Dale and Betty Bumpers

Vaccine Research CenterNational Institute of Allergy and Infectious DiseasesNational Institutes of HealthDepartment of Health and Human Services

Gary J. Nabel M.D., Ph.D.Vaccine Research CenterNIAID, NIHJuly 18, 2011

The Changing Face of HIV Vaccine Research

International AIDS Society Meeting 2011Rome, Italy

The Status of AIDS Vaccines-IAS 2011

1. Lessons from clinical trials.

2. Understanding why has it been so difficult to make an effective AIDS vaccine.

3. New and promising scientific developments moving to the clinic.

The Status of AIDS Vaccines-IAS 2011

1. Lessons from clinical trials.

2. Understanding why has it been so difficult to make an effective AIDS vaccine.

3. New and promising scientific developments moving to the clinic.

Timeline of HIV Vaccine Efficacy TrialsFrom 1990 to 2010

VaxGen USA

VaxGen Thai Trial

Step Trial

Thai Trial

Trial start/end

Trial analysis/results

First correlates

1990 1995 2000 2005 2010

1 year

1 year

6 months

16 months

HVTN 505 Enrollment inprocess

Timeline of HIV Vaccine Efficacy TrialsFrom 1990 to 2010

VaxGen USA

VaxGen Thai Trial

Step Trial

Thai Trial

Trial start/end

Trial analysis/results

First correlates

1990 1995 2000 2005 2010

1 year

1 year

6 months

16 months

HVTN 505 Enrollment inprocess

Recombinant gp120No Efficacy

Timeline of HIV Vaccine Efficacy TrialsFrom 1990 to 2010

VaxGen USA

VaxGen Thai Trial

Step Trial

Thai Trial

Trial start/end

Trial analysis/results

First correlates

1990 1995 2000 2005 2010

1 year

1 year

6 months

16 months

HVTN 505 Enrollment inprocess

Ad5 Gag Pol Nef T cell vaccineNo Efficacy

RV-144: Evidence that an AIDS Vaccine Can Prevent HIV-1 Infection in Humans

Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand.

Supachai Rerks-Ngarm, M.D., Punnee Pitisuttithum, M.D., D.T.M.H., . . . Prayura Kunasol, M.D., and Jerome H. Kim, M.D., for the MOPH–TAVEG Investigators.

N Engl J Med., 2009 Dec 3;361(23):2209-20.

- Modest 31% reduction in infection- limited duration

Proof of concept for a protective vaccine

Proof of concept study of a multiclade HIV-1 DNA plasmid/recombinant adenoviral prime-boost vaccine in HIV-uninfected, adenovirus type 5

seronegative, circumcised men who have sex with men. Estimate complete enrollment in 2012.

HVTN 505: A Phase 2 Clinical Efficacy Trial

Scott Hammer MD, Principal Investigator; Larry Corey MD, HVTN Principal Investigator

The Status of AIDS Vaccines-IAS 2011

1. Lessons from clinical trials.

2. Understanding why has it been so difficult to make an effective AIDS vaccine.

3. New and promising scientific developments moving to the clinic.

Why Has an HIV-1 Vaccine Been So Difficult?

A

CB

D

Problem 1: It is a Moving and Evasive Target

A

CB

D

Infinite number of viruses

? Role of Abs in immunity

Evolving neutralization profiles

The Structure of HIV-1 Env and Definition of CD4 Binding Site

Initial site of CD4 attachmentCD4-binding site

Inner domain Outer domain

Bridging sheet

Kwong et al. J Virol 2000.

Why Has an HIV-1 Vaccine Been So Difficult?

Kwong et al. J Virol 2000.

Problem 2: Glycans Mask Env and Creates an Even More Moving and Evasive Target

The Status of AIDS Vaccines-IAS 2011

1. Lessons from clinical trials.

2. Understanding why has it been so difficult to make an effective AIDS vaccine.

3. New and promising scientific developments moving to the clinic.

Resurfaced Stabilized Cores: Probes for Human Abs and Templates for Immunogens

Nabel, Schief, Kwong, Mascola

Resurfaced Stabilized Cores Cores

Alter surface residues to eliminate reactivity with non-

neutralizing antibodies

1. Probe to isolate B cells and clone broadly neutralizing abs

2. Prototype immunogens to elicit antibodies to the highly conserved CD4 binding site

CD4 binding site

Pan-Reactive Antibody VRC01 Neutralizes~90% of Natural Circulating Viruses

Wu et al. (2010)Science 329, 856.

