1
IAVI’s Integrated R&D Program
Accelerating AIDS vaccine development
Source: Joint United Nations Programme on HIV/AIDS
33 million
2007
7.5 million people living with HIV
1990
18.5 million1995
28.5 million2000
32 million2005
33 million people living with HIV worldwide
7,400 new HIV infections daily
25 million AIDS-related deaths to date
2.7 million people a year becomeinfected, including 370,000 children
270,000 children die of AIDSevery year
Women bear the brunt of theepidemic, representing almost60 percent of HIV-infected adults in Africa and half of adults worldwide
HIV continues to devastate
AIDS vaccines are part of a sustainable,comprehensive response
Deliver for today—better use of toolsPrevent further spread of the virus Treat those already infected Mitigate societal impacts
Develop better tools for the futureInvest in innovation for new technologies
(better drugs, diagnostics, barrier methods, microbicides, vaccines)
Better prevention—particularly AIDS vaccines—is critical for the affordability and sustainability of our commitments to universal access
Vaccines can take decades to develop
Measles
Hepatitis B
Human papilloma virus(cervical cancer)
Rotavirus(diarrheal disease)
Varicella zoster(chickenpox)
Pertussis(whooping cough)
Polio
Haemophilus influenza
Typhoid
Malaria
Human immunodeficiency virus(HIV/AIDS)
INFECTIOUS AGENT (Disease)
AGENT LINKEDTO DISEASE IN …
VACCINE LICENSEDIN U.S. IN …
1953
1965
1884
1973
1953
1906
1908
1889
Early ’80sto mid-’90s
1893
1983
1963
1981
2006
2006
1995
1948
1955
1981
1989
—
—
YEARSELAPSED
10
16
12-25
33
42
42
47
92
105
116
26
The Thai trial demonstrates an AIDS vaccine is possibleCorrelates may be found
Two very potent and broadly neutralizing antibodies discovered; more coming New targets for Immunogen designPassive immunity data from IAVI’s Neutralizing Antibody Consortium suggests that less antibody than previously thought may be requiredProof of principle possible
CMI Vectors show significant promiseSix vaccine concepts confer >2 logs suppression of viral load in pathogenic SIV- rhesus macaque modelCMV completely controls SIV infection in ~50% of monkeys
Recent Advances offer the most promise for AIDS vaccines since the discovery of HIV as the causal agent
RV144 trial: First HIV vaccine candidate to show efficacy
A Phase IIb test-of-concept trial, based on the expected number of HIV infection endpoints, conducted by Thailand Ministryof Public Health
Co-primary endpoints: Prevention of HIV infection and ability to reduce viral loadDuration: Six years (2003-2009)Sponsor: US Army, Surgeon GeneralTrial Cost/funders: US$ 105 million; US National Institute of Allergy and Infectious Diseases (75%), US Army (25%)
THE TRIAL
Vaccine candidate provided ~30% protection against acquisition of HIV; No effect on viral load or CD4 levels in the blood of volunteers who became HIV-infected during the studyTrend towards limited durability; vaccine effect appears short livedMode of transmission may be important factor; Vaccine possibly less efficacious in high-risk groupsVaccine likely not applicable to diversity of strains prominent in sub-Saharan Africa
THE RESULTS
26,675 Thai citizens screened; 16,402 Thai citizens (60% male, 40% female) enrolled; 16,395 received at least one dose of vaccine or placebo
THE VOLUNTEERS
Immune Mechanisms for an AIDS Vaccine
Cell Mediated Immunity
Neutralizing Antibodies
IAVI’s roles
Mission
To ensure the development of safe, effective, accessible, preventive HIV vaccines for use throughout the world
Political willand finance
Researchand development
Clinicaltrials
Production Health and other systems
Accessand uptake
FocusSpeedFlexibilityWillingness to take informed riskAccess is part of our mission
Core principles
An early model for the field
1986 ’87 ’88 ’89 1990 ’91 ’92 ’93 ’94 ’95 ’96 ’97 ’98 ’99 2000 ’01 ’02 ’03 ’04 ’05 ’06 ’07 ’08 ’091986 1989 1990 1996 1998 1999 2000 2001 2002 2003 2005
Product-development partnershipsin global health
Selected otherpublic-private partnershipsWorking on health issues
1977
BY YEAR STARTED
What is IAVI?
