1. 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
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
0.9
0.8
0.7
0.6
0.4
0.3
0.2
0.1
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. Hypothesis: IgG Antibodies to V1/V2
Can Protect Against HIV-1 Infection
IgG C N C'
IgG
V1/V2
IgG
V1/V2
V1/V2
V1/V2 IgG Antibody
Envelope on HIV-1 Infected Cell
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. Hypothesis: Monomeric IgA Can Block IgG
Binding to HIV-1 Env on Infected Cells
and Prevent IgG Protective Functions
IgG protective Ab
IgG
IgG
IgG
IgA C N C'
IgA
IgA
IgA Blocking Ab
Envelope on HIV-1 Infected Cell
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. Adapted from William Schief
V1/V2
PG9, PG16, CH01-CH04
2G12, PGT Abs
Carbohydrate
CD4 binding site
1b12, VRC01, VRC02,
VRC03, VRC-PG04,
HJ16, CH30-CH34
2F5, 4E10, 10E8
Membrane proximal region
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
PG9
PGT128
VRC01
4E10
2F5
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
PG9
PGT128
VRC01
4E10
2F5
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
HIV Antibody Responses

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

29. Protective Activity of HIV-1 Antibody Responses

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

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?

35. A Nuclear Arms Race

36. A Nuclear Arms Race

37. A Nuclear Arms Race

38. A Nuclear Arms Race

39. A Nuclear Arms Race

40. A Nuclear Arms Race

41. A Nuclear Arms Race

42. A Nuclear Arms Race

43. A Nuclear Arms Race

44. A Nuclear Arms Race

45. A Nuclear Arms Race

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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
Antibody
The initial neutralizing antibody response to HIV
“autologous nAb” ?
15%- Broadly neutralizing antibody

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”
The transmitted-
Founder virus
Escape virus
15%- Broadly neutralizing antibody
-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
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
Second CHAVI-ID at Scripps
Dennis Burton, PI
-ID 78

79. Collaborators -ID Duke Harvard Boston University 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 79

80. Acknowledgements -ID 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