hope in the tb pipeline: vaccines (dr. michael brennan)
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Hope in the TB Pipeline: VaccinesDr. Michael Brennan
Senior Advisor, Global Affairs
J2J Lung Health Media Training
42nd Union World Conference on Lung HealthLille, France
27 October 2011
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.”
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
The Tuberculosis PandemicSource: 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
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
The Pathway of TB Infection and Pathogenesis
Transmission Pulmonary Lung Disease
Dissemination Latent Disease
90%
10%
5%
Rei
nfe
ctio
n
The Pathway of TB Infection and Pathogenesis
Transmission Pulmonary Lung Disease
Dissemination Latent Disease
90%
10%
5%
Rei
nfe
ctio
n
Meeting the Public Health Need:Target Populations for TB Vaccines
Pre-infection
Infants Adolescents Adults HIV+ All Ages
Covered by existing vaccine
No coverage or impact from existing vaccine
8
•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
Active Disease
Latently Infected
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%
* A
dapt
ed f
rom
Chr
is D
ye,
WH
O
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
Impact of Immunization on Vaccine Preventable Disease
From: “Understanding Vaccines” USDHHS NIH/NIAID Science Education)
Smallpox
Potential Impact of a 50% Effective Vaccine
TB (all types) Incidence
0
400
800
1200
1600
2000
2010 2015 2020 2025 2030 2035 2040 2045 2050Year
Inci
den
ce p
er m
illio
n
Neonatal pre-exposureNeonate pre-exposure + add effectsPost-exposureMass pre-exposureMass pre-exposure + post-exposure
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
All age groups
39 & 37%
52%
80%92%
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
•A
dva
nce
the
pip
elin
e o
f TB
va
ccin
e c
an
did
ate
s
•W
ork
with
par
tne
rs to
ma
rket
affo
rdab
le, s
afe
an
d
effe
ctiv
e T
B v
acc
ine
s fo
r a
ll w
ho
ne
ed
the
m
•E
valu
ate
sur
rog
ate
imm
un
e a
ssa
ys a
nd
ani
ma
l mo
dels
tha
t pre
dic
t va
ccin
e in
duc
ed
pro
tect
ion
•D
eve
lop
clin
ica
l tria
l site
infr
ast
ruct
ure
an
d c
on
duct
clin
ica
l tria
ls
•M
an
ufa
ctu
re g
oo
d m
anu
fact
urin
g p
ract
ice
(G
MP
) lo
ts o
f TB
vac
cin
es
•D
eve
lop
regu
lato
ry s
trat
eg
ies
tha
t ad
van
ce th
e te
stin
g
and
lice
nsu
re o
f TB
va
ccin
es
Critical Needs in TB Vaccine Field
• 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.
Aeras’ Mission and the PDP Model
• 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
Aeras Africa OfficeCape Town, South Africa
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
Pre-clinical Development at Aeras
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
New Paradigm: Partnership & Collaboration
FoundationsGovernmentNGOsCivil Society Pharma &
Biotech Industry
Academia
Aeras
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
TB Vaccine DevelopmentA Decade of Progress but much more to do!
