NGOs
NGOs and
and Global
Global Public
Public
Health:
Health: PATH’s
PATH’s Work
Work on
on
Vaccines
and
Vaccines and
Immunization
Immunization
John
John Boslego,
Boslego, M.D.
M.D.
Director,
Director, PATH
PATH Vaccine
Vaccine
Development
Development Global
Global Program
Program
Jointly sponsored by the Upper Midwest Center for Public Health
Preparedness, the Iowa Association of Local Public Health Agencies, the Iowa
Department of Public Health, the Iowa Hospital Association, and the Iowa Medical
Society
UPPER
UPPER MIDWEST
MIDWEST CENTER
CENTER FOR
FOR PUBLIC
PUBLIC
HEALTH
HEALTH PREPAREDNESS
PREPAREDNESS WEBSITE:
WEBSITE:
WWW.PUBLIC-HEALTH.UIOWA.EDU/ICPHP
WWW.PUBLIC-HEALTH.UIOWA.EDU/ICPHP
For a videotape or CD-Rom contact:
Nicholas Champagne
(319) 384-4114
Nicholas-champagne@uiowa.edu
PATH: Narrowing the
Immunization Gap
University of Iowa Grand Rounds
October 12, 2007
1
Table of contents
I.
PATH’s work in vaccines and
immunization
II. Increasing availability of existing
vaccines
III. Closing the gap in uptake of
newly available vaccines
4
IV. Developing new vaccines for the
developing world
PATH: A catalyst for global health
PATH works to create sustainable,
culturally relevant solutions for
improved health by:
• Advancing technologies
• Strengthening health systems
• Encouraging healthy behaviors
5
Global presence
6
2
PATH’s vaccine work
• Vaccines and immunization make
up over 50% of PATH’s work.
• Our work spans a range of vaccinerelated activities from research and
development to advocacy,
financing, distribution,
administration, and uptake.
7
Spanning the spectrum of product
development and introduction
8
Working to save children’s lives
• Over 20 million
deaths
prevented in
the last 20
years.
9
• 28 million
children still
without basic
immunization.
3
Creating the right financial
incentives
10
Advance market commitments
•
First AMC pilot approved in February 2007 for pneumococcal
vaccines.
•
AMC is a binding contract to guarantee a viable market if new
pneumococcal vaccines are successfully developed.
•
$1.5 billion agreed to by UK, Italy, Russia, Canada, Norway, and
the Bill & Melinda Gates Foundation.
•
Administered by GAVI & the World Bank.
•
Companies compete to meet or exceed a “Target Product
Profile”.
•
Developing countries choose which product and pay a co-pay;
AMC funds round up the price so that manufacturers receive a
return on their investment.
11
Innovative vaccine technology
solutions for easier immunization
• Vaccine vial monitor—the
world’s smartest sticker
• Winner of the Tech
Museum’s Technology
Benefiting Humanity award
• Uniject™—rethinking the
needle
12
4
Table of contents
I.
PATH’s work in vaccines and
immunization
II. Increasing availability of existing
vaccines
III. Closing the gap in uptake of
newly available vaccines
13
IV. Developing new vaccines for the
developing world
Ensuring effective adoption of
existing vaccines
• In 2006, an estimated 28 million
children in developing countries
were not immunized* and 2.5
million children died of vaccinepreventable diseases.
14
*Basic immunization is categorized as receiving at least 3 doses of DTP.
Children’s Vaccine Program
• Created a renewed commitment to
immunization across international
organizations: WHO, UNICEF,
World Bank.
• Improved immunization coverage,
safety, and protection.
15
• Worked comprehensively: finance,
management, data collection, and
all success factors of immunization.
5
Children’s Vaccine Program
helping save lives in Cambodia
• Within one year, improved immunization rates
by 13% in targeted districts.
• Developed a financial sustainability plan that
allows for long-term planning and increased
advocacy for funding.
• Launched the new hepatitis B birth-dose
strategy. After nine months, it reached 40
percent of newborns in target areas.
16
Protecting India against
Japanese encephalitis
• JE primarily infects children under 15 and leaves
70% dead or with long-term neurological disability.
• PATH worked with a Chinese manufacturer to
license a JE vaccine in India and make it available
at an affordable price.
• 10.5 million children immunized in four high-risk
states in 2006 via partnership with the Indian
government.
