Tuberculosis Vaccine Candidates – 2010; Stop TB Partnership Working Group on New TB Vaccines
With updates from sponsors 22 22

23. Clinical Studies Sponsored by Aeras
TB Vaccines
Partnerships
Clinical Status
Adeno35 with transgene for
85A, 85B & TB10.4
[AERAS-402/Crucell Ad35]
Crucell / Aeras
Ph I adults India
Ph IIb infants S Africa, Kenya, Mozambique
Ph II HIV+ adults S Africa
Modified Vaccinia with 85A
[Oxford MVA85A/AERAS-485]
Oxford / Emergent
and Aeras
Ph IIb infants S Africa
Ph IIb HIV+ adults Senegal, S Africa
Fusion protein 85B & TB10.4 in IC31 adjuvant
[HyVac4/AERAS-404]
Sanofi Pasteur/ SSI/Intercell
Ph I adults EU
Fusion Protein M72 in AS02 adjuvant
[GSK M72]
GSK / Aeras
Ph II infants Gambia
rBCG with endosome perturbation and over-expression of Mtb antigens
[AERAS 422-rBCG]
Aeras
Ph I adults US 23

24. Clinical Trial Sites for Phase IIb Proof-of-Concept Trials
If successful next step licensing trial to prove effectiveness
MVA85A
2 Phase IIb trials underway
HIV+ Adults
Infants
Trial Locations
Senegal (HIV+)
South Africa (HIV+, infants)
Partners – Aeras, OETC, EDCTP, MRC, UCT/IIDMM, Laboratoire de Bacteriologie-Virologie du Centre Hospitalier Universitair Aristide Le Dantec
AERAS-402/Crucell Ad35
1 Phase IIb trial underway
Infants
Trial Locations
Kenya
Mozambique
South Africa
Uganda (future)
Botswana (future)
Partners - Aeras, Crucell, EDCTP, KEMRI/CDC, CISM, SATVI, NIH

25. TB Vaccine R & D Manufacturing
TB disease and Clinical Trials [Aeras]
St. John's National Academy
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 25

26. Regulatory Authorities used in Aeras studies

27. Regulatory Agency Capacity for Aeras Studies
COUNTRIES TB INCIDENCE REGULATORY AGENCY
US Very low Very Good
Europe Low Very Good
South Africa Very High Good
Brazil Medium Good
India Very High Good
China Very High Good
Uganda Very High Weak
Kenya Very High Weak
Botswana Very High Weak
Mozambique Very High Weak
Senegal Very High Weak
Gambia Very High Weak
Ethiopia Very High Weak

28. Collaboration at Trial Sites: Example South Africa
Partnerships with the South African Tuberculosis Vaccine Initiative (SATVI) & The Aurum Institute
Currently conducting clinical trials in infants and HIV+ adults
Most advanced site for large-scale TB vaccine trials in the world
Capacity Development & Utilization
State-of-the-art immunology laboratory
Local staff trained in clinical trial research

29. Accomplishments in South Africa
Approximately $14 million invested over 7 years to build infrastructure
Additional funding provided by European and Developing Countries Clinical Trials Partnership (EDCTP)
Clinical trials of TB vaccines ongoing in 2009:
- 3 Phase I trials
- 3 Phase II trials
- 1 Phase IIb Proof
of Concept trial

30. Local Benefits of Clinical Research
Retain local talent and expertise
Raise awareness about TB in the community
Support and enhance local clinical research capacity
Community health and education
Infrastructure remains in the community
Leverage investment in infrastructure to use for clinical trials of other diseases 30

31. New Partners: Emerging Countries
China, India, Brazil, South Africa
Expanding manufacturing capability
Evolving regulatory agency
Improving scientific research
Approving and distributing own products
Ready to enter the global stage

32. Funding Needs 2011-2015 $1.9 billion
Funding for TB research and development has increased in recent years, reaching US$ 614 million in 2009, but still falls far short of the annual target of US$ 1.8 billion that is included in the Global Plan to Stop TB 2011–2015.
- WHO Global Tuberculosis Control 2011 Report

33. Summary TB Vaccine Development
New TB vaccines could have a significant impact on the global TB epidemic
Tremendous progress is being made in the field of TB vaccine development, with two preventive vaccine candidates now in Phase IIb trials
GMP manufacturing capacity being developed and manufacturing agreements are being explored with particular emphasis on emerging economies
Regulatory pathways and market and economic impact research being conducted now to lay the groundwork to accelerate adoption and uptake of new TB vaccines
Scientific, infrastructure and financial challenges remain; solutions will require global partnership and commitment
With sufficient resources and positive results for current clinical trials, a new TB vaccine could be available by the end of the decade

34. Conference Sessions Featuring TB Vaccine R&D
October 28 Symposium on “Partnerships to Accelerate TB Vaccine”
2:30-4:30 pm in Room Rotterdam
October 28 satellite session on “Synergies in the development of new diagnostics, drugs and vaccines for tuberculosis”
4:45-6:45 pm in Room Faidherbe
Aeras and the TuBerculosis Vaccine Initiative (TBVI) have a booth in the Exhibit Hall (Booth #35) where visitors can learn more about progress in tuberculosis vaccine research and development

35. Netherlands Ministry of Foreign Affairs
Aeras gratefully acknowledges the support of the following major donors and contributors
Netherlands Ministry of Foreign Affairs
US Food and Drug Administration 35

36. Twitter: @aerasglobaltb
Thank You!
For more information:
Facebook: Aeras
Dr. Michael Brennan