Tuberculosis Vaccines:
A strategic blueprint for the next decade
Co-editors: Michael J. Brennan and Jelle Thole
The Global Burden of TB -2010
Estimated TB incidence rates, by country, 2010
TB cases
per 100 000
0–24
Estimated
number of cases
Estimated
number of deaths
8.8 million
1.45 million
25–49
50–99
100–299
>=300
No estimate
All forms of TB
(range: 8.5–9.2 million)
HIV-associated TB
1.1 million (13%)
(range: 1.0–1.2 million)
Multidrug-resistant
TB (MDR-TB)
440,000
(range: 1.2–1.6 million)
350,000
(range: 320,000–390,000)
about 150,000
(range: 390,000–510,000)
1/3 of the global population (2 billion) is estimated to be latently infected with TB
and at risk of developing the disease later in life
Full implementation of Global Plan: 2015 MDG
target reached but TB not eliminated by 2050
10000
Incidence/million/yr
Current rate
of decline
1000
TB incidence 10x
lower than today,
but >100x higher
than elimination
target in 2050
100
10
Elimination 16%/yr
Elimination
target: 1 /
million / year
by 2050
Global Plan 6%/yr
Current trajectory 1%/yr
1
2000
2010
2020
2030
Year
2040
2050
Predicted impact of new TB vaccine
250
A
no intervention
TB incidence/100 00/yr
200
neonatal
150
mass vaccination
(post-exposure)
mass vaccination
(pre-exposure)
100
50
mass vaccination
(dual action)
0
2010
250
2020
2030
ence/100 000/yr
2050
B
Young and Dye. 2006. Cell 124:683-7
no intervention
200
150
2040
drug treatment
mass vaccination
(dual action)
Why new TB vaccines
• Calmette & Guérin developed the
only available TB vaccine: BCG
(1906-1921)
• BCG reduces risk of severe pediatric TB disease - 40
thousand cases per year
• Protection against adult pulmonary TB, which
accounts for most TB worldwide, is poor or variable
at best
• Not known to protect against latent infection or
prevent reactivation
• High risk of disseminated BCG in HIV positive infants
TB vaccine candidates Tested in Clinical Trials, 2011 (Source: Stop TB Partnership)
Status
Products
Product Description [Citations]
Sponsors
Indication
Type of Vaccine
Global TB vaccine pipeline: 12 in clinical trials
Phase III
Mw [M. indicus pranii (MIP)]
MVA85A/AERAS-485
Department of
Biotechonology (Ministry of
Whole cell saprophytic non-TB mycobacterium
Science & Technology,
[1-3]
Government of ), M/s.
Cadila Pharmaceuticals Ltd.
Modified vaccinia vector expressing Mtb
antigen 85A [4-8]
Phase IIb
AERAS-402/Crucell Ad35
M72 + AS01
–
Oxford-Emergent
Tuberculosis Consortium
(OETC), Aeras
Viral Vectored
BCG-vaccinated infants
and adolescents; HIVinfected adults
Crucell, Aeras
Viral Vectored
BCG-vaccinated
infants, children and
adults
GSK, Aeras
Recombinant Protein
Adolescents/adults,
infants
Statens Serum Institute
(SSI), TBVI, EDCTP, Intercell
Recombinant Protein
Adolescents; adults
Adjuvanted recombinant protein composed of
Mtb antigens 85B and ESAT-6 [18-22]
VPM 1002
rBCG strain expressing listeriolysin and carries Max Planck, Vakzine Projekt
a urease deletion mutation [23-27]
Management GmbH, TBVI
Recombinant Live
–
RUTI
Fragmented Mtb cells [28-32]
Whole cell, Inactivated
or Disrupted
HIV+ adults, LTBI
diagnosed
AdAg85A
Replication-deficient adenovirus 5 vector
expressing Mtb antigen 85A [33-37]
Viral Vectored
Infants; adolescents;
HIV+
Hybrid-I+CAF01
Adjuvanted recombinant protein composed of
Mtb antigens 85B and ESAT-6 [19-20, 38-40]
SSI, TBVI
Recombinant Protein
Adolescents, adults
Hybrid 56 + IC31
Adjuvanted recombinant protein composed of
Mtb antigens 85B, ESAT-6 and Rv2660 [41-42]
SSI, Aeras, Intercell
Recombinant Protein
Adolescents, adults
HyVac 4/AERAS-404,
+ IC31
Adjuvanted recombinant protein composed of
a fusion of Mtb antigens 85B and TB10.4 [4346]
SSI, sanofi-pasteur, Aeras,
Intercell
Recombinant Protein
Infants
M. vaccae
Inactivated whole cell non-TB mycobacterium;
phase III in BCG-primed HIV+ population
NIH, Immodulon
completed; reformulation pending [47-51]
Whole cell, Inactivated
or Disrupted
BCG-vaccinated HIV+
adults
AERAS-422
Recombinant BCG expressing mutated PfoA
and overexpressing antigens 85A, 85B, and
Rv3407 [9-10, 52]
Aeras
Recombinant Live
Infants
rBCG30
rBCG Tice strain expressing 30 kDa Mtb
antigen 85B [53-57]
UCLA, NIH, NIAID, Aeras
Recombinant Live
Newborns,
adolescents, and adults
Whole cell extract
–
Whole cell, Inactivated
or Disrupted
–
Phase I
Phase I [concluded]
Whole cell, Inactivated
or Disrupted
Hybrid-I+IC31
Phase II
Phase III
[concluded]
Replication-deficient adenovirus 35 vector
expressing Mtb antigens 85A, 85B, TB10.4 [913]
Recombinant protein composed of a fusion of
Mtb antigens Rv1196 and Rv0125 & adjuvant
AS01 [14-17]
Target Populations
Archivel Farma, S.I.
