Measuring Immune Responses to PsA-TT using Human ......Week 4 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 e t i r S T i Age rSBA Geometric

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

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2-5 6-10 11-17 18-29

GeometricMeanhSBATiter

Age

hSBAGeometricMeanTiterWeek4

PsA-TT

PsACWY

1

2

4

8

16

32

64

128

256

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1024

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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

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2-10 11-17 18-29 Age

Titer ≥ 1:8

PsA-TT PsACWY

0

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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

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2-5 6-10 11-17 18-29


Age


Combined

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2-5 6-10 11-17 18-29


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Combined

0.1

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2-5 6-10 11-17 18-29


Age


Combined

8

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Age


Combined

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Combined

0.1

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2-5 6-10 11-17 18-29


Age


Combined

IgG: 2-5 < 6-10 < 11-17 < 18-29 hSBA: 2-5 = 6-10 < 11-17 < 18-29

Responses to PsACWY

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2-5 6-10 11-17 18-29


Age


PsA-TT

PsACWY

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PsA-TT

PsACWY

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2-5 6-10 11-17 18-29


Age


PsA-TT

PsACWY

9

1

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Age


PsA-TT

PsACWY

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2-5 6-10 11-17 18-29


Age


PsA-TT

PsACWY

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2-5 6-10 11-17 18-29


Age


PsA-TT

PsACWY

hSBA and IgG responses to PsACWY are age dependent

1

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2-5 6-10 11-17 18-29


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PsA-TT

PsACWY

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2-5 6-10 11-17 18-29


Age


PsA-TT

PsACWY

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2-5 6-10 11-17 18-29


Age


PsA-TT

PsACWY

10

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2-5 6-10 11-17 18-29


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PsA-TT

PsACWY

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2-5 6-10 11-17 18-29


Age


PsA-TT

PsACWY

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2-5 6-10 11-17 18-29


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PsA-TT

PsACWY

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PsA-TT

PsACWY

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PsA-TT

PsACWY

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2-5 6-10 11-17 18-29


Age


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

Documents

Measuring Immune Responses to PsA-TT using Human ......Week 4 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 e t i r S T i Age rSBA Geometric