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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. HIV Vaccine Enterprise: Progress in Basic Research. International AIDS Vaccine Meeting 2010 Atlanta, GA.

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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 HIV Vaccine Enterprise: Progress in Basic Research International AIDS Vaccine Meeting 2010 Atlanta, GA Gary J. Nabel M.D., Ph.D. Vaccine Research Center NIAID, NIH Sept. 28, 2010

  2. X X X Acquisition vs.Viral Load: Independent Parameters Vaccination to Control Viremia Vaccination to Prevent Acquisition

  3. Key Issues in AIDS Vaccine Development • Blocking infection vs. controlling viral load • Paradigm for HIV vaccine development differs from all licensed vaccine: basic science drives progress in rational vaccine design. • Basic science is done in clinical trials

  4. How Might a Vaccine Prevent Infection? Scenario 1: No Immune Protection Viral Load 1 2 3 4 5 Time (months

  5. How Might a Vaccine Prevent Infection? Scenario 2: Broadly Neutralizing Antibodies Viral Load 1 2 3 4 5 Time (months

  6. How Might a Vaccine Prevent Infection? Scenario 3: Highly Effective T Cell Vaccine Viral Load 1 2 3 4 5 Time (months CD8 CTL -

  7. How Might a Vaccine Prevent Infection? Scenario 4: Partially Effective nAb Response Viral Load 1 2 3 4 5 Time (months

  8. How Might a Vaccine Prevent Infection? Scenario 5: Partially Effective nAb and T Cells Viral Load CD8 CTL CD8 CTL 1 2 3 4 5 Time (months

  9. Basic Science and AIDS Vaccine Development • T cell vaccine vectors and concepts • Advances in B cell immunogen design • Modeling of HIV infection in the non-human primate

  10. Basic Science and AIDS Vaccine Development • T cell vaccine vectors and concepts • Advances in B cell immunogen design • Modeling of HIV infection in the non-human primate

  11. Next Generation T Cell Vaccines rLCMV Sim rAd rAd41 rAd35 rAd28 rAd26 rAd5 ch rAd simian Ads non Ads Human rAds New Vectors and Combinations • DNA prime + adenoviral vector boost • Heterologous rAd vector prime/boost • LCMV prime/boost • Chimp and simian Ads • Integrase-deficient lentiviral vectors rLVV

  12. Next Generation T Cell Vaccines rLCMV Sim rAd rAd41 rAd35 rAd28 rAd26 rAd5 ch rAd simian Ads non Ads Human rAds New Vectors and Combinations • DNA prime + adenoviral vector boost • Heterologous rAd vector prime/boost • LCMV prime/boost • Chimp and simian Ads • Integrase-deficient lentiviral vectors rLVV

  13. Next Generation Inserts: Expanding Breadth Informatically HIV/SIV Gag Chimeras and Chimeric Mosaics Mosaics (Env, Gag, Pol, Nef) B. Korber, B. Hahn, Norm Letvin, Bart Haynes

  14. Basic Science and AIDS Vaccine Development • T cell vaccine vectors and concepts • Advances in B cell immunogen design • Modeling of HIV infection in the non-human primate

  15. Neutralizing mAbs as of 2008 • Until last year (2009) - No new broadly NAb since 1996 • NAbs were unable to explain the potent neutralization found in some sera 2F5, 4E10 (1993, 1994) gp41 b12 (1994) gp120 trimer 2G12 (1996) CD4bs Co-receptor bs V3 447-D (1993)

  16. 2009 – 2010: New Potent mAbs against HIV-1 • PG9/16 – Quaternary neutralization epitope in regions of V2/V3 • VRC01, 02, 03 – target CD4bs • Neutralize more potently, and with far more breadth than prior mAbs (80% - 90%); often < 1 ug/ml • Additional new potent and broadly reactive NAbs at this meeting 2G12(glycan) PG9/16(V2/V3 region) PG9/16(V2/V3 region) VRC01 - 03 HJ16(CD4bs) 2F5, Z13, 4E10MPER Model of known neutralization epitopes based on atomic level structure of gp120 and the cryoelectron tomographic structure of trimeric Env Liu/Subramaniam Nature 2008Zhou/Kwong Nature 2007 Laura M Walker and Dennis R Burton Current Opinion in Immunology 2010

