Dale and Betty Bumpers
Vaccine Research Center
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Department of Health and Human Services
The Changing Face of HIV Vaccine Research
International AIDS Society Meeting 2011
Rome, Italy
Gary J. Nabel M.D., Ph.D.
Vaccine Research Center
NIAID, NIH
July 18, 2011
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 Trials
From 1990 to 2010
1990
1995
2000
2005
VaxGen USA
1 year
VaxGen Thai Trial
1 year
Step Trial
2010
6 months
Thai Trial
16 months
HVTN 505
Enrollment in
process
Trial start/end
Trial analysis/results
First correlates
Timeline of HIV Vaccine Efficacy Trials
From 1990 to 2010
1990
1995
2000
2005
VaxGen USA
1 year
VaxGen Thai Trial
1 year
Step Trial
2010
Recombinant gp120
No Efficacy
6 months
Thai Trial
16 months
HVTN 505
Enrollment in
process
Trial start/end
Trial analysis/results
First correlates
Timeline of HIV Vaccine Efficacy Trials
From 1990 to 2010
1990
1995
2000
2005
VaxGen USA
1 year
VaxGen Thai Trial
1 year
Step Trial
Thai Trial
Ad5 Gag Pol Nef
T cell vaccine
No Efficacy
HVTN 505
2010
6 months
16 months
Enrollment in
process
Trial start/end
Trial analysis/results
First correlates
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
HVTN 505: A Phase 2 Clinical Efficacy Trial
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.
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
B
C
D
Problem 1: It is a Moving and Evasive Target
Infinite number of viruses
A
? Role of Abs in immunity
B
C
D
Evolving neutralization
profiles
The Structure of HIV-1 Env and
Definition of CD4 Binding Site
Initial
site of CD4
CD4-binding
site attachment
Inner domain
Outer domain
Bridging sheet
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
Kwong et al. J Virol 2000.
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
Cores
CD4
binding site
Resurfaced Stabilized Cores
Alter surface
residues to eliminate
reactivity with nonneutralizing
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
Nabel, Schief, Kwong, Mascola
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
conformational
ly invariant site
of initial CD4
attachment.
gp120
outer domain
gp120
inner domain
bridging sheet
2009 – 2010: New Potent mAbs against HIV-1
PG9/16
(V2/V3 region)
VRC01 - 03
HJ16
(CD4bs)
2G12
• PG9/16 – Quaternary neutralization
epitope in regions of V2/V3
(glycan)
• VRC01, 02, 03, HJ16 – target
CD4bs
2F5, Z13, 4E10
MPER
• Additional 9 new potent and
broadly reactive Nabs, PGT,
directed to glycans on the outer
domain by IAVI/Scripps
investigators.
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
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.
Similar germlines
Divergence
in sequences
VRC01
VRC02
VRC03 VRCPG04 ……
VRCxx
Convergence
on recognition
Shared epitope
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 1
Donor 2
Donor 3
There is a common evolutionary
tree for VRC01-like antibodies from
different people.
How Do Broadly Neutralizing Antibodies Develop Normally
and How Do We Elicit Them for a Vaccine?
gp120
VRC01 germ line
Mature VRC01
The B cell precursor of VRC01 does not recognize Env
Maturation of Progressive VRC01 Intermediates
Unmutated
ancestor
VH gene
mutations
0
Donor 45/74/219
intermediate
23
Donor 45/74
intermediate
53
Mature
VRC01
93
Guiding the Pathway of Antibody Elicitation
VRC01
Intermediate 2
Intermediate 1
Unmutated Ancestor
Design of Immunogens to Elicit Broadly
Neutralizing Abs to the CD4 Binding Site
Structure-based design:
1. Trimers
2. Monomers
3. Outer Domains
Engraftment of a HIV Env Fragment onto a VLP
Engraftment of a HIV Env Fragment onto a VLP
Progress in HIV-1 Prevention Research
in 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.
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.
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.
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. PiwowarManning, 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. NielsenSaines, 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 Cohen
4:30 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
Immunogen
Design
Vaccine
Neutralizing
Antibody
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.
Acknowledgements
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
DIR/NIAID/NIH
S Schmidt
M Connors
L Shapiro
Doria-Rose
L Wu
D. Van Ryk
R Wyatt
D Wycuff Duke/CHAVI
L Xu
Bart Haynes
Y-P Yang
Z–Y Yang
P Kwong
T Zhou
J Zhu
Scripps/IAVI
D Burton
W. Koff
A Hessel
M Zwick
U Washington
D Baker
W Schief
Beth Israel
M Seaman
VRC Principal Investigators
Daniel
Douek
Barney
Graham
Mario
Roederer
Richard
Richard
Koup
Schwartz
John
Mascola
Srinivas
Rao
Gary
Nabel
Nancy
Sullivan
Peter
Kwong
Robert
Seder