• Continued use of this vaccine will protect 100
million children in India through 2010.
17
Table of contents
I.
PATH’s work in vaccines and
immunization
II. Increasing availability of existing
vaccines
III. Closing the gap in uptake of
newly available vaccines
18
IV. Developing new vaccines for the
developing world
6
Expanding access to newly
available vaccines
19
*Coverage estimates based on 3 doses for children in 72 GAVI eligible countries
**Year from availability refers to each year after 1990—the year Hib and Hep B were
introduced in the U.S.
Rotavirus Vaccine Program
• Over 500,000 children die each year from
rotavirus, mainly in the developing world.
RVP’s work:
• Determining vaccine safety and efficacy through
clinical trials in the regions hardest hit by these
diseases.
• Equipping country leaders with the evidence and
information needed for their decisions.
• Refining demand and supply forecasts with
manufacturers, countries, and funders.
20
Rotavirus Vaccine Program
• February 2006: U.S. adopts RotaTeq®.
• November 2006: GAVI Alliance offers
financial support to low-income countries to
begin using rotavirus vaccines.
• December 2006: Nicaragua introduces
RotaTeq® via donation by Merck.
21
7
How many lives can be saved
with accelerated introduction?
Lives Saved
200,000
180,000
160,000
Incremental Lives Saved:
1.4 Million
140,000
120,000
100,000
80,000
60,000
40,000
20,000
0
2006
2007
2008
2009
2010
2011
2012
2013
2014
Lives Saved Without Acceleration
2015
2016
2017
2018
2019
2020
2021
2022
2023
2024
2025
Lives Saved With Acceleration
22
Human papillomavirus project
• Lack of access to life-saving screening and
treatment significantly increase women's risks
of dying from cervical cancer in the
developing world.
• Over 500,000 women are diagnosed each
year with cervical cancer with a 50% death
rate, the majority of whom are in the
developing world.
23
Setting the stage for HPV
vaccination
• Demonstration projects in India,
Peru, Uganda, and Vietnam.
• Developing strategies for reaching
young girls.
• Working with stakeholders to
identify and resolve logistical
challenges of vaccination.
24
8
Table of contents
I.
PATH’s work in vaccines and
immunization
II. Increasing availability of existing
vaccines
III. Closing the gap in uptake of
newly available vaccines
25
IV. Developing new vaccines for the
developing world
Vaccine development at PATH
• Goal: Accelerate the development of new and lifesaving vaccines against selected major disease threats
in the developing world.
• Why: Vaccines against some disease threats (e.g.,
malaria, ETEC) are not available. Others (e.g.,
pneumococcal conjugate vaccine, rotavirus vaccine)
are not affordable or available in sufficient quantity.
• Method: Identify auspicious and affordable product
candidates and partner with industry, academia, public
health organizations, and developing world
manufacturers.
26
• PATH key contributions: Financial resources, technical
expertise, partnership creation.
Investing in vaccine
development
Two methods for creating more
attractive developing world markets:
• Pull mechanisms (e.g., AMC)
• Push mechanisms (e.g., investment in
development costs and global access)
27
9
Developing new, appropriate
vaccines for the developing world
28
PATH’s vaccine development
pipeline
29
Meningitis Vaccine Project
(MVP)
• Dates: 2001 to present, ongoing
• Location: Ferney, France
• Director: Dr. Marc LaForce
• Partner: World Health Organization
30
10
Meningococcal A
• Meningococcal A
kills 6,000 200,000 people
each year in 21
African countries.
31
• 10 - 20% of
survivors are left
with permanent
neurological
disorders and
deafness.
Vaccines against Group A
meningococcal
• Limitations of Group A polysaccharide
vaccines:
• Poor efficacy in young children.
• Do not provide long-lasting protection.
• No herd immunity.
• May not protect against all forms of carriage.
32
• New conjugate Group A vaccines are in
development that would address these
limitations.
Meningococcal Group A conjugate
vaccine product pipeline
• Four vaccine candidates including
Sanofi’s currently licensed vaccine, a
multivalent.
• MVP is working to develop a conjugate
vaccine for meningococcal Group A due
to the shortfalls of polysaccharide
vaccines and lack of commercial
interest in monovalent GpA conjugate
vaccine.
