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Promising HIV Vaccine Strategies: Where
We Have BeenWhere We Are Going
Barton Haynes
September 11, 2011
Bangkok, Thailand
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HIV Vaccine Development
Virus discovered 1983
Cause of AIDS 1984
Vaccine development began1984
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HIV Vaccine Development
Hepatitis B virus vaccine is theouter coat (envelope)
1984- take the outer coat of HIV
gp120 (envelope) and make thevaccine
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HIV Vaccine Development
Protection from virusesantibodies that block(neutralize) virus
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HIV Vaccine Development
HIV mutatesdiverse
--strains we used in thelaboratory not like strains infield
--Lab cultured strains easy toneutralize while field strains
difficult 6
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HIV Vaccine Development
Vaccines induce antibodiesagainst regions of the envelopethat neutralize the easy toneutralize HIV strains but do notneutralize field HIV strains.
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Membrane proximal
Carbohydrate
CD4 binding site
V3 Loop
V1V2 Loops
V2,V3 Quaternary
(conformational)
CD4 binding site
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Membrane proximal
Carbohydrate
CD4 binding site
V3 Loop
V1V2 Loops
V2,V3 Quaternary
(conformational)
CD4 binding site
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Membrane proximal
Carbohydrate
CD4 binding site
V3 Loop
V1V2 Loops
V2,V3 Quaternary
(conformational)
CD4 binding site
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Membrane proximal
Carbohydrate
CD4 binding site
V3 Loop
V1V2 Loops
V2,V3 Quaternary
(conformational)
CD4 binding site
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HIV Vaccine Development
AIDSVAX B/B 2 clade B
envelopes (Westernhemisphere)trial did notprotect
AIDSVAX B/E 1 clade B and 1clade AE (Thailand)trial did
not protect 13
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HIV Vaccine Development
Army, Thai Ministry of Health,NIAID, sanofi-pasteur
ALVAC (canary pox) carrying
HIV genes including anenvelope + AIDSVAX B/E
Low risk subjects14
ALVAC 120 92TH023 TM t t
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ALVAC gp120 92TH023-TM construct
lipid membrane
V3: green
cd4bs: yellow
V1V2: pink
17b-site: purple
gp120 N-terminus: dark blue
gp120 C-terminus: red
light blue: glycans
top view
core: 15 of 16 glycans built
v1v2: 6 of 8
v3: 1 of 1v4v5: included in core
TM domain
P. Huang, B. Schief
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HIV Vaccine Development
Army, Thai Ministry of Health,NIAID, sanofi-pasteur
ALVAC (canary pox) carrying
HIV genes including anenvelope + AIDSVAX B/E
Low risk subjects
31% protection 17
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Membrane proximal
Carbohydrate
CD4 binding site
V3 Loop
V1V2 Loops
V2,V3 Quaternary
(conformational)
CD4 binding site
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The RV144 ALVAC/HIV Prime, rgp120 B/E
Trial: Immune Correlates Analysis
Barton HaynesFor the RV144 Immune Correlates Working Group
September 13, 2011
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Objectives of the Study
RV144 Estimated Vaccine Efficacy = 31%(95% CI, 1.1 to 52.1, P=0.04)
Objective: To carry out a correlatesanalysis to begin to identify how thevaccine might work.
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Macrophage FcR-mediated
phagocytosis of virions and ADCC
of virus infected CD4 T cells.
NK cell FcR-mediated ADCC
5-9
CD4 T cells
Columnar EpitheliumStratified Squamous Epithelium
Mucus
Layer
2
4
Langerhan/dendritic cells CD4 T cells
HIV-1-infected cells
4
HIV-1 1
1
3
3
10,11
CD4
CCR5
47
HIV-1- CD4 interactions
NK Cell
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Definitions
Correlate of Risk-an immuneresponse that predicts whethervaccinees become HIV-1 infected.
It may be causally related toprotection from infection, or maybe only a surrogate marker foranother factor.
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Hypothesis Generating Study
Goal of the statistical analysis is todiscover correlates of risk
Such discoveries would generatehypotheses about the immuneresponses that contributed to
protection
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Case Control Study
Measured immune responses from:
41 Infected Vaccinees
205 Uninfected Vaccinees
40 Placebo Recipients
Question: What are the immunologicmeasurements in vaccinees that predict HIV-1
infection over 3 year follow-up? Sample Time point: 2 weeks (peak
immunogenicity) after final vaccination:
Cryopreserved specimens: 2.5 ml plasma and2 vials of cells 24
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HIV Vaccine Development--
Field is doing Two Things Figure out how ALVAC/HIV
AIDSVAX B/E worksthen make
it better
Figure out how to induce theantibodies against AchillesHeels of envelope that the body
doesnt normally want to make.25
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Membrane proximal
Carbohydrate
CD4 binding site
V3 Loop
V1V2 Loops
V2,V3 Quaternary
(conformational)
CD4 binding site