TB Vaccine Development Update
16th Annual Conference of the Union
North America Region
New Tools Session
24 February 2012
Lew Barker, MD, MPH
Aeras. Rockville, MD
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
2006. 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.”
Outline of Presentation
• Introduction: Need for New TB Vaccines
• New TB Vaccines: Challenges and Public
Health Impact
• Clinical Development Progress
• Conclusions
The Need for a New TB Vaccine
• BCG introduced over 90 years ago,
not improved upon since then
• Reduces risk of severe pediatric
(meningeal and miliary) TB disease,
but:
– Unreliable protection when given to
newborns against adult pulmonary TB
and TB transmission, which accounts for
most TB worldwide
– Wide use, but no apparent impact on the
global TB epidemic
– Not known to protect against latent TB
– Not recommended by WHO for use in
infants infected with HIV
– Many genotypes and phenotypes = BCGs
The Potential of New TB Vaccines
New, more effective TB vaccines could:
• 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
• Contribute significantly to global efforts
to control TB
Impact of Immunization on Vaccine
Preventable Disease
From: “Understanding Vaccines” USDHHS NIH/NIAID Science Education)
Challenges in
TB Vaccine Clinical Development
– Many potential antigens; no correlates of protection or validated
animal model and complex cell-mediated immunity
– TB case definition/diagnosis, especially for infants, difficult
– Very large sample sizes required for Phase III efficacy studies
– Limited numbers of field sites with high TB incidence for efficacy
studies
– Large-scale trials are extremely complex and expensive
– Lack of regulatory capacity for approving vaccines in developing
countries
SK Parida and SHE Kaufmann
Am J Resp Crit Care Med 2010; 182:1073-1079
8
Better TB Vaccines:
Reasons to be Optimistic
• Most people (80-90%) do not get disease when
infected w Mtb
• Evidence of limited BCG vaccine efficacy
• HIV/AIDS patients w low CD4 T cells more
susceptible to Mtb infection [ role of antibodies
controversial ]
• New TB vaccine candidates protect in TB animal
models
• New TB vaccines boost cellular immune responses
in multiple clinical studies
Potential Impact of a 50% Effective Vaccine
TB (all types) Incidence
2000
All age groups
Neonatal pre-exposure
Neonate pre-exposure + add effects
Post-exposure
Mass pre-exposure
Mass pre-exposure + post-exposure
Incidence per million
1600
1200
39 & 37%
52%
800
400
0
2010
80%
92%
2015
2020
2025
2030
Year
2035
2040
2045
2050
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):13980-5
TB Epidemiology: Differences in Disease Populations
in Different Countries Can Impact Vaccine Approach
TB Disease
India
Primary Infection
62%
19%
Re-infection
20%
9%
Reactivation
18%
72%
* Adapted from Chris Dye, WHO
Meeting the Public Health Need
Active Disease
Latently
Infected
Pre-infection
Infants
Adolescents
Covered by existing
vaccine
Adults
HIV+ All Ages
No coverage or
impact from
existing vaccine
Big Picture
• A vaccine or vaccine regimen (prime-boost) that interrupts
transmission is key to controlling TB incidence, and can
eventually have a big public health impact
• Need to prevent disease after initial infection or
reactivation from latency
• Need to focus on adolescents and young adults (and
possibly the elderly), and effect of vaccines in
communities
Strategy for
TB Vaccine Development
Preventive/Prophylactic Vaccines
–
–
Improve priming vaccines - Recombinant BCG
(rBCG) or live Mtb vaccine
Develop novel booster vaccines to extend and
enhance immune protection
• Deliver in infancy as part of prime-boost
regimen
• Deliver in adolescents or adults to boost
BCG received as infants
Immunotherapeutic vaccines
–
–
Prevent reactivation of latent TB
Shorten the course of chemotherapy
Global TB Vaccine Pipeline
(as of December 2000)
Phase I
Phase II
Phase IIb
Phase III
M. vaccae
NIH
Mw [M. indicus pranii
(MIP)]
Dept of Biotechnology
(India), M/s. Cadila
Prime
Boost