  17. A Proof of Concept for Vaccines?Broad and Potent Neutralizing Antibodies are Synthesized in Natural HIV-1 Infection Viruses ID50 > 150 > 500 Sera 15 - 25% sera display significant cross-clade breadth of neutralization-to what are they directed? • Doria-Rose, Wyatt, Korber, Mascola, Connors et al. J Virol 83:188-199 (2009) – VRC/NIAID: 110 clade B sera • Sather/Stamatatos J Virol 83:757-769 (2009) – SBRI/Vanderbilt: 64 clade B sera • Simek, Burton, Koff et al; J Virol 83: 7337-7448 (2009) – IAVI protocol G: >1700 clade A, B, C, D, E sera • Gray, Montefiori, Mascola, Morris et al. J. Virol. 83:8925-37 (2009): SAAVI/CHAVI/CAVD 70 clade C sera

  18. Strategy for Isolation of New Monoclonal Antibodies Based On HIV Protein Structure Designer Envelopes Stabilizing the inner/outer domains Inner Stabilizing inner domain and bridging sheet Outer Core Stabilized Core Resurfaced Stabilized Cores (RSC) Mascola et al. VRC Broadly Neutralizing Ab Isolation Nabel, Schief, Kwong, Mascola

  19. Resurfaced Stabilized Cores (RSC) as Epitope-Specific Probes for B-Cell Isolation Bill SchiefGary Nabel (ZY Yang)Peter Kwong (T Zhou gp120 core SA-PE SA-APC Biotin X resurfacedresidues glycans CD4 bindingsite DRSC3 RSC3 Kwong, Schief, Zhou, Nabel Wu et al. Science (2010) 329:856

  20. Strategy for Isolation of New mAbs Based on Epitope Specific Protein Probes epitope specific B cells + X RSC3 (positive) DRSC3 (negative)

  21. Three mAbs bind to the RSC protein RSC RSC/d371I VRC01 VRC02 VRC03 • Two closely related somatic variants (VRC01, VRC02) • bind to CD4bs region of gp120 • Neutralize ~90% viruses, often < 1ug/ml • 1 additional mAb (VRC03) • CD4bs directed • Neutralizes ~ 60% viruses Wu et al. Science (2010) 329:856

  22. Panel of 190 Diverse Viral Isolates Mike Seaman b12 VRC01 gp160 protein distance Neighbor-Joining tree IC50 < 1 μg/ml B D IC50 1-50 μg/ml 0.01 IC50 > 50 μg/ml CRF07_BC HXB2 HXB2 C G CRF02_AG CRF01_AE A

  23. Crystal Structure of VRC01:gp120 gp120 outer domain Inner domain CD4 binding loop Loop V5 CDR H2 Loop D CDR H1 CDR H3 CDR L1 CDR L3 Heavy chain Light chain Zhou/Kwong Science (2010) 329;811

  24. Mimicry of CD4 Receptor by Antibody VRC01 gp120 gp120 VRC01 heavy chain V-domain CD4 CD4 and VRC01 in highly similar positions

  25. 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

  26. Structural Models of Alternative Forms of HIV-1 Envelope

  27. Induction of CD4 BS Antibodies by Trimeric Immunogens in Rabbit

  28. 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

  29. Scope of Clinical Applications of Anti-HIV Neutralizing Antibodies • Scope • Prevention • Therapy • Eradication of reservoir

  30. Anti-HIV Neutralizing Antibodies • Scope • Prevention • Topical microbicides • Regulated gene expression (e.g. AAV, lentiviral vectors) • Passive infusion (systemic) • Therapy • Eradication of reservoir

  31. Anti-HIV Neutralizing Antibodies • Scope • Prevention • Therapy • Passive infusion - antiviral • Combination of antibodies • Combination of drugs/antibodies • Eradication of reservoir

