human and rhesus macaque immunologic responses to anthrax vaccine adsorbed cdc anthrax vaccine...
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Human and Rhesus Macaque Immunologic Responses To Anthrax
Vaccine Adsorbed
CDC Anthrax Vaccine Research Program Conrad P. QuinnChief, MPIR LaboratoryMVPD/DBD/NCIRD
FDA Advisory Committee Meeting16th November 2010
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
National Center for Immunization & Respiratory Diseases
Division of Bacterial Diseases
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CDC Anthrax Research
AVRP Anthrax Vaccine Adsorbed
• Phase 4 human clinical trialo Double blind, placebo controlledo Route change, dose reduction
• Non-human primate vaccine correlates of protectiono Inhalation anthrax model in Rhesus macaques
AIGIV Rabbit passive transfer model
o Ambulatory NZW infusion modelo Human anti-AVA serum o Proof of concept; prophylactic intervention for
inhalation anthrax
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The CDC Anthrax Vaccine Research Program
Document & assure efficacy of AVA
Minimize doses & optimize schedule
Define the AVA correlate of protection Find an immunologic marker(s) that:
• Endorses Human Clinical Trial endpoint• Confirms human vaccinee protection• Identifies when protection is achieved• Quantifies how long protection lasts
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An Integrated Study in Humans & Rhesus macaque NHP
AVA Human Clinical Trial
AVA MacaqueDose Ranging &
Immunogenicity Study
ImmunocompetenceModel
Building
Survival AgainstVirulent Challenge
NHPImmune Correlates
of Protection
Human Surrogate Markers
of Protection
HumanHumoral & Cellular
Immune Profiles
MacaqueHumoral & Cellular
Immune Profiles
Hu-AVA1/5 – 1/40
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Challenge vs. Vaccination in Rh. Macaques
StudyGroup
IALabel
Week 0
Week 2
Week 4
Month 6
Month 12
Month 18
Month 30
Month 42
8SQ 4SQ AVA AVA AVA AVA AVA AVA AVA AVA
8IM 4IM AVA AVA AVA AVA AVA AVA AVA AVA
7IM
3IM
AVA S AVA AVA AVA AVA AVA AVA
5IM AVA S AVA AVA S AVA S AVA
4IM AVA S AVA AVA S S S AVA
IM Placebo PLAC S S S S S S S S
SQ Placebo PLAC S S S S S S S S
Rh. macaque challenge time points
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Building Immunological Profiles
Modulation of rh. macaque immune response (3IM) Variable schedules in humans Quantification of antibody levels and functional competence (ELISA & TNA) Th1 – Th2 disposition Onset and duration of T cell memory & competence (SI) Onset and duration of B cell memory Data mining and bridging to humans
Correlate of protection in rh. macaques Surrogate of protection in human vaccinees
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Antibody Levels and Functional Competence Are Highly Correlated
y = 0.95x + 0.84 R2 = 0.86(n=6875)
Anti-PA IgG (µg/ml)
Leth
al T
oxin
Neu
tral
izat
ion
Tite
r (E
D5
0)
Regression Human– n=4568, Rsqrd=0.8672
• LOGED50=0.7811+0.9774LOGIGG– TNA range ED50 0-40,000– ELISA range 0-5781.7 (0-4585.6 when a
TNA result is present)
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Diluted AVA Elicits Long-term Circulating Anti-PA IgG
5.32 µg/ml3.40 µg/ml1.22 µg/ml
Macaque Anti-PA IgG
Time (weeks)
0 50 100 150 200 250
An
ti-P
A Ig
G (
g/m
l)
1
10
100
1000
10000
Hu_AVA1/5_AVA1/10_AVA1/20_AVA1/40_AVA
0 1m 6m
5.32 µg/ml
3.40 µg/ml
1.22 µg/ml
vaccination
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Diluted AVA Elicits Potent Anamnestic Responses to infection in Rh. Macaque NHP
Macaque Anti-PA IgG Anamnestic Resposnse To Infection
Time (weeks)
0 50 100 150 200 250
Ant
i-PA
IgG
( g
/ml)
1
10
100
1000
10000
Hu_AVA1/5_AVA1/40_AVA
vaccination
challenge challenge
5.32 µg/ml
3.40 µg/ml
4211 µg/ml
3134 µg/ml
37 µg/ml
25 µg/ml
2714 µg/ml
1009 µg/ml
2669 µg/ml
2.63 µg/ml
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PA Specific NHP T Cell Competence isMaintained for 52m
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3-IM Human Dose and Diluted AVA Provides Long Term Protection in Rhesus Macaque NHP
3-IM priming series. No booster vaccinations.
