CAVD Master PowerPoint template
Transcript of CAVD Master PowerPoint template
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Virus Panels for Assessing
Vaccine-Elicited Neutralizing Antibodies
Michael Seaman, Ph.D.
Center for Virology and Vaccine Research
Beth Israel Deaconess Medical Center
Harvard Medical School
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J. Virol. 2005, 79(16): 10103
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First Generation Clade B and C Reference Panels
J. Virol. 2005, 79(16): 10108
J. Virol. 2006, 80(23): 11776
Virology 2009, 385: 505
Clade B Panel (n=12)
Clade C Panel (n=12)
Southern Africa
Clade C Panel (n=12)
India
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CA-VIMC Standard Virus Panel Consortium:
>600 Functional env Clones for Pseudovirus Production
SVPCCarolyn Williamson
Francine McCutchan
Sodsai Tovanabutra
Eric Sanders-Buell
Jerome Kim
Beatrice Hahn
Ron Swanstrom
Feng Gao
Michael Thomson
Gama Bandawe
Cecilia Rademeyer
Ray Dolin
Lindsey Baden
Subtype Number
A 8
A (T/F) 3
B 12
B (T/F) 9
C 16
C (T/F) 15
BC 8
CRF01_AE 11
CRF01_AE (T/F) 4
CRF02_AG 9
G 7
D 4
D (T/F) 1
CD 5
AC/ACD 6
Total 118
Standard Multiclade Panel for
Assessing bNAb Potency/Breadth
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Neutralization Serotype Discovery Project
205 sera, multiclade
219 viruses, multiclade
SGA gp160sequence
Heatmap
Computational Analysis
Peptide arraybinding
gp160 sequences
NAb assay
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deCamp et al., 2014. J. Virol. 88(5):2489
Global Panel of Tier 2 HIV-1 Env Reference Strains
• Goal: Identify panel of Env pseudoviruses that are representative of the global epidemic
• Lasso statistical modeling identified 9 isolates that were highly predictive of
neutralizing activity seen with larger panel of 219
• Additional 3 isolates selected for greater genetic and antigenic diversity (B. Korber)
• Performed nearly as well as clade-matched panels for prediction of sub-type specific
responses
Isolate Clade
246_F3_C10_2 AC
Ce1176_A3 C
CNE55 CRF01_AE
X1632_S2_B10 G
Ce703010217_B6 C
BJOX002000.03.2 CRF07_BC
25710-2.43 C
TRO.11 B
CH119.10 CRF07_BC
X2278_C2_B6 B
CNE8 CRF01_AE
398_F1_F6_20 A
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deCamp et al., 2014. J. Virol. 88(5):2489
Neutralization Sensitivity of Global Panel
(Prototypic Tier 1A)
(Prototypic Tier 1B)
Global Panel
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Global Panel of Tier 2 HIV-1 Env Reference Strains
• Applicable to multiple vaccine platforms and clades of HIV-1 in
different parts of the world
• Facilitate cross-protocol comparisons
• Highly predictive of clade-specific responses
• Complementary to other panels that may be used, e.g., clade-
matched to vaccine and geographic region
• Useful as initial screen to identify and characterize bNAbs
deCamp et al., 2014. J. Virol. 88(5):2489
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Greater Neutralization Potency Within Clade
Hraber et al, 2014. J. Virol. 88(21):12623
Seaman et al, 2010. J. Virol. 84(3):1439
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Southern Africa Clade C NSDP Project
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200 early infection viruses that are more recent in the epidemic (1998-2010):• 130 South Africa (8 provinces)
• 28 Tanzania
• 23 Malawi
• 13 Zambia
• 6 Botswana
Mostly heterosexual transmissions (1 breastfeeding transmission)
Isolated within the first 100 days of infection. 67 seronegative (Fiebig I/II)
29 early seroconversion (Fiebig II/IV)