Stop-TB partnership TB vaccine candidates 2009
M. smegmatis
6
Why a strategic Blueprint?
• Outline the major challenges and key issues for
the next decade and communicate them to
broader audience
• Build consensus on key issues
• Demonstrate a coordinated approach to TB
vaccine development
• Use key challenges and questions in Blueprint as
a rallying point for forming new partnerships
• Use issues outlined in Blueprint for soliciting
specific funding from donors.
History of TB Vaccine Development
Blueprint I
1998
Past Decade of Progress
Global Forum I
Geneva 2001
2000
2002
No new
2000
preventive TB
vaccines in
clinical trials
2009
1st 202
preventive
vaccine enters
clinical
trials (MVA85A)
2011
1st
Phase IIb
2009
proof-of-concept
of preventive
vaccine initiated
15 vaccines
2011
studied in clinical
trials, 12 were in
clinical trials
Next Decade of Progress
Global Forum II
Estonia 2010
Annecy “Out of Box”
Vancouver, Keystone TB
Les Diablerets, TBVAC
Advocacy StopTB WG
2011
Blueprint II
March 2012
2012
Global Forum III
Cape Town, 2013
2013
to
2020
Phase III trials of preventive vaccines
One new TB vaccine introduced
Correlate of vaccine immunity established
Novel vaccines for all populations developed
Resources obtained that match need
Tuberculosis Vaccines: A Strategic
Blueprint for the Next Decade
• A unified global strategy
• Renewed, intensified and
well integrated international
effort
• Outlining major scientific
challenges, critical activities
and crucial questions
5 priority areas / 14 critical
activities
• Creativity in research and discovery
• Correlates of Immunity and
Biomarkers for TB Vaccines
• Clinical Trials – Harmonisation and
Cooperation
• Rational Selection of TB Vaccine
Candidates
• Building Support through Advocacy,
Communications and Resource
Mobilisation
Creativity in Research and Discovery
• Identify mechanisms of protective immunity
• Introduce new vaccine mechanisms
• Facilitate translational research, comparative
preclinical studies and animal models
Correlates of Immunity and
Biomarkers for TB Vaccines
• Explore novel approaches to identify
correlates of immunity
• Introduce novel assays in efficacy trials to help
establish correlates of immunity.
• Identify signatures of vaccine efficacy
Clinical trials: harmonization &
cooperation
• Determine TB prevalence and incidence,
select trial sites and choose target populations
• Design clinical trials to determine efficacy
using better defined clinical endpoints
• Address regulatory, ethical and sustainability
issues
Rational selection of TB vaccine
candidates
• Establish global criteria for assessing vaccine
candidates in clinical studies
• Obtain consensus on criteria to advance new
candidates
Building support through advocacy,
communications & resource mobilization
• Expand financing
• Raise awareness and build
support for the role of new
TB vaccines
• Broaden the base of TB
vaccine advocates
Implementing the Blueprint
• March 20th – Journal Publication Date and Launch
– Global Press Release from Working Group, Aeras, TBVI
– Adapted press releases for South Africa and other partners also on March 20
– Johannesburg Press Briefing, March 20th
– March 20th/21st – Congressional briefings in Washington, DC
– March 22nd – TBVI Event in Brussels
• Companion piece developed for distribution to broader audiences
• 3rd Flobal Forum on TB Vaccines (March 2013, Cape Town) structured to
address key challenges in Blueprint (www.tbvaccine2013.org)
Thanks
We are particularly grateful to all the researchers, clinicians, pharmaceutical companies,
governmental and non-governmental organizations, donors and other stakeholders who
completed survey questions that helped define the key priorities in TB vaccine development and
to those who participated in spirited discussions at the TB blueprint meetings held in 2010 and
2011.
The following who contributed directly to the content of the Blueprint.
Erna Balk, TBVI, Lelystad, The Netherlands
Lewellys Barker, Aeras, Rockville, United States of America
Jerrold Ellner, Boston University and Boston Medical Center Boston, USA
Bernard Fourie, University of Pretoria, Pretoria, South Africa
Luc Hessel, TBVI, Lelystad, The Netherlands
Stefan Kaufmann, Max Planck Institute for Infection Biology, Berlin, Germany
Melody Kennell, Aeras, Rockville, United States of America
Hassan Mahomed, University of Cape Town, Cape Town, South Africa
Tom Ottenhoff, Leiden University Medical School, Leiden, The Netherlands
Joris Vandeputte, TBVI, Lelystad, The Netherlands
Barry Walker, National Institute for Biological Standards and Control, Potters Bar, UK
Jennifer Woolley, Aeras, Rockville, United States of America
Thanks
The Blueprint was coordinated by the Stop TB Partnership Working Group on New TB
Vaccines with support from the World Health Organization, Bill & Melinda Gates Foundation,
Aeras, TuBerculosis Vaccine Initiative, and the EC FP 7 framework programme.
Members of the Stop TB Partnership Working Group on New TB Vaccines Leadership Team
Michel Greco, Chair
Ulrich Fruth, WHO & Jennifer Woolley, Aeras, Secretarat
Michael Brennan, Aeras
Jelle Thole, TBVI
Hassan Mahomed, SATVI
Susanne Verver, KNCV
Peggy Johnston, Jan Gheuens, Peter Small, Bill & Melinda Gates Fdn
Christine Sizemore, NIAID, NIH
Robert Nakibumba, Community Representative, Working Group on New TB Vaccines
TASO Uganda
Lucy Ghati, The National Empowerment Network of People Living with HIV/AIDS (NEPHAK), Kenya
Christian Lienhardt, StopTB Partnership
Dave Lewinsohn, Oregon Health and Sciences University
Didier Lapierre, GSK Biologicals