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

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

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.

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

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

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

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

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

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.

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

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.

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

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.

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

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.

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

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

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

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.

Human Antibody Light Chain Heavy Chain

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

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

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

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

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

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.

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

Here Is What We Actually Saw HIV-1 Antibody Responses

Protective Activity of HIV-1 Antibody Responses

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

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

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

A Nuclear Arms Race

A Nuclear Arms Race

A Nuclear Arms Race

A Nuclear Arms Race

A Nuclear Arms Race

A Nuclear Arms Race

A Nuclear Arms Race

A Nuclear Arms Race

A Nuclear Arms Race

A Nuclear Arms Race

A Nuclear Arms Race

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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”

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

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

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

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.

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.

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.

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

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

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) 2005-2012 Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID) 2012-2019 -ID