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Dale and Betty Bumpers Vaccine Research Center

Dale and Betty Bumpers Vaccine Research Center National Institute of Allergy and Infectious Diseases National Institutes of Health Department of Health and Human Services. The Changing Face of HIV Vaccine Research. International AIDS Society Meeting 2011 Rome, Italy.

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Dale and Betty Bumpers Vaccine Research Center

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  1. Dale and Betty Bumpers Vaccine Research Center National Institute of Allergy and Infectious Diseases National Institutes of Health Department of Health and Human Services The Changing Face of HIV Vaccine Research International AIDS Society Meeting 2011 Rome, Italy Gary J. Nabel M.D., Ph.D. Vaccine Research Center NIAID, NIH July 18, 2011

  2. The Status of AIDS Vaccines-IAS 2011 • Lessons from clinical trials. • Understanding why has it been so difficult to make an effective AIDS vaccine. • New and promising scientific developments moving to the clinic.

  3. The Status of AIDS Vaccines-IAS 2011 • Lessons from clinical trials. • Understanding why has it been so difficult to make an effective AIDS vaccine. • New and promising scientific developments moving to the clinic.

  4. Timeline of HIV Vaccine Efficacy TrialsFrom 1990 to 2010 1990 1995 2000 2005 2010 VaxGen USA 1 year VaxGen Thai Trial 1 year Step Trial 6 months Thai Trial 16 months HVTN 505 Enrollment inprocess Trial start/end Trial analysis/results First correlates

  5. Timeline of HIV Vaccine Efficacy TrialsFrom 1990 to 2010 1990 1995 2000 2005 2010 Recombinant gp120 No Efficacy VaxGen USA 1 year VaxGen Thai Trial 1 year Step Trial 6 months Thai Trial 16 months HVTN 505 Enrollment inprocess Trial start/end Trial analysis/results First correlates

  6. Timeline of HIV Vaccine Efficacy TrialsFrom 1990 to 2010 1990 1995 2000 2005 2010 VaxGen USA 1 year VaxGen Thai Trial 1 year Ad5 Gag PolNef T cell vaccine No Efficacy Step Trial 6 months Thai Trial 16 months HVTN 505 Enrollment inprocess Trial start/end Trial analysis/results First correlates

  7. RV-144: Evidence that an AIDS Vaccine Can Prevent HIV-1 Infection in Humans Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand. SupachaiRerks-Ngarm, M.D., PunneePitisuttithum, M.D., D.T.M.H., . . . PrayuraKunasol, M.D., and Jerome H. Kim, M.D., for the MOPH–TAVEG Investigators. N Engl J Med., 2009 Dec 3;361(23):2209-20. • - Modest 31% reduction in infection • limited duration • Proof of concept for a • protective vaccine

  8. HVTN 505: A Phase 2 Clinical Efficacy Trial Proof of concept study of a multiclade HIV-1 DNA plasmid/recombinant adenoviral prime-boost vaccine in HIV-uninfected, adenovirus type 5 seronegative, circumcised men who have sex with men. Estimate complete enrollment in 2012. Scott Hammer MD, Principal Investigator; Larry Corey MD, HVTN Principal Investigator

  9. The Status of AIDS Vaccines-IAS 2011 • Lessons from clinical trials. • Understanding why has it been so difficult to make an effective AIDS vaccine. • New and promising scientific developments moving to the clinic.

  10. Why Has an HIV-1 Vaccine Been So Difficult? A B C D

  11. Problem 1: It is a Moving and Evasive Target A B C D Infinite number of viruses ? Role of Abs in immunity Evolving neutralization profiles

  12. The Structure of HIV-1 Env and Definition of CD4 Binding Site Initial site of CD4 attachment CD4-binding site Inner domain Outer domain Bridging sheet

  13. Why Has an HIV-1 Vaccine Been So Difficult? Kwong et al. J Virol 2000.

  14. Problem 2: Glycans Mask Env and Creates an Even More Moving and Evasive Target Kwong et al. J Virol 2000.

  15. The Status of AIDS Vaccines-IAS 2011 • Lessons from clinical trials. • Understanding why has it been so difficult to make an effective AIDS vaccine. • New and promising scientific developments moving to the clinic.