33
• Development partnership with Serum
Institute of India using conjugation
chemistry from US FDA.
11
MVP Phase 2 clinical trial
results
• Comparison of the Group A conjugate
vaccine, PsA-TT with the licensed PsA
vaccine with Hib vaccine as control at two
sites in The Gambia and Mali.
• No safety issues to date.
• In African toddlers (12 to 23 months of age)
the PsA-TT vaccine induced 20x more
bactericidal antibodies than the currently
licensed tetravalent polysaccharide vaccine.
34
MVP Phase 2 results
serogroup A rSBA GMT (95% CI)
10000
35
1000
Baseline
100
4 week
10
1
PsA-TT
PsA/C
Hib-TT
Men A conjugate vaccine Phase 2/3
clinical studies (launched August 2007)
• PsA-TT-003 (Africa)
• A Phase 2/3, observer-blind, randomized, active controlled study to
compare the safety and immunogenicity of a meningococcal A
conjugate vaccine (PsA-TT) with meningococcal ACWY
polysaccharide vaccine administered in healthy subjects 2-29 years
of age (900 total subjects).
• PsA-TT-003a (India)
• A Phase 2/3, observer-blind, randomized, active controlled study to
compare the safety and immunogenicity of a meningococcal A
conjugate vaccine (PsA-TT) with meningococcal ACWY
polysaccharide vaccine administered in healthy children 2-10 years
of age (340 total subjects)
36
12
Men A conjugate vaccine
regulatory strategy
Goals
• License Men A conjugate vaccine to be used in 1- to 29year-old population (10 µg dose)
• Indian licensure (country of origin) (by
Sept. 2008)
• Burkina Faso, Mali, Niger licensure (by
Sept. 2008 for vaccine introduction in
2008 and 2009)
• WHO prequalification certificate (early
2010)
37
• Amend with infant indication (early 2010)
First introduction/post-licensure demonstration of the
men A conjugate vaccine (Burkina Faso: Nov. 2008)
Timeline, key activities and metrics
Phase 1: Preparation
& Capacity Building
Phase 2: Vaccination
through National
Mass Campaign
September 2007 – November 2008
Key
Activities
Strengthening surveillance systems
Strengthening vaccine delivery
systems
Phase 3: Evaluation &
Dissemination of
Results
November – December 2008
Vaccination of over 9.1
million 1- to 29-year-olds in
Burkina Faso
April – September 2009
Compilation and evaluation of
vaccine impact data, and safety
and operational lessons learned
Dissemination of information
across sub-Saharan Africa and
to potential donors
Improving waste management
Developing robust operations plans
Key
Metrics
Quality & completeness of
surveillance data
Effective implementation & followup (coverage results & completion
dates)
38
Number vaccinated
Cases, deaths, and disability
averted
Quality of data
Countries introducing vaccine
Funding for introduction
Efficient vaccine delivery & waste
management infrastructure
Malaria Vaccine Initiative (MVI)
• Dates: 1999 to present, ongoing
• Location: Bethesda, Maryland
• Director: Dr. Christian Loucq
39
13
Geographical incidence of
malaria
40
MVI’s units: Competencies and
performance management
Director
Communications & Advocacy
Finance & Administration
Policy & Access
Portfolio Management
Research & Development
Quality Management & Commercial Affairs
41
The first vaccine against a
parasite
• Complex, multi-stage parasite with multi-level
host-parasite interaction that creates unique
challenges to vaccine development.
• Vaccine candidates are being tested for each
of the three stages of host-parasite
interaction.
• Complex life cycle of the parasite may require
a combination of several components aimed
at different stages of the malaria parasite.