Why does VRC01 Work So Well?

1. Partial mimicry of CD4 binding to gp120

2. Binding focused on the conformationally invariant site of initial CD4 attachment.

gp120inner domain

gp120 outer domain

bridging sheet

2009 – 2010: New Potent mAbs against HIV-1

VRC01 - 03 HJ16(CD4bs)

2G12(glycan)

2F5, Z13, 4E10MPER

PG9/16(V2/V3 region)

• PG9/16 – Quaternary neutralization epitope in regions of V2/V3

• VRC01, 02, 03, HJ16 – target CD4bs

• Additional 9 new potent and broadly reactive Nabs, PGT, directed to glycans on the outer domain by IAVI/Scripps investigators.

PG9/16

(V2/

V3 re

gion)

These human antibodies neutralize more potently, and with far more breadth, than prior mAbs (80% - 90%; often < 1 ug/ml).

The Dark Ages of HIV-1 Broadly nAbs-pre-2010

VRC01-A New Window on HIV-1 Broadly nAb’s

VRC01

Similar germlines

Shared epitope

VRC01 VRC02 VRC03 VRCPG04 VRCxx……

Divergencein sequences

Convergenceon recognition

Independent Solutions Adopted by Abs to Recognize the CD4 BS Structure

•Independent VRC01-like antibodies have been isolated from multiple individuals.

•Deep sequencing of DNA from B cells of infected subjects indicates that hundreds or more similar antibodies are made in them.

VRC01-A New Window on HIV-1 Broadly nAb’s

VRC01

Deep Sequencing of Human VRC01 Antibodies: A New Vista on Immunoglobulin Diversification

How Do Broadly Neutralizing Antibodies Develop Normally and How Do We Elicit Them for a Vaccine?

Donor 2

Donor 1

Donor 3

There is a common evolutionarytree for VRC01-like antibodies from different people.

How Do Broadly Neutralizing Antibodies Develop Normally and How Do We Elicit Them for a Vaccine?

VRC01 germ line Mature VRC01

gp120

The B cell precursor of VRC01 does not recognize Env

Unmutated ancestor

VH gene mutations

Donor 45/74/219 intermediate

Donor 45/74intermediate

Mature VRC01

23 93530

Maturation of Progressive VRC01 Intermediates

Guiding the Pathway of Antibody Elicitation

VRC01

Intermediate 1

Unmutated Ancestor

Intermediate 2

Design of Immunogens to Elicit Broadly Neutralizing Abs to the CD4 Binding Site

1. Trimers

2. Monomers

3. Outer Domains

Structure-based design:

Engraftment of a HIV Env Fragment onto a VLP

Engraftment of a HIV Env Fragment onto a VLP

Progress in HIV-1 Prevention Researchin the Last Decade

Randomized, Controlled Intervention Trial of Male Circumcision for Reduction of HIV Infection Risk: The ANRS 1265 Trial.

Bertran Auvert, Dirk Taljaard, Emmanuel Lagarde, Joelle Sobngwi-Tambekou, Remi Sitta, Adrian Puren.

PLoS Medicine, 2005 Nov;2(11):e298.

Male circumcision for HIV prevention in men in Rakai,

Uganda: a randomised trial. Ronald H Gray, Godfrey Kigozi, David Serwadda, Frederick Makumbi, Stephen Watya, Fred Nalugoda, Noah Kiwanuka, Lawrence H Moulton, Mohammad A Chaudhary, Michael Z Chen, Nelson K Sewankambo, Fred Wabwire-Mangen, Melanie C Bacon, Carolyn F M Williams, Pius Opendi, Steven J Reynolds, Oliver Laeyendecker, Thomas C Quinn, Maria J Wawer.