Political willand finance
Researchand development
Clinicaltrials
Production Health and other systems
Accessand uptake
Integrated R&D
Professional project &
Portfolio management
Infrastructure and full staffing across vaccine disciplines
Validated laboratoriesApplied research
consortia
Vaccine preparedness
Epidemiological and social research
Policy studies
Communicationsand publications
Advocacy and training from community to international level
Early positioning in AIDS vaccine R&D
Basicresearch
Appliedresearch
Preclinical development
Clinicaldevelopment
Advanceddevelopment
Large-scaleEfficacy trials
Public sector, academia
Biotech companies Pharmaceutical companies
A well-established continuum of players moves new drugs to market
Basicresearch
Appliedresearch
Preclinicaldevelopment
Clinicaldevelopment
Advanceddevelopment
Large-scaleEfficacy trials
Public sector, academia
IAVI initially worked to ensure a vaccine for the developing world by focusing on product development
Biotech companies, pharmaceutical companies
Advocacy
Clinical trial network in developing world
Gap-filling science
Public sector, academia
Pharmaceutical companies,product-development partnerships
Filling the gap in AIDS vaccine R&D
Basicresearch
Appliedresearch
Preclinicaldevelopment
Clinicaldevelopment
Advanceddevelopment
Large-scaleEfficacy trials
But as product failures forced big players out or moved them downstream,a development gap grew …
… and IAVI moved to fill the void, creating new programs as needs arose
Human Immunology Lab (2001)
Neutralizing Antibody Consortium (2002)
Live Attenuated Consortium (2006)
AIDS Vaccine Design and Development Lab (2008)
IAVI Neutralizing Antibody Center at The Scripps Research Institute (2009)
Vectors Consortium (2007)
VACCINE DEVELOPMENT
IAVI’s R&D integrates each step
Public sector, academia
Pharmaceutical companies,product-development partnerships
RESEARCH CONSORTIA DESIGN & DEVELOPMENT LAB
(Brooklyn)
CLINICAL TRIALS NETWORK
PRODUCT-DEVELOPMENT PARTNERSHIPS (EXTERNAL)
INNOVATION FUND
HUMAN IMMUNOLOGY LAB (London)
NEW ALLIANCES
Preclinical development Clinical developmentApplied research
IAVI’s R&D integrates each step
Public sector, academia
Pharmaceutical companies,product-development partnerships
PRODUCT-DEVELOPMENT PARTNERSHIPS (EXTERNAL)
INNOVATION FUND
NEW ALLIANCES
Preclinical development Clinical developmentApplied research
CLINICAL TRIALS NETWORK
•Clinical research(e.g., Protocol G)
•Phase I trials•Feasibility studies•Small-scale efficacy trials
RESEARCH CONSORTIA
•Neutralizing antibodies•Vectors•Live attenuated
DESIGN & DEVELOPMENT LAB
•Antigen design•Vector design•Non-human primate prioritization•Process Development•Non-human primate studies
VACCINE DEVELOPMENT
•Toxicology studies•Pilot manufacturing•Regulatory affairs•Manufacturing
HUMAN IMMUNOLOGY LAB
•Assay development•Sample testing
Neutralizing Antibody Consortium
Vectors Consortium
Live Attenuated Consortium
Innovation Fund grant recipients
IAVI-supported clinical research centers
Other scientific and civil-society partners
IAVI facilities
IAVI Partners Around the GlobeIAVI Partners Around the Globe
UVRI-IAVI lab and clinic: Entebbe, Uganda
Before lab/clinic constructed
After lab/clinic constructed
Clinic: Multiple Phase I AIDS vaccine trials, accelerated approval and enrollment vs. historical controls
Expansion: Field sites doing clinical studies in preparation for future efficacy trials
Laboratory: Validated assays,Good Laboratory Practices training
Accredited and nowGates Foundation/CAVD reference lab