42
14
The five-year research and
development horizon (1)

Development of RTS,S
 Targets the CS protein, the dominant surface sporozoite antigen
 Recombinant HBsAg-CS protein fusion expressed in yeast
 AS02A formulation: 3D-MPL + QS21 with oil/water emulsion
 Complete program for infant/child indication for clinical disease
 Commence program for extension to adolescent female indication for pregnancy
malaria
 Commence improvements through combinations

Development of potent pre-erythrocytic candidates (anti-sporozoite neutralizing Ab plus
CD8+ T-cell killing of infected hepatocytes)
 Vectored CS, LSA1, Ag2
 Adeno, Listeria, rBCG (dual-use vector)
 Additional neo-antigens like Ag2 (SBRI-USMMRP discoveries)
 Live attenuated sporozoites
 Radiation attenuated (Sanaria)
 Genetically attenuated (SBRI)
43
The five-year research and
development horizon (2)

Modified role for recombinant subunit proteins (to boost pre-erythrocytic
vector prime, to induce blood-stage antibody “chasers” to clean up
breakthrough liver parasites)
 New adjuvants, formulations (with IDRI)
 Conjugates (with Merck & NIAID)

Assays and models to inform decisions/manage risk
 Merozoite neutralizing antibody (GIA Reference Center)
 Functional pre-erythrocytic bioassays (ISI, infected hepatocyte killing)
 Effector and memory T-cells (T-cell Reference Center)
 Automated infected RBC enumeration
 Chimeric parasites/transgenic mice
 Human challenge for blood stage candidate evaluation
 titrated sporozoite inoculum
 titrated infected RBC inoculum
44
 Q-PCR replication kinetics curve as endpoints
MVI’s current portfolio
Construct
Selection
45
Process
Development
Final
Formulation
Toxicology
Clinical
Phase 1a
Phase 1/2a
Monash
MSP4
ISA720
ICGEB/BBI
PvRII
AS01/AS02
WRAIR/GSK
AMA1
AS01/AS02
Monash
MSP5
ISA720
LaTrobe
MSP2
ISA720
MVDB
AMA1-C1
ISA720/A-CpG
GenVec
Ad5 CSP/
LSA1/Ag2
Sanaria
PfSPZ
Clinical
Phase 1/2b
Clinical
Phase 3
GSK
RTS,S
AS01/AS02
GenVec
Ad5 MSP1/
AMA1
15
Clinical trial results
• Phase 2b trials in 2,000 children
aged one to four years in Africa
showed RTS,S:
• Delays time to new infections of
Plasmodium falciparum by 45%.
• Reduces the risk of new episodes of
clinical malaria by 30%.
46
• Protects against new episodes of severe
malaria by 58%.
Vaccine efficacy against severe
and hospital malaria
Per RAP
(VE ± 95% CI)
p value
57.7
Severe malaria (11 vs 26)
0.019
0.018
0.379
32.3
Hospitalized malaria (42 vs 62)
0.053
0.046
0.486
47
0
50
100
Pneumococcal Vaccine Project
(PVP)
• Dates: 2005 to present, ongoing
• Location: Seattle, Washington
• Director: Dr. Mark Alderson
48
16
Geographical incidence of
pneumococcal
49
Vaccines against
pneumococcus
• Over 90 serotypes of pneumococcus exist and
are geographically dispersed.
• The current pediatric vaccine—Wyeth’s
Prevnar®—contains seven serotypes, those
most prevalent in the U.S. and Europe. This
vaccine contains a pneumococcal capsule
conjugated to a protein carrier.
• PATH’s project is focusing on pneumococcal
proteins common to all or most strains of the
bacterium. If successful, the vaccine would
provide broad protection to children worldwide.
50
Current vaccines
Novel vaccines
Polysaccharide based vaccines
Protein-based vaccines
Killed whole bacterial vaccine
90+ types
51
17
Intercell
• Austria-based biotechnology
company
• Developed Antigen Identification
Technology and applied to several
candidate products including S.
