7/14/2014 1 Program Hypothesis HA as the Principal Component of

7/14/2014
Elicitation of broadly-reactive HA head antibodies to
seasonal and pandemic viruses by COBRA vaccines
Program Hypothesis
Universal influenza vaccines can be rationally engineered
to elicit broadly cross-neutralizing epitopes
Second WHO Integrated Meeting on development and
clinical trials of Influenza vaccines that induce broadly
protective and long-lasting immune responses
5th – 7th May 2014
Geneva, Suisse
Universal antigens can be used in pre-immune hosts to re-focus the immune response,
preferentially recalling broadly neutralizing antibodies that provides breadth against multiple
strains within a subtype
Universal antigens can also be delivered with appropriate technologies to stimulate durable
and long-lasting immunity
Antigen
Selection
Adjuvant
(Formulation)
Production &
Delivery
System
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VAC C I N E & G E N E T H E R AP Y I N S T I T UT E
HA as the Principal Component of a
Universal Influenza Vaccine
Immune-refocusing of HA to increase breadth
HEAD:
Identify head
sequences which
stimulate broadly
neutralizing Abs
Benefits: Anti-head response
against receptor binding site potent
and MOA of current vaccine
Accepted surrogate marker (HAI)
Influenza Vaccine Program
Vaccines: A goal of influenza vaccine
development is the elicitation of crossprotective immunity. It is currently
impossible to predict which antigenic
variants may emerge and therefore an ideal
vaccine will elicit immunity to most potential
variants.
M1
100 µm
Risks: Breadth may be narrower
than anti-stem approaches

Pandemic Influenza: H5N1, H7N9, H2N2

Seasonal Influenza: H1N1, H3N2, and B

STEM:
Promote
immunogenicity of
the known broadly
neutralizing stem
epitopes
HA
NA
Benefits: Breadth may reach across
groups of influenza
Risks: Not as potent as anti-head,
higher amount of functional antistem Abs needed
Disease modulating?
No surrogate marker identified

Broadly-reactive HA immunogens
Broadly-reactive HA immunogens/
Universal influenza platforms
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7/14/2014
H5N1 Background
• Initially emerged in poultry and humans in 1997
• Diversity within subtype
Total Clade Distribution
– 10 phylogenetic clades
– Geographically distinct
0
– Human infections from
1
clades 0, 1, 2 and 7
2
Antigen Design
• Computationally Optimized Broadly Reactive Antigen (COBRA)
– Align amino acid sequences from Clade 2 human isolates
– Assemble ‘Layered’ Consensus
– Limit sampling bias
• Confirm presence of conserved linear epitopes
0
1
2
3
4
5
6
7
8
9
– (Immune epitope database; www.immuneepitope.org)
Giles et al. 2012. J. Inf. Dis. 205(10):1562-70.
Giles et al. 2012. Clin Vacc Immunol. 19(2):128-39.
Giles et al.. 2011. J. Virol. 86:1500-1513.
Giles BM and Ross TM. 2011. Vaccine. 29:3043-54.
5
Giles and Ross. 2011. Vaccine. 29:3043-54
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VAC C I N E & G E N E T H E R AP Y I N S T I T UT E
VAC C I N E & G E N E T H E R AP Y I N S T I T UT E
Mouse Antibody Responses
NHP Immunogenicity Breadth (HAI)
COBRA VLP
Whooper Swan Clade 2.2 VLP
Mock (Alum Only)
Receptor Blocking Antibody
(HAI Titers)
0
1
***
9
HAI GMT (Log2)
2.2
2.1
10
*** ***
*
8
*
7
2.3
**
**
*
*** p<0.001
** p<0.01
* p<0.05
4
7
***
*
**
***
*
***
6
5
4
V
V
B
C
8-12 week
BALB/c
3ug HA + Alum
C
6
la
de
5
C
3
C
0
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(H
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/4
83
la
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7)
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Virus
Giles et al. 2012. Clin Vaccine Immunol.19:128-39.
Giles and Ross. 2011. Vaccine. 29:3043-54
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VAC C I N E & G E N E T H E R AP Y I N S T I T UT E
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7/14/2014
Part I: COBRA 1st Generation
Second Generation H5N1 COBRA Vaccines
Hemagglutinin Structure
0
V
3
V
5
•
6
•
•
B C
Day 3 post-infection
•
Challenged with A/Whooper Swan/Mongolia/244/2005; Clade 2.2.
Giles et al. 2012. J. Inf. Dis. 205(10):1562-70.
5-10% diversity between
clades
COBRA diversity 1.5%
Receptor binding antibody
(similar yet different)
Can we utilize empirical
data and sequence
information to structurally
design antigens for
increased breadth and viral
coverage?
Human COBRA-2
Human/Avian COBRA-2
All H5 COBRA
Globular
Head
(HA1)
Stem
(HA2)
Site A
Site B
Site C
Site D
Site E
Crevar et al. Manuscript in progress.
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VAC C I N E & G E N E T H E R AP Y I N S T I T UT E
H5N1 COBRA
Summary
Ferret Experiments using human/avian H5N1 COBRA-2
and All H5N1 COBRA vaccines
Second
Generation
H5N1 COBRA
• An HA head-based approach has potential to replace SOC
Ferret Immunogenicity Breadth of HAI
Hemagglutination Inhibition Titers to H5N1
10
*
Log 2 HAI Titer
9
8
*
*
**
*
7
6
*
*
*
Human COBRA-2
Human-Avian COBRA-2
All H5 COBRA
Whooper Swan
**
*
* *
*
*
5
* p<0.05
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V iral Strain
VAC C I N E & G E N E T H E R AP Y I N S T I T UT E
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VAC C I N E & G E N E T H E R AP Y I N S T I T UT E
– Induces protection (vaccine efficacy) to a level comparable to SOC vaccines against
WHO recommended strains, AND
– Demonstrates breath of protection by providing consistent efficacy across
types/subtypes against drifted/mismatched strains
• New approaches for re-engineering HA have been
demonstrated to increase breadth of neutralizing antibody
response in pre-clinical studies
– COBRA antigens increase breadth of Ab response over wild-type HA
• Determining clinical POC in human translational studies is
feasible
– Progress into clinic with COBRA split-INV for POC
– Assess whether or not COBRA antigens stimulate breath of immune response in
humans as expected from pre-clinical animal model data
VAC C I N E & G E N E T H E R AP Y I N S T I T UT E
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7/14/2014
Acknowledgements
• VGTI Florida
Department of NeuroPathology
Clayton Wiley
Stephanie Bissel
–Donald Carter
–Corey Crevar
–Greg Kirchenbaum
–Terianne Wong
–Chalise Bloom
–Bradford Lefoley
–Chris Darby
–Neha Reddy
–Kevin Lee
–Rayleigh Chan
New York University
Elodie Ghedin
Icahn Mt. Sinai School of Medicine
Florian Krammer
UPMC
• University of Pittsburgh
–Dilhari DeAlmeida
–Kirsten Schneider-Orhum
–Brendan Giles
–Xian-Chun Tang
–Brooke Pierce
Shanta Zimmer
Rick Zimmerman
Kerry Empey
Influenza Projects
Supported by:
 NIH/NIAID
 NSF
 DoD
 PATH Vaccine Solutions
 Sanofi-Pasteur
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