Progress is being made in developing new tuberculosis (TB) vaccines. Currently, 15 vaccine candidates have entered clinical trials with 12 currently in clinical testing. The Oxford-Emergent Tuberculosis Consortium (OETC) is developing MVA85A, an attenuated viral vector vaccine that boosts BCG. MVA85A has undergone safety and immunogenicity testing in various populations and two Phase IIb efficacy trials in infants and HIV-infected adults are ongoing. While progress has been made, continued momentum and funding is needed to demonstrate efficacy in late-stage trials and build capacity to develop and deliver new TB vaccines globally.

1. Progress in new TB vaccine
development
Adam Stoten
Deputy General Manager
Oxford-Emergent Tuberculosis Consortium
“OETC” 1

2. Global Plan to Stop TB: 2011 - 2015
• STOP TB Targets
– By 2050, to reduce global incidence to less
than 1 per million population
– But will need 16% p.a. reduction to achieve
this goal; current rate of reduction is ~1%
p.a.*
• How?
– Use of current tools
• DOTS
– Introduction of new tools
• New drugs
• New diagnostics
• New vaccines
2
*Chris Dye, WHO, TB Vaccines, A Second Global Forum, 2010

3. Vaccination against TB
• Bacille Calmette-Guerin (BCG) first introduced in 1921
• 100 million doses per year, part of Expanded Programme for
Immunisation (EPI) schedule
• Variable efficacy
– Effective against severe forms of the disease in infants when given at
birth
– Variable protection against pulmonary disease
– Latitude effects; less effective near equator
• WHO recommends that BCG is not given to HIV+ subjects due to risk
of BCG-disseminated disease 3

4. Challenges for new TB vaccine
development
• It is difficult to determine the efficacy of a new TB vaccine candidate in the absence of
a validated correlate of protection
• Although prevalence of TB is high, low disease incidence rates dictate that efficacy
trials must recruit large numbers of subjects with long periods of follow up
• Large efficacy trials require significant trial site capacity in areas with high incidence
• Clinical diagnosis of disease is difficult, especially in infants
• Any successful vaccine will be required in huge quantities so a robust, scaleable
manufacturing process is needed for global supply at affordable cost
• Majority of doses will be needed in Developing World Countries and at low cost –
reduces incentive for participation of commercial vaccine developers
• Public funding support is vital for the progression of TB vaccine candidates through all
stages of development
4

5. Design of an improved TB vaccine
• Retain BCG in new regime?
• New vaccines needed to prevent:
– Infection in infants
– Primary disease
– Reactivation of latent TB
– TB in HIV+ individuals
• Potential for new therapeutic vaccines to be used in combination with
current drugs to shorten treatment time
• 3 basic strategies for preventative vaccines:
– Boost BCG with new vaccine
– Replace BCG with an improved BCG
– Use new vaccine to boost an improved BCG
5

6. TB Vaccine Development:
A Decade of Progress
2000 2002 2009 2012
No new preventive
2000 1st preventive
202 1st Phase IIb proof-
2009 15 vaccines have
2011
TB vaccines in vaccine enters of-concept of entered clinical
clinical trials clinical preventive vaccine trials, 12 currently in
trials (MVA85A) initiated clinical trials
• 15 novel TB vaccine candidates have been in clinical trials in the last decade
• Robust pipeline of 2nd generation candidates
• New delivery platforms are being explored
• Capacity and infrastructure development for large-scale trials occurring in several high burden
countries
• Epidemiological cohort studies conducted in several countries to provide baseline TB incidence
data
• Regulatory pathway elucidation and economic impact research being conducted now to lay the
groundwork to accelerate adoption and uptake of new TB vaccines
(J. Woolley, Aeras, 2012)

7. Global TB Vaccine Pipeline
Phase I Phase II Phase IIb Phase III
AdAg85A M72+AS01 MVA85A/ Mw [M. indicus pranii
McMaster University GSK, Aeras AERAS-485 (MIP)]
Oxford-Emergent Dept of Biotechnology
Hybrid-I+CAF01 VPM 1002 Tuberculosis (India), M/s. Cadila
SSI, TBVI Max Planck, Vakzine Consortium (OETC),
Projekt Mgmt, TBVI Aeras
H56+IC31
SSI, Aeras, Intercell Hybrid-1+IC31 AERAS-402/ Crucell
SSI, TBVI, EDCTP, Ad35
Intercell Crucell, Aeras
Hyvac 4/ AERAS-404
+IC31
SSI, sanofi-pasteur, Aeras, RUTI
Intercell Archivel Farma, S.L.
AERAS-422
Aeras
Prime
TB Vaccine Types
Boost
Viral-vectored: MVA85A, AERAS-402, AdAg85A
Protein/adjuvant: M72, Hybrid-1, Hyvac 4, H56 Post-infection
rBCG: VPM 1002, AERAS-422
Immunotherapy
Killed WC or Extract: Mw, RUTI
Source: Tuberculosis Vaccine Candidates – 2011
(J. Woolley, Aeras, 2012)