aureus and S. pneumoniae
52
• Candidate S. pneumoniae vaccine
consists of 3 distinct proteins
Antigen discovery at Intercell
Learn from individuals who‘s immune system has encountered the pathogen
Genomic peptide
libraries
Antibodies
Vaccine
Protection
Defined
peptides/proteins
Defined adjuvant
Serum from exposed
and diseased humans
Bacterial surface display
(10 to 150 amino acids)
Animal models
Clinical trials
53
Intercell antigen discovery for pneumococcus:
from proteome to antigenome to vaccine
2,236
Pneumococcus proteome
Collection, characterization & selection of sera
Exposed
humans
Antibodies
ELISA
Immunoblot
In vitro assay
Genomic libraries, antigen identification and confirmation
100-150
Genome
Antigen screen
Clone selection
Sequence analysis
Antigenome
Antigen validation
20-30
Conserved
Highly
immunogenic
Functional
antibodies
Animal studies
54
Surface
exposed
3-5
Protective antigens
18
Intercell: results for 2 components
of the protein vaccine
PROTECTION RESULTS – SEPSIS
• Two serotypes of S. pneumoniae (PJ-1259 – serotype 6B, 6301 – serotype 1)
Serotype 1 sepsis
Serotype 6B sepsis
100
100
PcsB-N
StkP-C
80
PspA
% survival
% survival
80
60
40
60
PBS
40
20
20
0
0
0
2
4
6
8
10
12
14
0
days post challenge
2
4
6
8
10
days post challenge
55
Intercell: results for 2 components
of the protein vaccine
PROTECTION RESULTS – PNEUMONIA
• Two serotypes of S. pneumoniae (WU2 – serotype 3, EF3030 – serotype 19F)
Serotype 3 pneumonia
1010
p=0.01
109
108
108
7
7
10
cfu / lung
10
cfu / lung
Serotype 19F pneumonia
1010
p=0.005
109
106
105
103
102
100
103
102
100
PspA
PBS
PcsB-N
StkP-C
PspA
Prevnar®
PBS
detection
limit
105
104
StkP-C
p=0.05
106
104
PcsB-N
p=0.01
PcsB-N
StkP-C
PspA Prevnar®
PBS
56
Children’s Hospital Boston
• Development of an inactivated
whole cell vaccine for Phase 1
clinical trials.
• Would require no refrigeration and
could be given through the nasal
passage.
57
• CHB established partnership with
Butantan in Brazil for developing
world manufacture.
19
Development of a whole-cell pneumococcal
mucosal vaccine for prevention of
colonization and invasive disease
Mutant S. pneumoniae Rx1 AL(-)
Unencapsulated
Autolysin-defective [growth density increased and
release of pneumolysin impaired]
Pneumolysin gene replaced with mutant
pneumolysoid
Killed by one hour treatment with ethanol (70%)
10 8 killed cells/dose
Adjuvant
Cholera toxin (holotoxin) 1 µg/dose or
CTB (recombinant) 4 µg/dose
58
CHB: WCV protection against
sepsis in mice
100
80
WCV+CT
60
P=0.017
40
CT
20
0
0
2
4
6
8
10
days since infection
59
Request for proposals
• Issued in 2006 for two areas:
Vaccine discovery and
development; and research
activities in support of vaccine
development.
• 45 letters of intent received.
60
• Anticipate additional partnership
announcements by the end of
2007.
20
Development of vaccine
candidates for diarrheal disease
• Diarrheal disease causes 18% of
childhood deaths worldwide, making
it one of the leading causes of
death.
• PATH is targeting viral and bacterial
causes of childhood diarrhea:
rotavirus, ETEC, and Shigella.
61
Rotavirus vaccine development
• India Rotavirus Vaccine Development
Program
• Dates: 2000 to present
• Advancing Rotavirus Vaccine Development
Project
• Dates: 2006 to 2011, ongoing
• Location: New Delhi, India
• Director: Dr. Rajat Goyal
62
New vaccines for rotavirus
• Partnership with manufacturer in
India: BBIL to develop a 116E
human attenuated monovalent
rotavirus vaccine.
63
• Successfully completed pre-clinical
toxicity and safety studies. Phase
1B/2A clinical trials in infants
underway.
21
New vaccines for rotavirus
• Developing a human bovine reassortant
vaccine with components from the U.S. NIH.
• Designed to include most of the rotavirus
serotypes that occur in the developing world,
particularly those that recently emerged in
Asia and Africa (e.g., G8, G9).
• Partnering with manufacturers in India
(Shantha) and China (Wuhan).
64
Shared technology platform
• Seven companies working on the
human reassortant vaccine through
NIH licenses.
• Creating a “shared technology
platform”—a toolbox of
technologies, training, and common
technical support to speed
development and global access.
65
Enteric Vaccine Initiative (EVI)
• Date: September 2007, ongoing
• Location: Washington, DC
• Director: Dr. Richard Walker
66
22
Enteric Vaccine Initiative
• Enterotoxigenic Escherichia coli
(ETEC) and Shigella are the leading
bacterial causes of diarrhea.
• Partnering with manufacturers
developing travelers vaccines to
address disease in children in
developing countries.
67
Current status of enteric
vaccine development
• Difficult to make comparisons
between vaccines under
development to identify the most
promising candidates.