104 seropositive with seronegative test within the previous 100 days (Fiebig V/IV)
Viruses phenotyped for Tier classification (global sensitivity to neutralization)
Clade C HIV-1 Env Pseudovirus Panel
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Expected Distribution of Tier PhenotypesM
ean
lo
g10 ID
50 +
/-S
D
Each virus assessed for neutralization sensitivity to 30 chronic clade C HIV+ plasma
Rademeyer et al., PLoS Path. 2016 (in press)
Tier 1A: n=2 (1.3%)
Tier 1B: n=17 (8.5%)
Tier 2: n=150 (75%)
Tier 3: n=31 (15.5%)
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Computational Selection of Optimal Tier 2
Clade C Reference Panel
(Peter Hraber, Bette Korber, manuscript in preparation)
Objective: Select 12 Envs from larger panel of 200 that will be optimal
for detecting vaccine-elicited neutralizing antibodies
Strategy: Select based on mAb IC50s and Env traits (loop length, charge,
PNGs); compare with serum ID50 profiles
Tier 2 Clade C Isolate
Ce703010010_C4
ZM233M.PB6
2759058_F10_B6
Ce704810053_2B7
So431_C1_1
ZM215F.PB8
3728.v2.c6
2969249
B005582-7_G7.8
CAP382.2.00.D7.19
Ce2103_E8
Ko243_H6.3
• Favored more sensitive viruses for detecting low-level
Nab activity
• Captured diversity of known bnAb sensitivities
• Captured diversity of Env properties associated with
neutralization sensitivity
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Non-Standardized Approach:
Rational Tier 2 Virus Panel Selection
• Select viruses on more sensitive end of spectrum
(top quartile of geometric mean serological activity)
• Viruses that are as close as possible to sequence of
vaccine immunogen
• Viruses that have good glycosylation and variable
loop properties
• Viruses that are highly sensitive to epitope-specific
bnAbs of interest
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gp41 MPER:
10E8**
V2 Glycan:
PGT145, PGDM1400**,
PG9, CAP256-VRC26.08,
CAP256-VRC26.25**
CD4 Binding Site:
VRC01*, VRC07,
VRC07-523, VRC13,
3BNC117*
V3 Glycan:
PGT121**, PGT128
10-1074*, 10-1074V
Sensitivity of 200 C Panel Viruses to bnAbs
gp120/gp41:
Next time
* Phase I/II trials in progress
** Planned phase I trial
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bnAb Lineage Vaccine Strategies:
Selection of Isolates with High Sensitivity Profile
Wagh et al, PLoS Path. 2016 12(3):e1005520
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Summary of Points for Consideration
Large numbers of Env pseudoviruses with geographic,
genetic, and antigenic diversity have been extensively
characterized and optimized panels have been developed:
• Global Panel for standardized assessments of NAb across multiple
HIV-1 vaccine platforms in different parts of the world
• Optimally selected clade matched panels representative of
circulating strains in regions in which vaccine trials being conducted
• Rational selection of isolates based on properties of vaccine
immunogen(s) to increase the probability of detecting Tier 2
neutralization
• Rational selection of isolates based on bnAb sensitivities for lineage
induction vaccine strategies
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Acknowledgements
Duke University
Kelli Greene
Hongmei Gao
David Montefiori
LANL
Kshitij Wagh
Tanmoy Bhattacharya
Alan Lapedes
Peter Hraber
Bette Korber
VISC
Allan deCamp
Raphael Gottardi
Steve Self
Clade C Panel
Carolyn Williamson
Cecilia Rademeyer
Lynn Morris
Jerome Kim
Feng Gao
Beatrice Hahn
Ronald Swanstrom
SVPC
Carolyn Williamson
Francine McCutchan
Sodsai Tovanabutra
Eric Sanders-Buell
Jerome Kim
Beatrice Hahn
Ron Swanstrom
Feng Gao
Michael Thomson
Gama Bandawe
Cecilia Rademeyer
Ray Dolin
Lindsey Baden