8. Global TB Vaccine Pipeline
Phase I Phase II Phase IIb Phase III
AdAg85A M72+AS01 MVA85A/ Mw [M. indicus pranii
McMaster University GSK, Aeras AERAS-485 (MIP)]
Oxford-Emergent Dept of Biotechnology
Hybrid-I+CAF01 VPM 1002 Tuberculosis (India), M/s. Cadila
SSI, TBVI Max Planck, Vakzine Consortium (OETC),
Projekt Mgmt, TBVI Aeras
H56+IC31
SSI, Aeras, Intercell Hybrid-1+IC31 AERAS-402/ Crucell
SSI, TBVI, EDCTP, Ad35
Intercell Crucell, Aeras
Hyvac 4/ AERAS-404
+IC31
SSI, sanofi-pasteur, Aeras, RUTI
Intercell Archivel Farma, S.L.
AERAS-422
Aeras
Prime
TB Vaccine Types
Boost
Viral-vectored: MVA85A, AERAS-402, AdAg85A
Protein/adjuvant: M72, Hybrid-1, Hyvac 4, H56 Post-infection
rBCG: VPM 1002, AERAS-422
Immunotherapy
Killed WC or Extract: Mw, RUTI
Source: Tuberculosis Vaccine Candidates – 2011
(J. Woolley, Aeras, 2012)

9. OETC and MVA85A
• The Oxford-Emergent Tuberculosis Consortium “OETC” was formed as a
joint venture between the University of Oxford and Emergent Product
Development UK
• OETC’s purpose is to develop and commercialise MVA85A for developed
and developing world markets
MVA85A Attenuated viral vector encoding 85A TB
antigen
Mode of action Boost to BCG
Preclinical testing Improves BCG induced protection in mice,
guinea pigs, non-human primates and cows
Clinical testing in healthy Has undergone safety and immunogenicity
subjects testing in healthy adults, adolescents, children
and infants
Clinical testing in high risk Has undergone safety and immunogenicity
subjects testing in HIV–infected and latent TB-infected
adults
Status Two Phase IIb efficacy studies ongoing in
infants and HIV-infected adults 9

10. MVA85A Trial Results
• A single dose of MVA85A has been shown to be well tolerated and to induce
what we believe is the right kind of immune response in:
– Healthy adults, adolescents, children and infants
– Adults with latent TB
– Adults with HIV
• Immune responses were lower in HIV infected adults than in healthy adults so
a second dose has been introduced into trials in this population
• MVA85A has been shown to have no adverse effects on existing EPI
schedule vaccines when co-administered
• Next important step is to determine whether these promising immune
responses translate into protection from disease
• MVA85A will be the first new TB vaccine candidate to generate efficacy data
in infants, with results due at the end of 2012
10

11. MVA85A Phase IIb efficacy trials
Target Pop. Infants HIV+ Adults
Objectives • Safety • Safety
• Immunogenicity • Immunogenicity
• Efficacy • Efficacy
Location South Africa South Africa and Senegal
Subjects 2797 1400
Doses Single dose Two doses
Designed to show 60% improvement over 60% improvement
BCG alone
Partners Aeras, Wellcome Trust, EDCTP, Aeras, UCT, Le
SATVI Dantec
Status Recruitment complete Recruitment ongoing 11

12. Summary
• Great progress has been made in the last 10 years
• We cannot afford to lose momentum at this critical stage for the TB
vaccine pipeline
• New vaccine candidates such as MVA85A are on the brink of
demonstrating efficacy
• More funding is needed, particularly for conduct of Phase III trials
and for capacity building
• Importance of support for funding mechanisms such as EDCTP II
to enable late stage vaccine trials
12

13. 1000th infant vaccinated in Phase IIb trial of MVA85A at Worcester trial site, South Africa. 13