Presentation is loading. Please wait.

Presentation is loading. Please wait.

Washington D.C., USA, 22-27 July 2012www.aids2012.org The Path Forward for HIV-1 Vaccine Development Barton F. Haynes, MD Duke Human Vaccine Institute.

Similar presentations


Presentation on theme: "Washington D.C., USA, 22-27 July 2012www.aids2012.org The Path Forward for HIV-1 Vaccine Development Barton F. Haynes, MD Duke Human Vaccine Institute."— Presentation transcript:

1 Washington D.C., USA, July 2012www.aids2012.org The Path Forward for HIV-1 Vaccine Development Barton F. Haynes, MD Duke Human Vaccine Institute Duke University School of Medicine Duke Center For HIV/AIDS Vaccine Immunology-Immunogen Discovery -ID

2 Why Try To Develop An HIV Vaccine? Prevention of HIV: a major priority Treatment as prevention Microbicides Pre-exposure prophylaxis Voluntary male circumcision Preventing mother to child transmission Preventive HIV vaccine-most powerful preventive tool: cornerstone of an integrated prevention program

3 How Do Vaccines Work? Traditional viral vaccines allow infection to occur but prevent symptoms and therefore prevent disease In contrast, HIV vaccine must totally prevent infection. Once infection occurs the immune system has difficulty controlling the virus. A major mode of preventing infection is neutralizing antibodies.

4 Roadblocks for HIV-1 Vaccine Development Need to understand what types of antibodies can prevent transmission Inability to induce broad neutralizing antibodies

5 New Clues for HIV Vaccine Development Immune correlates of infection risk found in the RV144 Thai vaccine trial New broad neutralizing antibodies and the role of the host in limiting broad neutralizing antibody induction

6 New Clues for HIV Vaccine Development Immune correlates of infection risk found in the RV144 Thai vaccine trial New broad neutralizing antibodies and the role of the host in limiting broad neutralizing antibody induction

7 RV144 ALVAC Prime, AIDSVAX B/E Trial 31.2% Estimated Vaccine Efficacy Years Probability of HIV Infection (%) Placebo Vaccine C. Modified Intention-to-Treat Analysis* Objective: To carry out a correlates analysis to begin to identify how the vaccine might work

8 Immune Correlates Case Control Study Measured immune responses from: 41 Infected Vaccinees 205 Uninfected Vaccinees 40 Placebo Recipients Question: What are the immunologic measurements in vaccinees that predict HIV- 1 infection over 3 year follow-up? NEJM 366: 1275, 2012

9 Immune Correlates of Risk of Infection Correlate of Risk of Infection- an immune response that predicts whether vaccinees become HIV-1 infected. It may be causally related to protection from infection, or may be only a surrogate marker for another factor. Therefore, this type of analysis only raises hypotheses regarding what immune responses might be protective.

10 C C C N C' N Hypothesis: IgG Antibodies to V1/V2 Can Protect Against HIV-1 Infection IgG Envelope on HIV-1 Infected Cell IgG V1/V2 IgG Antibody V1/V2 NEJM 366: 1275, 2012

11 Process For Evaluation of RV144 V1/V2 Correlate of Risk of Infection Isolate of V1/V2 monoclonal antibodies from RV144 vaccinees. Test antibodies for ability to protect rhesus macaques from SHIV retrovirus infection. Test for V1/V2 antibodies as correlates of infection risk in new efficacy clinical trials.

12 C C C N C' N Hypothesis: Monomeric IgA Can Block IgG Binding to HIV-1 Env on Infected Cells and Prevent IgG Protective Functions IgA IgG Envelope on HIV-1 Infected Cell IgA IgG IgG protective Ab IgA Blocking Ab NEJM 366: 1275, 2012

13 Process For Evaluation of RV144 IgA Correlate of Increased Risk of Infection Isolate of IgA envelope monoclonal antibodies from RV144 vaccinees. Test antibodies for ability to mitigate the protective effect of other antibodies in rhesus macaques challenged with SHIV retroviruses. Test for IgA envelope antibodies as correlates of infection risk in new efficacy clinical trials.

