IAVI's Integrated R&D Program: Accelerating AIDS vaccine development

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



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


Pharmaceutical companies,product-development partnerships

Filling the gap in AIDS vaccine R&D

Basicresearch

Appliedresearch

Preclinicaldevelopment

Clinicaldevelopment

Advanceddevelopment


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



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



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


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


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


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

IAVI's Integrated R&D Program: Accelerating AIDS vaccine development

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