the path forward for hiv-1 vaccine development

Washington D.C., USA, 22-27 July 2012www.aids2012.org

The Path Forward for HIV-1 Vaccine Development

Barton F. Haynes, MDDuke Human Vaccine Institute

Duke University School of MedicineDuke 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

RV144 ALVAC Prime, AIDSVAX B/E Trial31.2% Estimated Vaccine Efficacy

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Years

Prob

abili

ty o

f HIV

Infe

ctio

n (%

)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.

C CC

NC' C'

N

Hypothesis: IgG Antibodies to V1/V2Can Protect Against HIV-1 Infection

IgG IgG

Envelope on HIV-1 Infected Cell

IgG

V1/V2 IgG AntibodyV1/V2

V1/V2

V1/V2

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.

C CC

NC' C'

N

Hypothesis: Monomeric IgA Can Block IgG Binding to HIV-1 Env on Infected Cells and Prevent IgG Protective Functions

IgA IgA

IgG IgG

Envelope on HIV-1 Infected Cell

IgA

IgG IgG protective Ab

IgA Blocking Ab

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-10E8Greater breadth of neutralization, more potent

2F5, 4E10, 10E8Membrane proximal region

2G12, PGT AbsCarbohydrateCD4 binding site

1b12, VRC01, VRC02, VRC03, VRC-PG04, HJ16, CH30-CH34

V1/V2PG9, PG16, CH01-CH04

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

4E102F5

PGT128

PG9

VRC01

Burton et alScience 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


Excess accumulation of

somatic mutations(10-30%)

Antibodies with excess somatic mutations are unusual because they are usually eliminated by tolerance deletion


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

4E102F5

PGT128

PG9

VRC01

Burton et alScience 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

Protective Activity of HIV-1

Antibody

Responses

Effect of Interference of

HIV-1 Broad

Neutralizing Antibody

Responses By Tolerance Controls

Our Own Normal Tissue Molecules

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

The HIV-1 Arms RaceHIV-1 Antibody

The transmitted-Founder virus



The initial neutralizing antibody response to HIV

“autologous nAb”





Escape virus





Escape virus

85%- Non- or poor-Neutralizing

antibody

The HIV-1 Arms Race



15%- Broadly neutralizing

antibody


Escape virus

HIV-1 Antibody

The HIV-1 Arms Race: Isolation of Broad Neutralizing Antibodies From Chronically Infected Patients




antibody

HIV-1 Antibody

?

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.

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

HIV-1 Antibody

?

The HIV-1 Arms Race--Mapping the Virus and Antibody From the Time of Transmission




antibody


Escape virus

HIV-1 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

Scientific Leadership Group

Bart Haynes, PIJoseph SodroskiBette KorberAndrew McMichaelGeorge ShawGarnett Kelsoe

Stuart Shapiro, NIAIDKelly SoderbergCherie LahtiThomas Denny

Team LeadersThomas Kepler Alan PerelsonBeatrice HahnDavid GoldsteinDavid MontefioriAndrew FireStephen HarrisonRobin ShattockSampa Santra

-ID

Second CHAVI-ID at ScrippsDennis Burton, PI

CollaboratorsDukeHua-Xin (Larry) LiaoGeorgia TomarasNathan VandergriftJohn WhitesidesGarnett KelsoeMunir AlamMattia BonsignoriTony MoodyThomas DennyRuijun ZhangDavid Montefiori and

Team

Boston UniversityThomas Kepler and

Team

NIH-Vaccine Research Center

Gary NabelPeter KwongJohn MascolaRebecca LynchTonquin ZhouJason McLellan

Our Patients

HarvardAndreas FinziJoseph SodroskiSteve HarrisonNorm Letvin and Team

MHRPNelson MichaelJerome Kim and TeamThai Ministry of Health and Mahidol University

-ID

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

-ID

the path forward for hiv-1 vaccine development

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