Measuring Immune Responses to PsA-TT using Human ......Week 4 PsA-TT PsACWY 1 2 4 8 16 32 64 128 256...
Transcript of Measuring Immune Responses to PsA-TT using Human ......Week 4 PsA-TT PsACWY 1 2 4 8 16 32 64 128 256...
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Measuring Immune Responses to PsA-TT using Human Complement Serum Bactericidal Antibody Assays
Margaret C. Bash M.D. MPH
Laboratory of Bacterial Polysaccharides Center for Biologics Evaluation and Research
Food and Drug Administration
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Evaluating New Meningococcal Vaccines Why Test with Human Complement?
• Evaluation of new vaccines using immunogenicity to estimate efficacy – SBA with rabbit complement (rSBA), human
complement (hSBA), anti-polysaccharide IgG concentration
• Human complement – Difficult to identify and qualify
– Different sources may give different titers – Lack of hSBA standard sera complicates assay
validation and interpretation
• Neisseria meningitidis – Adapted to evade human host defenses by
down-regulating hC’ activity
– Immunogenicity results can differ by assay type 2
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Application of hSBA to MVP Clinical Trials
• PsA-TT clinical trials with hSBA testing – 001 Phase 1 in Indian young adults
• hSBA of PsA-TT and Ps groups – 002 African toddlers
• hSBA subset ~ 30% of participants – 003 African individuals 2 through 29 years of age
• hSBA subset ~ 40% of participants – 004 African study in infants with EPI
• hSBA subset ~ 20%
• hSBA results – PsA-TT similarly immunogenic in all ages – hSBA responses higher following PsA-TT compared to Ps – Strong response to Ps challenge in PsA-TT primed toddlers – Age dependent decline in antibody – Results for individual sera show poor correlation between assays
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PsA-TT 003: Safety and Immunogenicity in Africans 2 to 29 Years of Age
120 hSBA 60 hSBA 60 hSBA 60 hSBA 30 hSBA 30 hSBA
120 hSBA 60 hSBA 60 hSBA 60 hSBA 30 hSBA 30 hSBA
hSBA subset = 360 (40%)
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Immune Response to PsA-TT or PsACWY hSBA Geometric Mean Titer
• hSBA response to PsA-TT similar in all age groups
• Higher hSBA GMT following PsA-TT in all age groups
• hSBA response to Ps lower in children 2-10 years of age than in adolescents and adults – No difference between age
groups 2-5 and 6-10 5
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GeometricMeanhSBATiter
Age
hSBAGeometricMeanTiterWeek4
PsA-TT
PsACWY
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1024
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8192
16384
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GeometricMeanrSBATiter
Age
rSBAGeometricMeanTiterWeek4
PsA-TT
PsACWY
1
10
100
2-5 6-10 11-17 18-29
GeometricMeanIgGConcentration
Age
IgGGeometricMeanConcentrationWeek4
PsA-TT
PsACWY
128
64
32
16
8
4
2
1
G
eom
etric
Mea
n hS
BA
Tite
r
4 Week 4
Age (years)
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hSBA Immune Responses at Week 4 by Vaccine and Age Group
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30
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100
2-10 11-17 18-29 Age
Titer ≥ 1:8
PsA-TT PsACWY
0
10
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50
60
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90
100
2-10 11-17 18-29 Age
Four-fold Rise
PsA-TT PsACWY
** ** **
**
**p<0.0001 6
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Correlation Between Immunoassays
0 5 10 150
5
10
15
20
Log hSBA
Log
rSB
A
0 5 10 150
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2
3
4
Log hSBA
Log
ELI
SA
5 10 15 200
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3
4
Log rSBA
Log
ELI
SA
Scatter Plots: Sera from PsA-TT Group at Week 4
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Pre-existing Antibody by Age Group
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128
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GeometricMeanhSBATiter
Age
hSBAGeometricMeanTiterWeek0
Combined
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2
4
8
16
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64
128
256
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1024
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8192
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GeometricMeanrSBATiter
Age
rSBAGeometricMeanTiterWeek0
Combined
0.1
1
10
100
2-5 6-10 11-17 18-29
GeometricMeanIgGConcentration
Age
IgGGeometricMeanConcentrationWeek0
Combined
8
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128
2-5 6-10 11-17 18-29
GeometricMeanhSBATiter
Age
hSBAGeometricMeanTiterWeek0
Combined
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GeometricMeanrSBATiter
Age
rSBAGeometricMeanTiterWeek0
Combined
0.1
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10
100
2-5 6-10 11-17 18-29
GeometricMeanIgGConcentration
Age
IgGGeometricMeanConcentrationWeek0
Combined
IgG: 2-5 < 6-10 < 11-17 < 18-29 hSBA: 2-5 = 6-10 < 11-17 < 18-29