  16. Resurfaced Stabilized Cores: Probes for Human Abs and Templates for Immunogens Resurfaced Stabilized Cores Cores Alter surface residues to eliminate reactivity with non-neutralizing antibodies CD4 binding site • Probe to isolate B cells and clone broadly neutralizing abs • Prototype immunogens to elicit antibodies to the highly • conserved CD4 binding site Nabel, Schief, Kwong, Mascola

  17. Pan-Reactive Antibody VRC01 Neutralizes ~90% of Natural Circulating Viruses Wu et al. (2010)Science 329, 856.

  18. Why does VRC01 Work So Well? • Partial mimicry of CD4 binding to gp120 • Binding focused on the conformationally invariant site of initial CD4 attachment. gp120 outer domain gp120inner domain bridging sheet

  19. 2009 – 2010: New Potent mAbs against HIV-1 • PG9/16 – Quaternary neutralization epitope in regions of V2/V3 • VRC01, 02, 03, HJ16 – target CD4bs • Additional 9 new potent and broadly reactive Nabs, PGT, directed to glycans on the outer domain by IAVI/Scripps investigators. 2G12(glycan) PG9/16(V2/V3 region) PG9/16(V2/V3 region) VRC01 - 03 HJ16(CD4bs) 2F5, Z13, 4E10MPER These human antibodies neutralize more potently, and with far more breadth, than prior mAbs (80% - 90%; often < 1 ug/ml).

  20. The Dark Ages of HIV-1 Broadly nAbs-pre-2010

  21. VRC01-A New Window on HIV-1 Broadly nAb’s VRC01

  22. Independent Solutions Adopted by Abs to Recognize the CD4 BS Structure • Independent VRC01-like antibodies have been isolated from multiple individuals. • Deep sequencing of DNA from B cells of infected subjects indicates that hundreds or more similar antibodies are made in them. Similar germlines VRC01 VRC02 VRC03 VRCPG04 …… VRCxx Divergence in sequences Convergence on recognition Shared epitope

  23. VRC01-A New Window on HIV-1 Broadly nAb’s VRC01

  24. Deep Sequencing of Human VRC01 Antibodies: A New Vista on Immunoglobulin Diversification

  25. How Do Broadly Neutralizing Antibodies DevelopNormally and How Do We Elicit Them for a Vaccine? Donor 1 Donor 2 Donor 3 There is a common evolutionary tree for VRC01-like antibodies from different people.

  26. How Do Broadly Neutralizing Antibodies Develop Normally • and How Do We Elicit Them for a Vaccine? gp120 VRC01 germ line Mature VRC01 • The B cell precursor of VRC01 does not recognize Env

  27. Maturation of Progressive VRC01 Intermediates Unmutated ancestor Donor 45/74/219 intermediate Donor 45/74 intermediate Mature VRC01 VH gene mutations 0 23 53 93

  28. Guiding the Pathway of Antibody Elicitation VRC01 Intermediate 2 Intermediate 1 Unmutated Ancestor

  29. Design of Immunogens to Elicit Broadly Neutralizing Abs to the CD4 Binding Site • Trimers • Monomers • Outer Domains Structure-based design:

  30. Engraftment of a HIV Env Fragment onto a VLP

  31. Engraftment of a HIV Env Fragment onto a VLP

  32. Progress in HIV-1 Prevention Researchin the Last Decade Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men. Robert M. Grant, M.D., M.P.H., Javier R. Lama, M.D., M.P.H., . . . Ana I. Martinez, R.Ph., David N. Burns, M.D., M.P.H., and David V. Glidden, Ph.D., for the iPrEx Study Team. N Engl J Med., 2010 Dec 30;363(27):2587-99. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Ronald H Gray, Godfrey Kigozi, David Serwadda, Frederick Makumbi, Stephen Watya, Fred Nalugoda, Noah Kiwanuka, Lawrence H Moulton, Mohammad A Chaudhary, Michael Z Chen, Nelson K Sewankambo, Fred Wabwire-Mangen, Melanie C Bacon, Carolyn F M Williams, Pius Opendi, Steven J Reynolds, Oliver Laeyendecker, Thomas C Quinn, Maria J Wawer. Lancet, 2007;369:657–66. Randomized, Controlled Intervention Trial of Male Circumcision for Reduction of HIV Infection Risk: The ANRS 1265 Trial. BertranAuvert, Dirk Taljaard, Emmanuel Lagarde, Joelle Sobngwi-Tambekou, RemiSitta, Adrian Puren. PLoS Medicine, 2005 Nov;2(11):e298. This article is being published today, July 18, 2011, at NEJM.org. Presentation: Mike Cohen 4:30 PM today Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women. QuarraishaAbdoolKarim, Salim S. AbdoolKarim, Janet A. Frohlich, Anneke C. Grobler, Cheryl Baxter, Leila E. Mansoor, Ayesha B. M. Kharsany, SengeziweSibeko, Koleka P. Mlisana, Zaheen Omar, Tanuja N. Gengiah, Silvia Maarschalk, Natasha Arulappan, MukelisiweMlotshwa, Lynn Morris, Douglas Taylor, on behalf of the CAPRISA 004 Trial Group November 2000. Science, 2010 Sep 3;329(5996):1168-74. Prevention of HIV-1 Infection with Early Antiretroviral Therapy Myron S. Cohen, Y. Q. Chen, M. McCauley,T. Gamble, M. C. Hosseinipour,N. Kumarasamy, J. G. Hakim,J. Kumwenda, Beatriz Grinsztejn, Jose H.S. Pilotto,S. V. Godbole, S. Mehendale, S. Chariyalertsak,B.R. Santos, K. H. Mayer, I. F. Hoffman,S. H. Eshleman, E. Piwowar-Manning, L. Wang,J. Makhema, L. A. Mills, G. de Bruyn,I. Sanne, J. Eron, J. Gallant,D. Havlir, S. Swindells, H. Ribaudo,V. Elharrar, D. Burns, T. E. Taha,K. Nielsen-Saines, D. Celentano, M. Essex and T. R. Fleming, for the HPTN 052 Study Team. N Engl J Med., 10.1056/NEJMoa1105243 • (10.1056/NEJMoa1105243)

  33. With So Much Success with Prevention, Do We Still Need an AIDS Vaccine? June 4, 2011

  34. Contributions of a Vaccine to the HIV Prevention Portfolio • Vaccine is given once; protection lasts a lifetime. • Durable protection is conferred to the person at risk. • An effective vaccine is among the most cost-effective medical interventions.

  35. New Paths Forward to AIDS Prevention Based on Broadly Neutralizing Antibodies and Structure VRC01-gp120 structure NeutralizingAntibody Immunogen Design Passive Transfer Vaccine

  36. Summary • An understanding of HIV-1 entry has provided an opportunity for AIDS vaccine development through the definition of highly conserved invariant viral structures that are the target of broadly neutralizing antibodies. • Definition of the specificities and targets of broadly neutralizing antisera and monoclonal antibodies have facilitate the identification of “structural” serotypes and catalyzed new approaches to vaccine design. • It is now possible to elicit CD4 BS and other neutralizing abs through structure-based vaccine design. • Significant hurdles remain but the opportunities have never been more promising, and the need for a highly effective AIDS vaccine remains urgent.

  37. Acknowledgements VRC/NIH X Wu L Chen I Georgiev C Huang C-M Hogerkorp Y Kwon Y Li N Longo M Louder J Mascola K McKee S O’Dell M Roederer Scripps/IAVI D Burton W. Koff A Hessel M Zwick U Washington D Baker W Schief Beth Israel M Seaman DIR/NIAID/NIH M Connors Doria-Rose D. Van Ryk Duke/CHAVI Bart Haynes S Schmidt L Shapiro L Wu R Wyatt D Wycuff L Xu Y-P Yang Z–Y Yang P Kwong T Zhou J Zhu

  38. VRC Principal Investigators Barney Graham Daniel Douek Richard Koup Richard Schwartz Mario Roederer JohnMascola Nancy Sullivan Srinivas Rao Gary Nabel Peter Kwong Robert Seder

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