Lancet, 2007;369:657–66.

Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women.

Quarraisha Abdool Karim, Salim S. Abdool Karim, Janet A. Frohlich, Anneke C. Grobler, Cheryl Baxter, Leila E. Mansoor, Ayesha B. M. Kharsany, Sengeziwe Sibeko, Koleka P. Mlisana, Zaheen Omar, Tanuja N. Gengiah, Silvia Maarschalk, Natasha Arulappan, Mukelisiwe Mlotshwa, Lynn Morris, Douglas Taylor, on behalf of the CAPRISA 004 Trial Group November 2000.

Science, 2010 Sep 3;329(5996):1168-74.

Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men.

Robert M. Grant, M.D., M.P.H., Javier R. Lama, M.D., M.P.H., . . . Ana I. Martinez, R.Ph., David N. Burns, M.D., M.P.H., and David V. Glidden, Ph.D., for the iPrEx Study Team.

N Engl J Med., 2010 Dec 30;363(27):2587-99.

Prevention of HIV-1 Infection with Early Antiretroviral Therapy

Myron S. Cohen, Y. Q. Chen, M. McCauley,T. Gamble, M. C. Hosseinipour,N. Kumarasamy, J. G. Hakim,J. Kumwenda, Beatriz Grinsztejn, Jose H.S. Pilotto,S. V. Godbole, S. Mehendale, S. Chariyalertsak,B.R. Santos, K. H. Mayer, I. F. Hoffman,S. H. Eshleman, E. Piwowar-Manning, L. Wang,J. Makhema, L. A. Mills, G. de Bruyn,I. Sanne, J. Eron, J. Gallant,D. Havlir, S. Swindells, H. Ribaudo,V. Elharrar, D. Burns, T. E. Taha,K. Nielsen-Saines, D. Celentano, M. Essex and T. R. Fleming, for the HPTN 052 Study Team.

N Engl J Med., 10.1056/NEJMoa1105243

This article is being published today, July 18, 2011, at NEJM.org.

Presentation: Mike Cohen4:30 PM today

(10.1056/NEJMoa1105243)

With So Much Success with Prevention, Do We Still Need an AIDS Vaccine?

June 4, 2011

Contributions of a Vaccine to the HIV Prevention Portfolio

1. Vaccine is given once; protection lasts a lifetime.

2. Durable protection is conferred to the person at risk.

3. An effective vaccine is among the most cost-effective medical interventions.

New Paths Forward to AIDS Prevention Based on Broadly Neutralizing Antibodies and Structure

VRC01-gp120 structure

NeutralizingAntibody

ImmunogenDesign

Vaccine Passive Transfer

Summary

1. An understanding of HIV-1 entry has provided an opportunity for AIDS vaccine development through the definition of highly conserved invariant viral structures that are the target of broadly neutralizing antibodies.

2. Definition of the specificities and targets of broadly neutralizing antisera and monoclonal antibodies have facilitate the identification of “structural” serotypes and catalyzed new approaches to vaccine design.

3. It is now possible to elicit CD4 BS and other neutralizing abs through structure-based vaccine design.

4. Significant hurdles remain but the opportunities have never been more promising, and the need for a highly effective AIDS vaccine remains urgent.

DIR/NIAID/NIH M Connors Doria-Rose D. Van Ryk

Duke/CHAVI Bart Haynes

VRC/NIH X Wu L Chen I Georgiev C Huang C-M Hogerkorp Y Kwon Y Li N Longo M Louder J Mascola K McKee S O’Dell M Roederer

Scripps/IAVI D Burton W. Koff A Hessel M Zwick

U Washington D Baker W Schief

Beth Israel M Seaman

Acknowledgements

S Schmidt L Shapiro L Wu R Wyatt D Wycuff L Xu Y-P Yang Z–Y Yang P Kwong T Zhou J Zhu

VRC Principal Investigators

Srinivas Rao

Gary Nabel

NancySullivan

Peter Kwong Robert

Seder

RichardSchwartz

RichardKoup

Barney Graham

Mario Roederer

DanielDouek

JohnMascola