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
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
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
3
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%)
4
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
1
2
4
8
16
32
64
128
2-5 6-10 11-17 18-29
GeometricMeanhSBATiter
Age
hSBAGeometricMeanTiterWeek4
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
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)
hSBA Immune Responses at Week 4 by Vaccine and Age Group
0
10
20
30
40
50
60
70
80
90
100
2-10 11-17 18-29 Age
Titer ≥ 1:8
PsA-TT PsACWY
0
10
20
30
40
50
60
70
80
90
100
2-10 11-17 18-29 Age
Four-fold Rise
PsA-TT PsACWY
** ** **
**
**p<0.0001 6
Correlation Between Immunoassays
0 5 10 150
5
10
15
20
Log hSBA
Log
rSB
A
0 5 10 150
1
2
3
4
Log hSBA
Log
ELI
SA
5 10 15 200
1
2
3
4
Log rSBA
Log
ELI
SA
Scatter Plots: Sera from PsA-TT Group at Week 4
7
Pre-existing Antibody by Age Group
1
2
4
8
16
32
64
128
2-5 6-10 11-17 18-29
GeometricMeanhSBATiter
Age
hSBAGeometricMeanTiterWeek0
Combined
1
2
4
8
16
32
64
128
256
512
1024
2048
4096
8192
2-5 6-10 11-17 18-29
GeometricMeanrSBATiter
Age
rSBAGeometricMeanTiterWeek0
Combined
0.1
1
10
100
2-5 6-10 11-17 18-29
GeometricMeanIgGConcentration
Age
IgGGeometricMeanConcentrationWeek0
Combined
8
1
2
4
8
16
32
64
128
2-5 6-10 11-17 18-29
GeometricMeanhSBATiter
Age
hSBAGeometricMeanTiterWeek0
Combined
1
2
4
8
16
32
64
128
256
512
1024
2048
4096
8192
2-5 6-10 11-17 18-29
GeometricMeanrSBATiter
Age
rSBAGeometricMeanTiterWeek0
Combined
0.1
1
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
Responses to PsACWY
1
2
4
8
16
32
64
128
2-5 6-10 11-17 18-29
GeometricMeanhSBATiter
Age
hSBAGeometricMeanTiterWeek4
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
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
2
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
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
10
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
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
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
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
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
13
PsA-TT 002 10 Month Boost
SBA-H GMT 1 Month Post Primary Immunization Pre-Boost and 1 Month Post Booster Dose
1
10
100
1000
Log
GM
T
PsA-TT Primed Post Primary 10 months
p<0.0001
p<0.02 p<0.01
14
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
15