Presentation by Dennis Burton, Scripps Research Institute.

1. “An HIV Vaccine: The Neutralizing
Antibody Problem:”
Dennis Burton
Dept of Immunology & Microbial Science and IAVI
Neutralizing Antibody Center, The Scripps Research Institute
Center for HIV/AIDS Vaccine Immunology
and Immunogen Discovery (CHAVI-ID)
Ragon Institute of MGH, Harvard and MIT
Symposium on Innovations in Vaccines R&D
London, Sep 5th 2012

2. A global view of HIV-1 infection
33 million people living with HIV, 2009
UNAIDS: 2010 Report on the global AIDS epidemic. 2010

3. AIDS compromises human development …
Reversing the spread of AIDS is one of the
eight U.N. Millennium Development Goals
The AIDS pandemic undermines:
• Poverty reduction
• Improvements in child and maternal health
• Improvements in nutrition
• Gains in basic education
• Control of other infectious diseases

5. Host cell
The
proteins
in HIV CCR5
entry.
CD4
Env spike
(gp120)3 (gp41)3
Virion

6. NAbs block
viral entry.
Successful
vaccines
induce
NAbs.
Neutralizing Antibody (NAb)
For HIV,
need to
induce
broadly
NAbs
(bNAbs).

8. Can antibodies be made to conserved
parts of the HIV spike: are there
vulnerabilities in the armor?
Yes
A proportion of HIV-infected donors, over
time, make broadly neutralizing antibodies.

9. Reverse engineering an HIV vaccine
broadly
neutralizing (protective)
antibodies
Env
HIV-infected individual
Molecular characterization
of Ab-Env
Immunogen design
and testing
*
*
combination of several immunogens *modified Env
= vaccine
(adapted from Burton, Nat. Rev. Immunol., 2:706, 2002)

10. The NAb Problem: IAVI NAC Approach
Structure-based
bnMAbs immunogen design
Determining structure Analysis of Ab responses
of Env-Ab complexes
MAb Structural Immunogen Immunogen Clinical
Identification Biology Design Screening Dev.
Feedback loops
Major Block
Tools of
IAVI Slow
structural
Protocol G Immunogen
genomics
Screen

11. Rapid progress since 2009 in terms of
potency and breadth of bnMAbs
coverage (%)

12. A low dose of MAb PGT121 protects against high
dose SHIV162P3 vaginal challenge in macaques
av. serum conc.
dose PGT121 at challenge no. of macaques
(mg/kg) (μg/ml) protected % protection
5 95 5/5 100
1 15 5/5 100
0.2 1.7 3/5 60
control Ab n.d. 0/4 0
5mg/kg

13. >12 V2 / glycans
Vaccine targets defined
MAbs (PG9) by bnMAbs, Sep 2012
Glycans
1 (2G12)
V3 / V4 / glycans
>25 (cluster of targets:
PGT120s, PGT130s)
V3/CD4i
2 (3BC176) gp120
MPER
>5 (10E8)
CD4bs gp41
>25 (VRC01)
viral
membrane

14. The NAb Problem: IAVI NAC Approach
Structure-based
bnMAbs immunogen design
Determining structure Analysis of Ab responses
of Env-Ab complexes
MAb Structural Immunogen Immunogen Clinical
Identification Biology Design Screening Dev.
Feedback loops
Major Block
Tools of
IAVI Slow
structural
Protocol G Immunogen
genomics
Screen

15. Ab-gp120 structures, 2011-12
(Ian Wilson et al) mini-V3
N332
N30
PGV04-gp120 outer
domain complex:
CD4bs PGT128-gp120 outer
domain complex
V3/glycans
PGT128-trimer
complex by EM

16. The NAb Problem: IAVI NAC Approach
Structure-based
bnMAbs immunogen design
Determining structure Analysis of Ab responses
of Env-Ab complexes
MAb Structural Immunogen Immunogen Clinical
Identification Biology Design Screening Dev.
Feedback loops
Major Block
Tools of
IAVI Slow
structural
Protocol G Immunogen
genomics
Screen

17. Successful HIV vaccination will require
considerable ingenuity in immunogen design
and immunization protocols that go far
beyond current norms.

18. How to translate structural data into
immunogens?
•Stabilize the antibody-bound target epitope
conformation.
•Expose that conformation to the immune system.
Dampen responses to off-target epitopes.
•Multimerize with epitope pointed outward.
Additional immunogen features may be needed for HIV,
including the ability to activate germ line B cells and to
boost
guide antibody maturation along certain pathways. prime
Bill Schief and colleagues

19. High affinity antibodies are generated by
antigen-driven mutation and selection from a
naïve repertoire
Ab affinity
Somatic
hypermutation
Memory
B cell
naïve Antigen
B-cell
mature Ab
Plasma
Y
Germline Ab cell

20. The evolution of antibodies in natural HIV
infection: clues for vaccine design and
strategies?
From germ line antibodies
to broadly neutralizing
antibodies in natural HIV
infection-what is the
route?
IAVI Protocol G: 1,800
donors, few time points
Protocol C: 500 donors,
longitudinal study

21. The central role of CD4 T helper (Tfh) cells in
Ab responses
Memory
B cell
naïve Antigen
B-cell mature Ab
Tfh
cell
Germline
Ab
Germinal center Plasma
Y
cell

22. NAC/CHAVI-ID Priorities (Sept 2012)
I. Complete definition of HIV Env vulnerabilities
(“enough” bnMAbs, “enough” structures).
II. Understanding the development of bnAb
responses in natural HIV infection
III. Epitope directed Immunogen Design
IV. Trimer-based Immunogen Design
V. Immunogen evaluation

23. Collaborators
Scripps IAVI VRC CHAVI-ID
Ian Wilson Wayne Koff Gary Nabel Rafi Ahmed
Pascal Poignard Rick King John Mascola Dan Barouch
Dennis Burton
Bill Schief Clinical sites Peter Kwong Shane Crotty
Rich Wyatt Members of the Adam Godzik
Neutralizing Ragon Julie McElrath
Andrew Ward Bruce Walker Michel Nussenzweig
Antibody
Chi-Huey Wong Consortium Galit Alter Bali Pulendran
Joe Sodroski Chris Scanlan
Protocol G & C Bill Schief
scientists & Cornell Guido Silvestri
Monogram donors John Moore Bruce Walker
Theraclone Ian Wilson
Miami Rich Wyatt
David Watkins