NIAID Vaccine Research Center: A Mission to Prevent HIV Infection

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1 NIAID Vaccine Research Center: A Mission to Prevent HIV Infection AIDS Vaccine Awareness Day 20 year anniversary May 18, 2017 Barney S. Graham, MD, PhD Deputy Director

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6 Origins of the VRC May 18, 1997 Fall of 1997 Fall of 1998 June 9, 1999 May 18, 1997 Commencement address Morgan State University June 9,1999 Cornerstone Ceremony, President Clinton Fall, 1997 Design of VRC Fall, 1998 Ground breaking June 9, 1999 Cornerstone Ceremony, HHS Secretary Donna Shalala, President Clinton, Senator Dale Bumpers and Betty Bumpers

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8 AIDS Vaccine Development A Global Imperative

9 Estimated number of adults and children newly infected with HIV during 1999 North America Caribbean Latin America Western Europe North Africa & Middle East sub-saharan Africa 4.0 million Eastern Europe & Central Asia East Asia & Pacific South & South-East Asia Australia & New Zealand 500 Total: 5.4 million

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12 Relative focus on vaccine effector mechanisms Brief History of HIV Vaccines gp160/gp120 subunits Poxvirus vector + protein rad5-gag/pol/nef DNA/rAd5-Env/gag/pol/nef Antibody CD8 T cells

13 Why do we need a vaccine for HIV? Still more than 5000 infections a day globally ~5 people are infected for every 2 that are placed on ARVs

14 NIAID VRC Research & Development: From AIDS to Zika August 2000 AIDS/HIV Chikungunya Ebola/Marburg Influenza Malaria MERS-CoV, SARS RSV Smallpox Tuberculosis W/E/V equine encephalitis viruses West Nile virus, Zika Engineering Lab Pilot Plant Vaccine Evaluation Clinic Immunology Lab Partners for Advanced Development

15 Vaccine Technology Platforms Genetic immunization Plasmid DNA (SARS, WNV, Flu, Zika) Viral vector (HIV, Ebola) Virus-like particles (ChikV) Human Monoclonal Antibodies (HIV, Ebola) Viral Protein immunization Nano-particles (Flu, RSV) Subunit protein (HIV, RSV, MERS)

16 VRC Contribution to History of DNA Vaccines Expression in situ (Wolff et al.) CTL, protection (Ulmer et al.) First patents issue Human antibodies (Roy et al.) First DNA vaccine product licensed for animal health Antibodies (Tang et al.) First clinical trials begin FDA Guidance #1 Human CTL (Wang et al.) Codon-modification improves immune responses FDA Guidance #2 First Vaccine Efficacy Trial Utilizing DNA Vaccine (HIV) Neutralizing antibody induced in humans (WNV) Adapted from Ulmer and Liu

17 Structure of Prefusion RSV F Glycoprotein Prefusion Postfusion

18 Stabilized RSV Pre-F Induces Potent Neutralizing Activity November 1, 2013 Pre-F induces fold higher NT activity than post-f

19 Prefusion Structure of HKU1 CoV Spike Spike trimer from top view shows domain swapping between protomers Knowing the atomic level structure of the CoV Spike trimer will guide stabilizing mutations for MERS and SARS vaccine antigens Geisel School of Medicine at Dartmouth Jason McLellan Nianshuang Wang The Scripps Research Institute Andrew Ward Robert Kirchdoerfer Christopher A. Cottrell Jesper Pallesen Hannah L. Turner 19

20 Presidential visits to the VRC have focused on Ebola Barack H. Obama George W. Bush

21 Targeting viral fusion proteins with NT antibodies 21

22 Conformational Fixation of HIV-1 Env Young Do Kwon, Peter Kwong et al NSMB

23 Identifying mabs with Reproducible Modes of Recognition VRC01 class

24 VRC01 Clinical Development June 2010 Jan 19, 2012 May 29, 2013 Aug 7, 2013 Sept 6, 2013 Oct 1, 2013 Nov 20, 2013 August 29, 2014 April 21, 2015 April 2016 Initiated development of VRC01 as clinical product VRC01 Pre-IND meeting IRB Submission: VRC 601 [HIV Infected Cohort] IND Submission VRC receives FDA safe to proceed notification IRB Submission: VRC 602 [Healthy Vol Cohort] IRB Approval: VRC 602 HVTN 104 IMPAACT P1112 (Phase I in infants) HVTN 703/ HPTN 081 Phase 2b Efficacy Trial August 2010 August 2012 July 2013 Aug 26, 2013 Sept 30, 2013 Nov 12, 2013 Dec 9, 2013 April 10, 2015 Publication: Zhou et. al. Science Aug Wu et. al. Science Aug cgmp manufacturing at VPP VRC VPP vials VRC01 IRB Approval: VRC 601 VRC 601 First IV Infusion (1 mg/kg IV) VRC 601 First SC Infusion (5 mg/kg SC) VRC 602 First Infusions (5mg/kg IV), (5mg/kg SC) Therapeutic ACTG 5340 and mg/ml Panel of Experts Bethesda July 2010 International Consultation Entebbe January 2013 Passive Immunization and Vaccine Design Bethesda August 2014

25 Passive Antibody Prevention Can a passively infused monoclonal antibody prevent HIV-1 infection in high risk adults AMP = Antibody Mediated Prevention Study VRC01 administered at 30 mg/kg, or 10 mg/kg, vs placebo Administered once every 8 weeks by IV infusion High risk men in North and South America High risk women in South and East Africa 4200 subjects Mike Cohen (HPTN) Larry Corey (HVTN) 5/4/2017

26 Lineage-based Vaccine Design Initial antigen (vaccine) Sequential Immunization 30 Broadly-reactive neutralizing antibody Mascola, Haynes Immun Rev (2013)

27 NIAID Vaccine Research Center Connected to the history of AIDS Vaccine Awareness Day Still focused on developing vaccines or mabs that prevent HIV infection Advancing vaccine concepts that are relevant to other viral diseases