IAVI’s Clinical Work: A HistoryIAVI’s Clinical Work: A History
2000 2001 2002 2003 2004 2005 2006 2007 2008 20092000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Australia
IAVI-sponsored clinical trials and HIV epidemiology studies, by year started
IAVI’s Clinical Trials: A history
IAVI-sponsored AIDS vaccine clinical trials
2000 2001 2002 2003 2004 2005 2006 2007 2008 20092000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Countries participatingin IAVI trials
DNA+Ad5—VRC
Phase II
First AIDS vaccine trial in Kenya
DNA
First AIDS vaccine trial in Zambia
First AIDS vaccine trial in Rwanda
DNAcandidates
AAV candidates
Adeno-based candidates
ADARC DNAand MVA candidates
All trials are Phase I, except where noted
Belgium, Germany, India, Kenya, Rwanda, South Africa, Switzerland, Uganda, United Kingdom,United States, Zambia,
Start date
Final volunteer visit
DNA+MVAcandidates
ADMVA
ADMVA
TBC-M4
ADVAX
Phase IIa
Ad35
ADVAX+TBC-M4
First AIDS vaccine trial in India, Germany
MVAcandidates
PreP
“Insanity: doing
the same thing
over and over
again and
expecting
different results.”
—Albert Einstein
IAVI’s Mechanisms of Innovation
•Scientific Consortia directed at major scientific challenges
•Vaccine Development Laboratory
•Innovation Fund
•Incentives, Prizes, etc.
•Accelerated Clinical Testing
Mechanisms of Innovation are now more important than ever
Pushing the envelope with a new model …
Partnership with BMGF
Move beyond mainstream HIV vaccine research; Venture capital approach
‘Seed capital’ grants for feasibility studies
Non-dilutive, minimal diligence, speed
Welcome creativity, ‘unproven’ ideas
Draw from other disciplinesCross fertilization of ideas
Adopt advances, not trying to re-create the wheel
Venture Advisory Committee
Paul Klingenstein Aberdare
Amir NashatPolaris
Mike PowellSofinnova
Bryan Roberts Venrock
Otello Stampacchia Omega Funds
Greg WeinhoffCHL Medical
Brook ByersKPCB(founding member)
The neutralizing antibody challenge
Most licensed vaccines elicit neutralizing antibodies
Neutralizing antibodies protect against SIV/HIV challenge in animal models
Broadly neutralizing antibodies in humans against HIV exist, although they are weak. This is a solvable problem
But no candidate vaccine in the pipeline elicits broadly neutralizing antibodies against HIV gp41
b12
2G12
2F54E10/Z13
CD4
gp120
The IAVI Neutralizing Antibody Consortium
1. More than 1,800 blood samples collected from HIV-positive individuals around the world
IAVI Human Immunology Laboratory, London
200 200
25
91
238
200
81
200
200
Number of donor samples from each site200
215
Protocol G: An example of the IAVI network in action
IAVI Human Immunology Laboratory, London
200 200
25
91
238
200
81
200
200
Number of donor samples from each site200
215
1. More than 1,800 blood samples collected from HIV-positive individuals around the world2. Samples sent to Monogram Biosciences to screen for neutralization using IAVI algorithm
Protocol G: The IAVI network in action
3. IAVI and the Neutralizing Antibody Consortium review data
About 1% are “elite neutralizers”
Blood samples collectedAbout 10% are donors of interest
Protocol G: The IAVI network in actionProtocol G: The IAVI network in action
Elite Neutralizers: score ≥ 2.5
(N=18) Clade A Clade B Clade C CRF01_AE
Rank Score Country 94UG103 92BR020 JRCSF IAVI C22 93IN905 92TH0211 3.67 Ivory Coast 900 900 2700 2700 2700 2700