14 New Clues for HIV Vaccine Development Immune correlates of infection risk found in the RV144 Thai vaccine trial New broad neutralizing antibodies and the role of the host in limiting broad neutralizing antibody induction

15 Why Broad Neutralizing Antibodies? RV144 trial did not induce broad neutralizing antibodies (JID 206: 431, 2012). Hypothesis is that protection is via a “non-neutralizing” mechanism such as antibody killing of virus-infected cells. Broad neutralizing antibodies potently protect rhesus macaques from challenge with chimeric simian- human immunodeficiency viruses (SHIVs). (J. Virol: 84: 1302, 2009; PLoS Path. 5: e , 2009) To date no vaccine induces broad neutralizing antibodies.

16 New Broad Neutralizing Antibodies CD4 binding site- VRC01, CH31, PG04 V1/V2- PG9, PG16, CH01-04 Glycan- PGT125, PGT128 gp41 MPER-10E8 Greater breadth of neutralization, more potent

17 2F5, 4E10, 10E8 Membrane proximal region 2G12, PGT Abs Carbohydrate CD4 binding site 1b12, VRC01, VRC02, VRC03, VRC-PG04, HJ16, CH30-CH34 V1/V2 PG9, PG16, CH01-CH04 BnAb Antibodies: Dennis Burton, Herman Katinger, Michel Nussenzweig, John Mascola, Bart Haynes, Robin Weiss Adapted from William Schief

18 Antibody Fab Binding to HIV Envelope Achilles’ Heels 4E10 2F5 PGT128 PG9 VRC01 Burton et al Science 337: 183, 2012

19 Definitions Tolerance mechanisms- immune mechanisms to remove or inactivate self-reactive antibodies Somatic mutations- process in germinal centers of acquisition of antibody mutations that lead to potent antibodies Antibody self-reactivity- trait of antibodies to bind multiple molecules including self (our own) molecules. Self-reactivity also called auto- reactivity.

20 Human Antibody Light Chain Heavy Chain

21 Characteristics of Broad Neutralizing Antibodies Long regions where antibodies bind HIV (antibody combining regions) Antibodies with long antibody combining regions are fequently eliminated by tolerance mechanisms

22 Characteristics of Broad Neutralizing Antibodies Excess accumulation of somatic mutations (10-30%) Antibodies with excess somatic mutations are unusual because they are usually eliminated by tolerance deletion

23 Characteristics of Broad Neutralizing Antibodies Self-reactive with host molecules in addition to reacting with HIV-1 envelope Antibodies with self-reactivity are usually frequently eliminated by tolerance deletion

24 Summary: Unusual Traits of Broad Neutralizing Antibodies Long antibody combining sites -Controlled by deletional tolerance mechanisms Extremely Somatically Mutated- either a rare event, or escape from tolerance controls Self-reactive- Controlled by tolerance mechanisms

25 Antibody Fab Binding to HIV Envelope Achilles’ Heels 4E10 2F5 PGT128 PG9 VRC01 Burton et al Science 337: 183, 2012

26 Immunoglobulin Humanized Mice: Recombinant Mice That Only Make One Antibody: A Human Broad Neutralizing Antibody Express a human broad neutralizing antibody and see if tolerance mechanisms delete or modify the antibody in mouse B cells. Gold standard for determining how mammalian immune system handles a particular antibody to determine if the broad neutralizing unusual traits are sufficiently strong to induce tolerance mechanisms. Immunization models.

27 HIV-1 Antibody Responses If No Immune Tolerance Interference With Development of Broad Neutralizing Antibodies, Here Is What We Would See

28 HIV-1 Antibody Responses Here Is What We Actually Saw

29 Protective Activity of HIV-1 Antibody Responses

30 Effect of Interference of HIV-1 Broad Neutralizing Antibody Responses By Tolerance Controls Our Own Normal Tissue Molecules

31 Broad Neutralizing Antibodies Unusual (15-20% of patients; vaccinees = 0%) Unusual traits– many controlled by tolerance Mouse model expressing only broad neutralizing antibody – most deleted, few survive Goal is to awaken remaining B cells in mice and humans

32 What Can We Learn From Patients in Whom Broad Neutralizing Antibodies Do Develop?

33

34

35 A Nuclear Arms Race

36

37

38

39

40

41

42

43

44

45

46 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus

47 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb”

48 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb” Escape virus

49 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb” Escape virus

50 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb” Escape virus

51 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb” Escape virus

52 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb” Escape virus

53 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb” Escape virus

54 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb” Escape virus

55 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb” Escape virus

56 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb” Escape virus

57 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb” Escape virus

58 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb” Escape virus

59 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb” Escape virus

60 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb” Escape virus

61 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb” Escape virus

62 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb” Escape virus

63 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb” Escape virus

64 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb” Escape virus

65 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb” Escape virus

66 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb” Escape virus

67 The HIV-1 Arms Race HIV-1Antibody The transmitted- Founder virus The initial neutralizing antibody response to HIV “autologous nAb” Escape virus 85%- Non- or poor- Neutralizing antibody