Number Survived / Number Challenged(Survival Rate)
Challenge Time
Undiluted 1/5 1/10 1/20 1/40
12 Months - -8/10
(80.0%)11/20
(55.0%)13/20
(65.0%)
30 Months10/10
(100.0%)8/8 (100.0%)
6/9(66.7%)
7/8(87.5%)
-
52 Months8/10
(80.0%)9/9
(100.0%)6/10
(60.0%)- -
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LO
G10 E
LIS
A A
NT
IBO
DY
CO
NC
EN
TR
AT
ION
1
10
100
1,000
10,000
WEEK
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190
STUDY_ARM TRT-8SQ TRT-8IM TRT-7IMTRT-5IM TRT-4IM CONTROL
Human 3-IM Priming Establishes Long Term Responses
PLAC
433.20
310.02
254.80
320.45
216.83
7IM 47.77 8IM 38.078SQ 35.695IM 21.584IM 6.02PLAC 1.85
3 yrs
6.02(5.28-6.87)
1yr
21.58(18.9-24.7)
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PA Specific Human T Cell Competence isMaintained for 43m
T cell SI were detectable by 0.5m, significantly above control levels by 1m, and sustained for 43m irrespective of schedule.
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Rabbit Passive Transfer Studies – AIGIV• Human anti-AVA IgG fraction
• Minimum of 4 doses AVA SC• Single intravenous infusion• 24hr prior to aerosol exposure• 3 dose levels human AIGIV• 200 LD50 equivalents B. anthracis Ames• Flebogamma protein control• Ambulatory, minimal invasion, maximum
access• Facilitates long term, multiple infusions,
combination therapies
29log taktf
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GMC AIGIV Profiles in Rabbits Challenge
Infusion
608 µg/ml
333 µg/ml
145 µg/ml
292 µg/ml
161 µg/ml
65 µg/ml
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AIGIV Passive Transfer Survival
20mg/kg AIGIV10mg/kg AIGIV
5mg/kg AIGIV
Flebogamma ControlsNaïve Controls
292 µg/ml
161 µg/ml
65 µg/ml
GMTTD 3.9dGMTTD 4.9d
GMTTD 5.7d
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Correlates of Protection Modeling
Approach: David Madigan, Columbia U, NY
• Least Squares Regression Analyses • LASSO - automatic variable selection and estimation
algorithm via constrained maximum likelihood logistic regression
o Evaluation of NHP data• Bayesian multi-level models
o Bridging between genera Chuck Rose, Lydia Foster, CDC
• Linear Mixed Effects Model (log-log transformed) • Anti-PA IgG longevity and decay in humans and NHPs
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Active Immunization Antibody Decay in Humans and NHP fits a Conventional
Power Law Model
-2
-1
0
1
2
3
4
5
6
7
0 1 2 3 4 5
Ln(Week)
Ln
(Ig
G)
Human and NHP1/5_AVA slopes and intercepts are not
statistically significantly different
Human
NHP_1/5_AVA
NHP_1/10_AVA
NHP_Hu_AVA
NHP_1/20_AVA
N = 94 vaccinated animals
29log taktf
29log taktf
From C.Rose & L.Foster
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Segregation of NHP Survivors by wk30 Anti-PA IgG Levels and Decay Kinetics
n= 94 vaccinated animals
74µg/ml anti-PA
55/58 survivors 18/36 survivors
= alive = dead
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Interpretive Value of the GUP Anti-PA IgG Response
Significant NHP survival at 30 and 52 months post-vaccination
IgG and TNA ED50 are correlated with survival
Other assays (SI) only weakly correlate with survival
IgG and TNA ED50 are highly correlated with each other
NHP anti-PA IgG responses to1/5 diluted 3-IM AVA and human responses to a 3-IM schedule fit the same decay model
Peak response to 3-IM vaccination combined with decay kinetics may be useful in predicting protection in NHP
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1. Anti-PA IgG antibodies are an adequate, if not perfect, correlate of protection from which to bridge between animal models and humans
2. Bridging from animals to humans may be achieved from active immunization studies
3. Antibody passive transfer studies comprise only one facet of the protective immune
response are required to overcompensate for the absence of CMI may set unnecessarily high requirements for
measureable circulating antibody from active immunization
4. GUP vaccine efficacy informs PEP Effects of concomitant abx on human immune response
to AVA need to be evaluated
Conclusions