2000 202 2009 2011
2000 2002 2009 2011
No new preventive TB vaccines in clinical trials
1st preventivevaccine 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
•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
AERAS-422Aeras
AdAg85AMcMaster University
Hybrid-I+CAF01SSI
Hyvac 4/ AERAS-404SSI, Sanofi-Pasteur, Aeras, Intercell\
SSI H56-IC31SSI, Aeras, Intercell, TBVI
M72+AS01GSK, Aeras
RUTIArchivel Farma
VPM 1002Max Planck, Vakzine Projekt Mgmt, TBVI
Hybrid-1+IC31SSI, TBVI, EDCTP, Intercell
MVA85A/AERAS-485Oxford-Emergent Tuberculosis Consortium (OETC), Aeras
AERAS-402/ Crucell Ad35Crucell, Aeras
Mw [M. indicus pranii (MIP)]Dept of Biotechnology (India), M/s. Cadila
Phase II Phase IIIPhase IIbPhase I
Source: Tuberculosis Vaccine Candidates – 2010; Stop TB Partnership Working Group on New TB Vaccines
With updates from sponsors
Prime
Boost
Post-infection
Immunotherapy
TB Vaccine TypesViral-vectored: MVA85A, AERAS-402, AdAg85AProtein/adjuvant: M72, Hybrid-1, Hyvac 4, H56rBCG: VPM 1002, AERAS-422Killed WC or Extract: Mw, RUTI
Currently 12 novel TB Vaccines are in Clinical Trials
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 / Emergentand 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
and Aeras
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
Clinical Trial Sites for Phase IIb Proof-of-Concept Trials
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
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
If successful next step licensing trial to prove effectiveness
SATVI/U of Cape TownWorcester, South Africa
Makerere UniversityKampala, Uganda
KEMRI/CDCKisumu, Kenya
St. John's National AcademyPalamaner, India
Cambodian Health CommitteeSvay Rieng, Cambodia
Manhica Health Research Centre Manhica, Mozambique
TB
Vac
cin
eR
& D
Man
ufa
ctu
rin
g
TB
dis
ease
an
d C
lin
ical
Tri
als
[Aer
as]
TB Vaccine Clinical Site Clinical Trial Regulatory Agency
MVA85A/AERAS-485
South Africa Senegal
Phase IIb Phase IIb
MCC CNERS
AERAS-402/Crucell Ad35
US India South Africa Kenya Mozambique Botswana Uganda
Phase I Phase I Phase I; Phase IIb Phase IIb Phase IIb Phase IIb Phase IIb
FDA DCGI MCC KEMRI MoH DRU NDA
SSI/SP H4-IC31 India
Sweden Finland South Africa Switzerland
Phase I Phase I Phase I Phase II Phase I
DCGI MCA FICORA MCC CHUV
AERAS-422 US
South Africa Phase I Phase I
FDA MCC / DAFF
SSI H56-IC31 South Africa Phase 1 MCC
Regulatory Authorities used in Aeras studies
CO
UN
TR
IES
T
B IN
CID
EN
CE
RE
GU
LA
TO
RY
AG
EN
CY
US
V
ery
low
Ver
y G
ood
Eur
ope
L
ow
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ery
Goo
d
Sou
th A
fric
a
Ver
y H
igh
Goo
dB
razi
l
Med
ium
Goo
dIn
dia
V
ery
Hig
hG
ood
Chi
na
Ver
y H
igh
Goo
d
Uga
nda
V
ery
Hig
hW
eak
Ken
ya
Ver
y H
igh
Wea
kB
otsw
ana
V
ery
Hig
hW
eak
Moz
ambi
que
V
ery
Hig
hW
eak
Sen
egal
V
ery
Hig
hW
eak
Gam
bia
V
ery
Hig
hW
eak
Eth
iopi
a
Ver
y H
igh
Wea
k
Regulatory Agency Capacity for Aeras Studies
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
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
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
New
Par
tner
s: E
mer
gin
g C
ou
ntr
ies
Ch
ina,
In
dia
, B
razi
l, S
ou
th A
fric
a
• Ex
pa
nd
ing
ma
nu
fac
turi
ng
ca
pa
bili
ty
• Ev
olv
ing
re
gu
lato
ry a
gen
cy
• Im
pro
vin
g s
cie
nti
fic
res
ear
ch
• Ap
pro
vin
g a
nd
dis
trib
uti
ng
ow
n p
rod
uct
sR
eady
to
ente
r th
e gl
obal
sta
ge
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
• 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
Summary TB Vaccine Development
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
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
Twitter: @aerasglobaltbFacebook: Aeras
Dr. Michael Brennanmbrennan@aeras.org
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