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
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
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
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
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 RaceHIV-1 Antibody
The transmitted-Founder virus
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
Escape virus
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
Escape virus
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
Escape virus
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
Escape virus
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
Escape virus
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
Escape virus
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
Escape virus
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
Escape virus
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
Escape virus
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
Escape virus
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
Escape virus
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
Escape virus
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
Escape virus
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
Escape virus
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
Escape virus
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
Escape virus
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
Escape virus
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
Escape virus
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
Escape virus
The HIV-1 Arms RaceHIV-1 Antibody
The transmitted-Founder virus
The initial neutralizing antibody response to HIV
“autologous nAb”
Escape virus
85%- Non- or poor-Neutralizing
antibody
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-1 Antibody
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-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
The initial neutralizing antibody response to HIV
“autologous nAb”
15%- Broadly neutralizing
antibody
HIV-1 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”
15%- Broadly neutralizing
antibody
The transmitted-Founder virus
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