New Priorities for IAVI Dr. Seth Berkley President & CEO, International AIDS Vaccine Initiative 4 August 2008 XVII International AIDS Conference Mexico City, Mexico

An AIDS Vaccine is Possible Immune control is possible: Majority of HIV-infected individuals initially suppress viral load Populations resistant to HIV infection Long-term non-progressors: control infection for many years Highly exposed, uninfected: CSWs, MSMs Children of infected mothers Experimental candidates: Live attenuated SIV & challenge Broadly neutralizing antibodies in Macaques

AIDS VACCINE BLUEPRINT 2008 A Challenge to the Field A Roadmap for Progress

AIDS Vaccines: Global Update- August 2008 Summary & IAVI Assessment Successful development of an AIDS vaccine will likely require: Induction of broadly neutralizing antibodies Control of HIV as well as live attenuated SIV controls against homologous challenge e.g. as well as human “elite controllers” No candidate currently in the pipeline achieves these objectives New and improved functional T-cell assays beyond ELISPOT will help to prioritize candidates for development Success will likely require: Breakthrough in the solution to the HIV neutralizing antibody problem Development of more potent vector(s) e.g. replicating viral vectors Determination of the HIV antigenic inserts which must be included in a vaccine to confer protection against globally diverse subtypes of HIV

There won’t be an AIDS vaccine without a solution to the HIV Neutralizing Antibody Problem Broadly neutralizing antibodies in humans against HIV exist… How to Elicit Neutralizing Antibodies to HIV

Characterize Sera and Identify BN-Mabs Clinical Dev. Immunogen Screening Immunogen Design Structural Biology Protocol G High thru-put Robot Proteins Peptides Sugars “needle in haystack” Major Block Slow Immunogen Screen Research Consortia focus on Key Challenges e.g. Neutralizing Antibody Consortium Broadly neutralizing antibodies Determining structure of novel antigens High thru-put immunogen design Assays to rapidly screen immunogens

Emory ZEHRP Lusaka, Zambia DTHF Cape Town, South Africa VTC & AFIRMS Bangkok, Thailand CeDReS Abidjan, Côte d’Ivoire PSF Kigali, Rwanda MRC-UVRI Entebbe, Uganda KAVI Nairobi, Kenya NSRL Victoria, Australia SUNY-Brooklyn, United States St. Stephen’s Centre London, England Protocol G Research Partners

Protocol G: The Search for Broadly Neutralizing MAbs from HIV+ Subjects Serum Collected>1500 Shipped and Stored (Core Lab)>1500 Neutralization Assay (Monogram) >1,390 Donor of interest identified >140 PBMC’s collected/shipped to Core Lab >30 Monoclonal Ab Identified>5 Neutralization Assay MAb (Monogram) 5 Monoclonal Ab Characterized NAC Investigators

Oxford Indian Institute of Science IAVI Scripps Harvard U. Wisconsin U. Marseilles U. Washington Cornell University U. Pennsylvania Instituto di Recerca in Biomedicina NIH Vaccine Research Center International Centre for Genetic Engineering and Biotechnology IAVI Neutralizing Antibody and Discovery Laboratory Network Academia Sinica Karolinska Institutet Dana Farber

NAC Membership Scientific Director Dennis Burton-TSRI Executive Director Wayne Koff- IAVI Structural Virology, Crystallography, Protein Chemistry, Immunology, Immunogen Modeling Dennis Burton - TSRI Ian Wilson - TSRI Peter Kwong - VRC (NIAID) Richard Wyatt - VRC (NIAID) Gary Nabel - VRC (NIAID) Joseph Sodroski – Harvard Medical School John Moore – Cornell University Robert Doms – U. Pennsylvania David Baker – U. Washington Bill Schief – U. Washington Mechanisms of Neutralization and Resistance Pascal Poignard – University of Marseilles Quentin Sattentau – University of Oxford B Cell Immunobiology/Monoclonal Antibody Identification Antonio Lanzavecchia - IRB, Bellinzona Non-Human Primate Models Ronald Desrosiers – Harvard Medical School David Watkins – University of Wisconsin Carbohydrate Antigen Design / Glycobiology Raymond Dwek – University of Oxford Ben Davis – University of Oxford Chi-Huey Wong – TSRI Protein Antigen Design / Medicinal Chemistry Phil Dawson - TSRI Stephen Kaminsky – IAVI Tim Zamb – IAVI Raghavan Varadarajan- Indian Inst. Sciences VS Chauhan, ICGEB, India