68 The HIV-1 Arms Race The initial neutralizing antibody response to HIV “autologous nAb” 15%- Broadly neutralizing antibody The transmitted- Founder virus Escape virus HIV-1Antibody

69 The HIV-1 Arms Race: Isolation of Broad Neutralizing Antibodies From Chronically Infected Patients The initial neutralizing antibody response to HIV “autologous nAb” 15%- Broadly neutralizing antibody HIV-1Antibody ?

70 Steps of A B Cell Lineage-Based Approach to Vaccine Design Haynes, B, Harrison, S, Kelsoe, G and Kepler T, Nature Biotech., 2012 KEY POINTS: 1.The antibody a B cell makes also serves as its surface receptor recognizing vaccines. 2.Those vaccines that bind the strongest to antibody are the best vaccines.

71 Goals of B Lineage Design Drive broad neutralizing lineages Drive shorter lineages with fewer mutations Drive lineages with either no self-reactivity or “acceptable self-reactivity” Give lineages that are normally “subdominant” the ability to compete and become “dominant”

72 The HIV-1 Arms Race: Isolation of Broad Neutralizing Antibodies From Chronically Infected Patients The initial neutralizing antibody response to HIV “autologous nAb” 15%- Broadly neutralizing antibody HIV-1Antibody ?

73 The HIV-1 Arms Race--Mapping the Virus and Antibody From the Time of Transmission The initial neutralizing antibody response to HIV “autologous nAb” 15%- Broadly neutralizing antibody The transmitted- Founder virus Escape virus HIV-1Antibody -ID

74 Conclusions The HIV vaccine field is invigorated, is working hard, is collaborating, and is treating this problem as a global emergency. RV144 immune correlates analysis has provided clues/hypotheses to test for finding immune correlates of protection

75 Conclusions New broad neutralizing antibodies and new insights into why broad neutralizing antibodies are not made have provided hope that strategies can be developed for their elicitation.

76 Conclusions The biology of HIV-1, the escape mechanisms of the virus from bnAb induction, and the unusual traits of bnAbs when they are induced are necessitating new strategies of vaccine design.

77 Conclusions New strategies for driving broad neutralizing lineages to be dominant - B cell lineage immunogen design - mapping the virus and antibody during the “Virus-Ab Arms Race” Recreate this scenerio with a vaccine + strong adjuvant.

78 Duke CHAVI-ID Scientific Leadership Group and Team Leaders Scientific Leadership Group Bart Haynes, PI Joseph Sodroski Bette Korber Andrew McMichael George Shaw Garnett Kelsoe Stuart Shapiro, NIAID Kelly Soderberg Cherie Lahti Thomas Denny Team Leaders Thomas Kepler Alan Perelson Beatrice Hahn David Goldstein David Montefiori Andrew Fire Stephen Harrison Robin Shattock Sampa Santra -ID Second CHAVI-ID at Scripps Dennis Burton, PI

79 Collaborators Duke Hua-Xin (Larry) Liao Georgia Tomaras Nathan Vandergrift John Whitesides Garnett Kelsoe Munir Alam Mattia Bonsignori Tony Moody Thomas Denny Ruijun Zhang David Montefiori and Team Boston University Thomas Kepler and Team NIH-Vaccine Research Center Gary Nabel Peter Kwong John Mascola Rebecca Lynch Tonquin Zhou Jason McLellan Our Patients Harvard Andreas Finzi Joseph Sodroski Steve Harrison Norm Letvin and Team MHRP Nelson Michael Jerome Kim and Team Thai Ministry of Health and Mahidol University -ID

80 Acknowledgements Supported by: Collaboration for AIDS Vaccine Discovery Grant From the Bill and Melinda Gates Foundation National Institute of Allergy and Infectious Diseases (NIAID) Division of AIDS (DAIDS) U.S. Department of Health and Human Services (HHS) Center for HIV/AIDS Vaccine Immunology (CHAVI) Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID) ID


Download ppt "Washington D.C., USA, 22-27 July 2012www.aids2012.org The Path Forward for HIV-1 Vaccine Development Barton F. Haynes, MD Duke Human Vaccine Institute."

Similar presentations


Ads by Google