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Responses to PsACWY
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128
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GeometricMeanhSBATiter
Age
hSBAGeometricMeanTiterWeek4
PsA-TT
PsACWY
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128
256
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8192
16384
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GeometricMeanrSBATiter
Age
rSBAGeometricMeanTiterWeek4
PsA-TT
PsACWY
1
10
100
2-5 6-10 11-17 18-29
GeometricMeanIgGConcentration
Age
IgGGeometricMeanConcentrationWeek4
PsA-TT
PsACWY
9
1
2
4
8
16
32
64
128
2-5 6-10 11-17 18-29
GeometricMeanhSBATiter
Age
hSBAGeometricMeanTiterWeek4
PsA-TT
PsACWY
1
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4
8
16
32
64
128
256
512
1024
2048
4096
8192
16384
2-5 6-10 11-17 18-29
GeometricMeanrSBATiter
Age
rSBAGeometricMeanTiterWeek4
PsA-TT
PsACWY
1
10
100
2-5 6-10 11-17 18-29
GeometricMeanIgGConcentration
Age
IgGGeometricMeanConcentrationWeek4
PsA-TT
PsACWY
hSBA and IgG responses to PsACWY are age dependent
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1
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128
256
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1024
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2-5 6-10 11-17 18-29
GeometricMeanrSBATiter
Age
rSBAGeometricMeanTiterWeek52
PsA-TT
PsACWY
1
2
4
8
16
32
64
128
2-5 6-10 11-17 18-29
GeometricMeanhSBATiter
Age
hSBAGeometricMeanTiterWeek52
PsA-TT
PsACWY
1
10
100
2-5 6-10 11-17 18-29
GeometricMeanIgGConcentration
Age
IgGGeometricMeanConcentrationWeek52
PsA-TT
PsACWY
10
1
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8
16
32
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128
256
512
1024
2048
4096
8192
16384
2-5 6-10 11-17 18-29
GeometricMeanrSBATiter
Age
rSBAGeometricMeanTiterWeek52
PsA-TT
PsACWY
1
2
4
8
16
32
64
128
2-5 6-10 11-17 18-29
GeometricMeanhSBATiter
Age
hSBAGeometricMeanTiterWeek52
PsA-TT
PsACWY
1
10
100
2-5 6-10 11-17 18-29
GeometricMeanIgGConcentration
Age
IgGGeometricMeanConcentrationWeek52
PsA-TT
PsACWY
1
2
4
8
16
32
64
128
256
512
1024
2048
4096
8192
16384
2-5 6-10 11-17 18-29
GeometricMeanrSBATiter
Age
rSBAGeometricMeanTiterWeek52
PsA-TT
PsACWY
1
2
4
8
16
32
64
128
2-5 6-10 11-17 18-29
GeometricMeanhSBATiter
Age
hSBAGeometricMeanTiterWeek52
PsA-TT
PsACWY
1
10
100
2-5 6-10 11-17 18-29
GeometricMeanIgGConcentration
Age
IgGGeometricMeanConcentrationWeek52
PsA-TT
PsACWY
Persistence – Week 52
Antibody titers decline during first year following immunization Antibodies remain higher following PsA-TT compared to PsACWY in young children Decline in hSBA and IgG is greater in young children than in adolescents and adults
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0 50 1000
1
2
3HMPMMMPPMPP
Week
log
GM
T
First Vaccina*on
Second Vaccina*on
Persistence of hSBA in Toddlers Following Second Dose - PsA-TT 002
11
Hib Ps PsA-TT Ps, 1/5 Ps Ps, PsA-TT PsA-TT. 1/5 Ps PsA-TT, PsA-TT
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Summary
• PsA-TT induces a strong hSBA antibody response – Consistent with rSBA and anti-PsA IgG
immunoassay results • hSBA titers decline over 52 weeks
– Especially in children younger than 10 years of age but hSBA titers remain higher than in Ps immunized children of the same age
– There is a difference in antibody persistence following 2 vs. 1 dose of PsA-TT by hSBA
• The differences between immunoassays are not well understood
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Acknowledgments • Health Protection Agency, Manchester UK
– Ray Borrow and Helen Findlow • CDC
– George Carlone and Brian Plikaytis • PATH
– YiJia Tang • Diagnosearch
– Varsha Parulekar • CBER
– Gregory Price, Aimee Hollander Brian Mocca • Meningitis Vaccine Project
– MVP vaccine trial team – Seth G.S. Medical College & KEM Hospital, The Nizam’s Institute of
Medical Sciences, and Topiwala National Medical College & BWI, India. – Centre pour les Vaccins en Développement CVD-Mali, Bamako, MALI
and Medical Research Council, Basse, GAMBIA – Centre pour les Vaccins en Développement CVD-Mali, Bamako, MALI,
Medical Research Council, Basse, GAMBIA and Institut de Resherche pour le Developpement (IRD) Dakar, SENEGAL
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PsA-TT 002 10 Month Boost
SBA-H GMT 1 Month Post Primary Immunization Pre-Boost and 1 Month Post Booster Dose
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10
100
1000
Log
GM
T
PsA-TT Primed Post Primary 10 months
p<0.0001
p<0.02 p<0.01
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PsA-TT Primed Toddlers Booster responses Study PsA-TT 002
0%
20%
40%
60%
80%
100%
2 4 8 16 32 64 128 256 512 1024 2048
PsA-TT 1 month n=56psA-TT 10 months n=53post PsA-TT boost n=13post 1/5 PS challenge n=22
Reverse Cumulative Distribution of hSBA Titers after PsA-TT Primary dose, Booster dose or PS Challenge
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