From NAC 1.0 to NAC 2.0; our highest priority Consortium Investigators Core Resources Brooklyn Lab Protocol G Management & Ops Scripps Center Oxford Satellite Center Expanded Core Resources Expanded Brooklyn Lab Consortium Investigators Novel Approaches Expanded Clinical Research Expanded Management & Ops

Innovative Research: A Novel Approach to Antibodies ID broadly neutralizing antibodies Insert genes into vector Inject vector into body Maintain antibody levels over time

5 x Weeks After Injection Human IgG 1 (µg/ml) 5 x Vector Dose In vivo production of human IgG 1 (b12) is sustained for > 6 months Vector (AAV) mediated gene transfer: Proof of concept in mice (I) Courtesy of Phil Johnson, Children’s Hospital of Philadelphia

Vector Mediated Ab Gene Transfer Protection Against SIV Naive4L6 5L7 N4 Wks post SIVmac316 i.v. Challenge Plasma Viral Load (log 10 ) Courtesy of Phil Johnson, Children’s Hospital of Philadelphia

The Benefits of Replication

The Platforms Used to Design Vaccines Safety vs Efficacy In AIDS Vaccine Design

NDV HSV Construct vectors Small animal models NHP model Primary candidate emerges Replicating Vector Portfolio Clinical Candidates CMV HSV CDV VEEV VSVReo CMVCDV VEEV VSVReoSeV IAVI / Gates IAVI / Academic Partner SeV IAVI / Biotech Partnership NDV IAVI / Biotech Exploratory In vitro expression, Stability screen VSV MV Ad Attenuated VSV Wyeth / Profectus Measles virus GSK / Crucell Adenovirus 5 / 7 NCI Vaccinia virus (Tiantan) National Center for AIDS Beijing VV Non-IAVI

IAVI AIDS Vaccine Development Laboratory  : SUNY-Downstate  4Q 2008: Brooklyn Army Terminal (30,000 sq feet)

IAVI AIDS Vaccine Development Laboratory (Brooklyn) A unique industrial-style, not for profit, applied Research laboratory fully dedicated to AIDS Vaccine Discovery and Development Replicating Viral Vectors: The next generation of candidate AIDS vaccines Preclinical Immunology: Systematic comparison and prioritization of vaccine candidates Integrates IAVI’s Neutralizing Antibody and Control of HIV programs Process Development to accelerate Concept to Clinic

Mechanisms of Innovation are now more important than ever Pushing the envelop with a new model…. Partnership with the BMGF Move beyond mainstream HIV vaccine research; Venture capital approach Venture Advisory Committee Brook Byers (Kleiner Perkins Caufield & Byers), Paul Klingenstein (Aberdare), Mike Powell (Sofinnova), Bryan Roberts (Venrock), Greg Weinhoff (CHL Medical) ‘Seed capital’ grants for feasibility studies Non dilutive, minimal diligence, speed Welcome creativity, ‘unproven’ ideas Draw from other disciplines Cross fertilization of ideas Adopt advances, not trying to recreate the wheel

Innovation Fund Completed Grants Current pipeline reflects Fund focus areas  Novel assay / high throughput screening technologies  VaxDesign (US)  In vitro mimic of human immune system for rapid vaccine evaluation  Spaltudaq (US)  Human B cell screening technology for identification of new bnMAbs  Novel Antigen Discovery/Delivery  Lipoxen (UK)  Liposome delivery technology for antigen presentation  Strand (India)  In silico protein structure modeling to design immunogens mimicking the 4E10 epitope

Roadmap for Developing an AIDS Vaccine Solving the Neutralizing Antibody Problem Solving the Problem of How to Control HIV Infection

Kilifi-CGMRC, Kenya Entebbe-MRC, Uganda Chennai-TRC, India Medunsa, South Africa Soweto, South Africa IAVI East Africa IAVI Southern Africa Kangemi and KNH-KAVI, Kenya Masaka-MRC, Uganda Kigali-PSF, Rwanda Lusaka-ZERHP, Zambia Cape Town-DTHC, South Africa Pune-NARI, India IAVI India IAVI Network of Collaborative Sites: Vaccine Trials & Clinical Research

IAVI Gratefully Acknowledges the support of our Donors

IMAGINE a World Without AIDS