Post-infection
Immunotherapy
Currently 12 novel TB Vaccines are in Clinical Trials
Phase I
Phase II
AERAS-422-§
M72+AS01
Aeras
GSK, Aeras
AdAg85A
RUTI
McMaster University
Archivel Farma
Hybrid-I+CAF01
VPM 1002
SSI
Max Planck, Vakzine
Projekt Mgmt, TBVI
Phase III
MVA85A/
AERAS-485
Mw [M. indicus pranii
(MIP)]
Oxford-Emergent
Tuberculosis
Consortium (OETC),
Aeras
Dept of Biotechnology
(India), M/s. Cadila
AERAS-402/
Crucell Ad35
Crucell, Aeras
Hyvac 4/ AERAS-404
SSI, Sanofi-Pasteur,
Aeras, Intercell\
Phase IIb
Hybrid-1+IC31
SSI, TBVI, EDCTP,
Intercell
SSI H56-IC31
SSI, Aeras, Intercell, TBVI
Prime
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
Boost
Post-infection
Immunotherapy
Candidates in Phase IIb:
AERAS-485 / MVA85A
•
Recombinant Modified Vaccinia Ankara Expressing Mtb Antigen 85A
•
Multiple clinical trials completed and ongoing, including in:
–
–
–
–
Adults with latent TB infection
HIV+ adults
Infants
Adolescents and children
Safety and immunogenicity demonstrated in all clinical trials to date
•
Two Phase IIb proof-of-concept trials underway
– Enrollment of 2797 infants in South Africa completed in April 2011
– Study in HIV+ adults recently initiated in South Africa in Senegal, designed
to enroll 1400 participants
– Results of Phase IIb trial in infants available in early 2013
AERAS-402: Ad35-Vectored TB Vaccine

ITR
E1
L1-L3
E2B
L4
E2A
E3
L5
E4 ITR
Genomic Structure
E1 deleted;
replaced by
gene expressing
Ag85A/Ag85B/TB10.4
fusion protein
E3 partially
deleted
• Jointly developed by Crucell NV, Leiden, Netherlands and
Aeras
• Vector is replication deficient Adenovirus Serotype 35 (Ad35)
Candidates in Phase IIb:
AERAS-402 / Crucell Ad35
• Adenovirus 35 (Ad35)-vectored vaccine containing M. tuberculosis antigens
85A, 85B, and TB10.4
• Multiple trials completed and ongoing, including in:
–
–
–
–
Adults with latent TB infection
Adults with active TB
HIV+ adults
Infants
• Acceptable safety profile to date and appears to be immunogenic (CD8+ T
cell responses preferentially)
• Multicenter Phase IIb proof-of-concept study underway
– Currently (Feb 2012) in expanded safety (n=250) and early efficacy phase
– Targeted enrollment:4000 infants across multiple trial sites in Africa,
Phase IIb Proof-of-Concept Trials
MVA85A
AERAS-402/Crucell Ad35
2 Phase IIb trials underway
1 Phase IIb trial underway
•Infants (South Africa)
•HIV+ Adults (South
Africa, Senegal)
Partners – Aeras, Wellcome,
Emergent/OETC, EDCTP,
MRC (The Gambia),
IIDMM/UCT, SATVI/UCT
(South Africa), Laboratoire de
Bacteriologie-Virologie du
Centre Hospitalier Universitair
Aristide Le Dantec (Senegal)
•Infants (Kenya,
Mozambique, South
Africa, Uganda,
Botswana)
Partners - Aeras, Crucell,
EDCTP, SATVI/UCT(South
Africa),KEMRI/CDC (Kenya),
CISM (Mozambique),
NIAID/DAIDS:IMPAACT and
HVTN (6 sites)
Together, these trials are designed to enroll ~8,000 volunteers
TB Vaccine Development
A Decade of Progress but much more to do!
2000
No new
2000
preventive TB
vaccines in
clinical trials
2002
1st preventive
202
vaccine enters
clinical
trials (MVA85A)
2009
2011
1st Phase
2009 IIb
proof-of-concept
of preventive
vaccine initiated
15 vaccines
have
2011
entered clinical
trials, 12 currently
in clinical trials
•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
Summary
TB Vaccines Development
•
New TB vaccines could have a significant impact on the global TB epidemic
•
Considerable progress is being made in the field of TB vaccine development,
with two preventive vaccine candidates now in Phase IIb trials
•
Manufacturing capacity being developed and manufacturing agreements are
being explored with particular emphasis on emerging country manufacturers
•
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, it is
possible for a new TB vaccine to be available by the end of this decade
Aeras gratefully acknowledges the support
of the following major donors and
contributors
Netherlands Ministry of Foreign Affairs
US Food and Drug Administration
Thank You!
For more information:
www.aeras.org
lbarker@aeras.org