2 3 Zambia 300 300 2700 300 2700 27005 2.83 Ivory Coast 300 300 900 300 2700 27005 2.83 Ivory Coast 300 900 2700 900 2700 1005 2.83 Kenya 300 900 900 900 2700 3005 2.83 South Africa 300 900 900 2700 2700 1005 2.83 Rwanda 300 2700 900 2700 2700 <1008 2.69 Zambia 345 345 1190 1190 1190 345
10 2.67 UK 300 900 900 2700 900 10010 2.67 Zambia 900 900 900 300 2700 10010 2.67 Uganda 900 900 900 2700 900 <10015 2.5 Ivory Coast 300 900 300 900 900 30015 2.5 South Africa 100 300 300 2700 900 900
15 2.5 South Africa 300 300 300 2700 2700 10015 2.5 UK 300 900 300 900 900 30015 2.5 South Africa 2700 100 300 2700 2700 <10015 2.5 Uganda 900 900 900 900 900 <10015 2.5 Zambia 300 <100 900 300 2700 2700
Note: Donor that yielded two bnAbs- Score =2.1
4. Request for new samples to be collected from donors of interest
IAVI
IAVINAC at Scripps
IAVI Human Immunology Laboratory
5. New samples make their way to Monogram Biosciences for screening
Protocol G: The IAVI network in action
IAVI
IAVINAC at Scripps
IAVI Human Immunology Laboratory
6. IAVI and NAC request samples be sent to partner labs for antibody rescue
Theraclone
RockefellerUniversity
IAVINACat Scripps
HuMabs
Protocol G: The IAVI network in action
IAVI AIDS Vaccine Design and Development Lab
IAVI Neutralizing Antibody Centerat the Scripps Research Institute
IAVI Human Immunology Lab
Neutralizing Antibody Consortium members
7. When antibodies are identified, IAVI’s immunogen design partners take over
IAVI has submitteda proposal to build an applied research lab in India
StrandLife Sciences
Elevation Biotech
Chembiotek
IAVI Innovation Fund recipients
Lipoxen Pepscan
ProSci
Avatar
Protocol G: The IAVI network in action
Chennai
Pune
Kilifi
Rustenburg
Cape Town
Lusaka
Copperbelt
Kigali
Masaka
Entebbe
Nairobi
8. Ultimately, the process comes full circle with clinical testing of vaccine candidates
IAVI’s Network of Clinical Research CentersIAVI’s Network of Clinical Research Centers
Replication of the vaccine may be required for virus control
No Vaccine
Vaccine = Single-Cycle SIV
Vaccine = Live attenuated SIVmac239
Evans, DT. et al (2005)
Balancing safety and efficacy in AIDS vaccine design
Cytomegalovirus controls SIV to levels only previouslyachieved with live attenuated SIV
0 7 14 21 28 35 42 49 56 63 70101
102
103
104
105
106
107
108
109RhCMV / Ad5
n = 5
n = 7
Time Post Infection (days)
Pla
sma
Vir
al L
oad
0 7 14 21 28 35 42 49 56 63 70
n = 26
n = 1
101
102
103
104
105
106
107
108
109Unvaccinated Controls RhCMV Vectors Alone
0 7 14 21 28 35 42 49 56 63 70101
102
103
104
105
106
107
108
109
n = 6
n = 6
p = .0017 p < .0001
n=1
n=26
n=6
n=6
n=7
n=5
54% of CMV vector-vaccinated monkeys controlled viral load to undetectable levels . . .
L Picker, OHSU
Control of SIV No control of SIV
Unvaccinated (n=27) 4% 96%
CMV alone (n=12) 50% 50%
CMV + Ad5 (n=12) 60% 40%
IAVI is an essential component in the search for an AIDS vaccine
IAVI’s mission has never changed but its programs have evolved continuously over the years, driven by the scientific data and the need to bridge key gaps in the field
IAVI operates globally and in partnership with others, which means the organization can work with the most gifted researchers and advance the most promising approaches regardless of their origin
IAVI’s integrated R&D program quickly and seamlessly moves a vaccine approach through every step, from concept to design to development to manufacturing to regulatory approval to clinical trial and if necessary back again
A preventive vaccine is the only way to end the AIDS epidemic
Imagine a worldwithoutwithout AIDSAIDS
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