The Path Forward for HIV-1 Vaccine Development

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 Trial31.2% Estimated Vaccine Efficacy C. Modified Intention-to-Treat Analysis* 1.0 0.9 0.8 Placebo 0.7 0.6 Vaccine Probability of HIV Infection (%) 0.5 0.4 0.3 0.2 0.1 0.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years 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' N N C C C Hypothesis: IgG Antibodies to V1/V2 Can Protect Against HIV-1 Infection IgG IgG IgG V1/V2 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. C' C' N N C C C Hypothesis: Monomeric IgA Can Block IgG Binding to HIV-1 Env on Infected Cells and Prevent IgGProtective Functions IgGprotective Ab IgG IgG IgG IgA 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: e1000433, 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. 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. If No Immune Tolerance Interference With Development of Broad Neutralizing Antibodies, Here Is What We Would See HIV-1 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 ResponsesBy 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?

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

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

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

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

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