• Very few vaccine candidates have
progressed to assessment in
developing countries.
68
• Many previous vaccine candidates
have not moved through
development due to lack of
adequate resources.
Potential EVI portfolio
ETEC
• Attenuated ETEC
• Inactivated ETEC whole cell
• LT Patch +/- other ETEC antigens
• Shigella-vectored ETEC*
colonization and toxin antigens
69
*Combination vaccine which addresses both disease targets
23
Potential EVI portfolio
Shigella
• Shigella-vectored ETEC*
colonization and toxin antigens
• Inactivated Shigella whole cell
• Shigella conjugate
• Ty21a-vectored Shigella LPS
70
*Combination vaccine which addresses both disease targets
Influenza Vaccine Project
• Date: 2006 to 2007, completed
• Location: Washington, DC
• Director: Dr. John Boslego
• Consultant: Dr. Kathryn Edwards,
Vanderbilt University
71
• Management consultants: Oliver
Wyman, Inc.
Influenza vaccines landscape
analysis
• Develop strategies to increase access to
pandemic influenza vaccines among
developing world populations, and identify
and quantify potential investment
opportunities for highest priority strategies.
• Conduct technical evaluation and
prioritization of influenza vaccine
technologies in existence or development.
Auspicious technologies will be targeted for
future funding and accelerated development.
72
24
73
Influenza vaccine landscape
analysis findings
•
The global need for a pandemic vaccine is an estimated 7 billion
courses.
•
Planning for the availability of a pandemic vaccine should envision
at most a six-month time horizon, and likely shorter.
•
Should an outbreak of pandemic influenza occur today, the “best
case” scenario within this timeframe is that 1.2 billion courses of
pandemic vaccine could be produced from current capacity within
six months.
•
In the short term, new adjuvants could facilitate “dose sparing” but
in the long term, new innovative technologies that could increase
global supply are needed.
•
Proposal submitted to advance promising new pandemic flu
vaccines through development.
74
Near term strategy: Is real-time response viable?
Real time response is not a viable solution in the near-term
since existing infrastructure would only serve a small portion
of the world’s population within 6 months of outbreak.
Real-time Global Pandemic Capacity – “Best Case”
7.0 B
Global Demand = 6.8B
6.0 B
Pandemic
Courses
Filled in
6 Month
Timeframe
5.0 B
4.0 B
2.8 B
3.0 B
2.0 B
1.2 B
1.2 B
2007
2008
Availability Timeframe
~2yrs
for Global Need
~2yr
1.8 B
1.9 B
2.0 B
2.0 B
2009
2010
2011
2012
~1.4yrs
~1.3yrs
~1.3yrs
~1.3yrs
1.0 B
0.0 B
2013
~1yr
75
25
Longer term strategy: Which technology?
Live and recombinant technologies are the
most cost-effective for pandemic production.
Index of Manufacturing Costs (Per Course)
Cost per course indexed to Egg Inactivated
1,000
900
1,000
854
800
100
90
85
80
70
60
48
50
42
40
30
20
10
14
0
Egg
Cell
Inactivated Inactivated
76
High Cost
Egg Inactivated Cell
Recombinant
w / adj
Inactivated
w/ adj
Medium Cost
9
3
Egg
Live
3
Cell
Live
3
Recombinant
w / adj
Low Cost
Improving health in Kenya
77
Improving health in Cambodia
78
26
Improving health in Cambodia
79
John Boslego, MD
Director, Vaccine Development
jboslego@path.org
202.822.0033
www.path.org
Our
Our Next
Next Event
Event
Implementation
Implementation of
of National
National Strategy
Strategy for
for
Pandemic
Pandemic Influenza
Influenza
Thursday,
October
18,
2007
Thursday, October 18, 2007
11:30
11:30 –– 12:30
12:30 CDT,
CDT, Room
Room E331
E331 General
General
Hospital
Hospital and
and Live
Live Web-Cast
Web-Cast
Please
Please Visit
Visit Our
Our Website
Website For
For More
More Information:
Information:
WWW.PUBLIC-HEALTH.UIOWA.EDU/ICPHP
WWW.PUBLIC-HEALTH.UIOWA.EDU/ICPHP
For a videotape or CD-Rom contact:
Nicholas Champagne
(319) 384-4114
Nicholas-champagne@uiowa.edu
27