  32. Anti-HIV Neutralizing Antibodies • Scope • Prevention • Therapy • Eradication of reservoir • - Fc mediated: Virolysis, ADCC • - Targeting viral reservoirs • Ab-toxin chimeras

  33. Basic Science and AIDS Vaccine Development • T cell vaccine vectors and concepts • Advances in B cell immunogen design • Modeling of HIV infection in the non-human primate

  34. Vaccine-Mediated Protection AgainstSIVsmE660 Infection Acquisition of Established Infection Peak Viral Load Control p = 0.31 Vaccine Plasma log10 RNA copies/mL Control Vaccine Letvin, Mascola et al., VRC NHP Studies

  35. The Three Pillars of a Highly Effective AIDS Vaccine Clinical Efficacy Trials Non-human Primate Models Neutralizing Antibodies and T cell immunogens

  36. mAb Isolation Acknowledgments VRC and NIAID Collaborators Bill Schief • Xueling Wu • Yuxing Li • Rich Wyatt • Mark Connors • Nicole Doria-Rose • Krisha McKee • Mark Louder • Sijy O’Dell • Steve Schmidt • Diane Wycuff • Mario Roederer • Carl Hogerkorp • Tongqing Zhou • Zhi-Yong Yang • Peter Kwong • John Mascola

  37. The Neutralizing Antibody Vaccine Concept A broad and potent neutralizing antibody response will prevent HIV infection or control HIV disease through inactivation of virus and/or by mobilization of antibody-dependent or innate immune responses to virus infected cells . Cell-free virus Neutralizing antibodies HIV-infected cells • External Viral Protein • Envelope Env CD4 ADCC, Complement Provirus

  38. Structure Based Vaccine Design Recessed receptor binding sites: CD4 and CCR5 Decoy effects from monomer and V regions: induction of non-neutralizing antibodies

  39. Unbound CD4-bound conformation The coreceptor binding domain is only formed after CD4 engagement. Major Conformational Alterations of HIV Env Upon Engaging the CD4 Receptor Chen et al. & Harrison, Nature 2005

  40. Structure Assisted Vaccine Design: Constraint of Conformational Flexibility Mutagenic stabilization of the CD4-bound conformation of gp120: have engineered four domain-stabilizing disulfides and three cavity-filling mutants. (Zhou, et al. & Wyatt, Nabel & Kwong)

  41. Overall Structure of b12:gp120 Complex b12 binds to gp120 conformational invariant surface. Tongqing Zhou et al. Nature 445,732-737 (2007)

  42. A Site of Vulnerability on HIV-1

  43. b12-Epitope Structure-Base Design • Trimers • Monomeric gp120 (core) and cloaks • Outer domain of gp120 • Scaffolding gp120 core “cloaked core” Outer Domain CD4-binding loop Complex epitope

  44. b12-Epitope Structure-Base Design • Trimers • Monomeric gp120 (core) and cloaks • Outer domain of gp120 • Scaffolding

  45. Modeled HIV-1 Env Trimer and Glycan Shield 90° rotation Kwong et al. J Virol 2000.

  46. b12-Epitope Structure-Base Design • Trimers • Monomeric gp120 (core) and cloaks • Outer domain of gp120 • Scaffolding gp120 core “cloaked core”

  47. “Cloaking” of Irrelevant HIV gp120 Surface Determinants with SIV Inner domain Outer domain Cloak siv_8b_11_2a 180o CD4 binding loop Bridging Sheet Core (8B) Wild type HXB2 Cloak 2NXY-11b-comp-6e_0007

  48. Designs: View from CD4 Binding Face siv_8b_sg_11b 2nxy-11b- comp-6e_0007 siv_8b_11_2a 2nxy_11b_1 2nxy-11b- redes-8_0105 2nxy- polar1pt5_0177 2nxy-11b- redes-8_0105 2nxy-11b- comp-2g_0017

  49. Designs: View from Backside 2nxy-11b- comp-6e_0007 siv_8b_11_2a siv_8b_sg_11b 2nxy_11b_1 2nxy-IIc- 25_0188 2nxy- polar1pt5_0177 2nxy-11b- comp-2g_0017 2nxy-11b- redes-8_0105

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