This document discusses the emergence of the H7N9 avian influenza virus in China and the potential for developing a universal influenza vaccine. It finds that H7N9 has very poor conservation with currently circulating flu strains. Using immunoinformatics tools, EpiVax predicts H7N9 to be poorly immunogenic due to its low epitope content. However, EpiVax has developed an integrated "iVAX" vaccine design toolkit that maps T cell epitopes, identifies conserved segments, and designs immunogenic consensus sequences to potentially develop a universal flu vaccine with protection against H7N9.
Night 7k to 12k Navi Mumbai Call Girl Photo 👉 BOOK NOW 9833363713 👈 ♀️ night ...
Extremely rapid H7N9 vaccine design by EpiVax
1. Extremely
Rapid
H7N9
Immunogenicity
Analysis
and
Vaccine
Design
April
13
2013
Annie
De
Groot
M.D.
CEO/CSO
www.epvax.com
1
2. Adapted
from
a
Presenta?on
to
NIAID
Universal
Flu
Vaccines:
Now
More
than
Ever
EpiVax
has
a
flu
SBIR
that
was
scored
and
we
are
wai?ng
for
a
decision
about
funding
21
March
2013
Presented
by
Annie
De
Groot
MD
to
Rachelle
Salomon,
NIH,
NIAID,
DMID
EpiVax:
Lenny
Moise,
Frances
Terry,
Bill
MarMn
Mindy
Cote,
Ryan
Tassone,
Howie
LaMmer
Lauren
Levitz,
ChrisMne
Boyle
VGTI:
Ted
Ross
2
5. WHO
Report
Graph
This
picture
shows
the
geographically
wide
distribuMon
of
flu
cases
-‐
suggesMng
widespread
distribuMon
of
the
virus
rather
than
a
point
outbreak.
6. Time
to
consider
T
cell
epitopes?
hVp://www.ncbi.nlm.nih.gov/pmc/arMcles/PMC2936654/
8. Worry:
CDC
-‐
No
Cross-‐reacMve
Ab
• Preliminary
studies
of
individuals
showed
that
anMbodies
induced
by
seasonal
influenza
vaccinaMon
were
not
cross-‐
reacMve
with
novel
H1N1.
• What
if
the
T
cell
epitopes
were
cross-‐
reacMve?
Would
that
help?
Centers
for
Disease
Control
and
PrevenMon.
Serum
anMbody
response
to
a
novel
influenza
A
(H1N1)
virus
a_er
vaccinaMon
with
seasonal
influenza
vaccine.
MMWR
Morb
Mortal
Wkly
Rep
2009;58(19):521–4.
9. Second
Exposure
Response
if
Exposure
or
Related
or
strain
is
VaccinaMon
Unrelated
Strain
idenMcal.
.
.
Or
if
cross-‐reacMve
.
.
.
if
no
T
cell
epitopes
cross-‐
reacMve
T
cell
response
IniMal
response
to
exposure
or
vaccinaMon
11. Iden?fied
immunogenic
and
conserved
Sequences
–
Predicted
Cross
Protec?on
Immunogenic
Enough
Cross-‐
T cell protecMve
Epitopes
epitopes that
Seasonal
Flu
vaccinaMon
or
exposure
may
protect
Conserved
T-Cell
Epitopes
De Groot et al. Vaccine 2009;27:5740-7
12. Valida?on
that
cross-‐conserved
T
cell
epitopes
are
an?genic
“Immunized”
with
Brisbane
HA
whole
Flu
vaccine
-‐
Response
to
X-‐Conserved
T
cell
epitopes
HA394-411
0.09 0.034
No Ag
Culture Antigen
0.027
1.19 6.44
Brisbane HA
CD154
IFNγ
4.7
hVp://www.ncbi.nlm.nih.gov/pmc/arMcles/PMC3130614/
Schanen et al. Vaccine 2011;29:3299-309
17. What
about
Immunogenicity?
Vaccine
anMgen
epitope
epitope
epitope
1
+
1
+
1
=
Response
Immune
response
to
a
vaccine
anMgen
can
be
predicted
by
measuring
the
number
of
T
cell
epitopes
contained
in
the
anMgen
with
immunoinformaMcs
tools.
19. New
H7N9
Flu
is
Predicted
to
be
POORLY
IMMUNOGENIC
- 80 -
www.EpiVax.com
- 70 -
- 60 -
- 50 - Hemagglu?nin
- 40 -
A/Brisbane/59/2007(H1N1)
- 30 -
- 20 -
Neuraminidase
A/Perth/16/2009
(H3N2)
- 10 -
Average
Epitope
Content
- 00 - (Random
Expecta?on)
A/Brisbane/59/2007(H1N1)
- -10 - A/Shanghai/1/2013
(H7N9)
- -20 -
A/Perth/16/2009
(H3N2)
- -30 -
A/Shanghai/1/2013
(H7N9)
Immunogenicity
based
on
T
- -40 - helper
epitope
content
per
amino
- -50 - acid.
See
De
Groot
and
MarMn,
Clinical
Immunology,
2009
- -60 -
- -70 -
20. New
Case
in
Beijing
H7N9%Cases%and%Deaths%/%WHO%Report%
60# 70%#
50# 60%#
50%#
40#
40%#
30#
30%#
20#
20%#
10# 10%#
0# 0%#
#
#
#
#
#
r#
r#
r#
r#
r#
r#
r#
r#
GE
pr
pr
pr
pr
Ap
Ap
Ap
Ap
Ap
Ap
Ap
Ap
+A
+A
+A
+A
RA
1+
3+
4+
5+
6+
7+
8+
9+
10
11
12
13
E
AV
Total#Cases# Total#Deaths# New#Cases/Day# Mortality#Rate#
New
Case
in
Beijing
24. Fully
integrated
From
genome
to
vaccine
• EpiMatrix – maps T cell epitopes
• ClustiMer - Promiscuous / Supertype Epitopes
Seamless
Vaccine
• BlastiMer - Avoiding “self” - autoimmunity
Design
• Conservatrix – Identifies Conserved Segments
Integrated
toolkit
is
• EpiAssembler - Immunogenic Consensus Sequences
unique
to
iVax
• Aggregatrix – Optimizing the coverage of vaccines
• VaxCAD - Processing and Assembly
24
25. A
beber/faster
way
to
make
flu
vaccine?
BeVer
understanding
of
vaccine
MOA
Egg-‐based/Cell
Genome-‐
Whole
(live/ Culture
Based
Derived,
Epitope
killed)
flu
Whole
Ag
(HA)
Driven
(GD-‐ED)
vaccines
vaccines
Vaccines
Improve
vaccine
safety
and
efficacy
Accelerate
Vaccine
Design
Genome-‐derived
Epitope-‐driven
Influenza
Vaccines
(R21
/
NIAID
/
NIH
26. T
cells
=
Immune
System
Body
Armor
T
cell
response
cannot
prevent
InfecMon
but
.
.
.
T
cell
response
can
arm
against
Disease
27. FastVax: Vaccines on demand
Rapid
deployment
when
genome
sequence
is
in
hand
• High throughput computing This
can
be
• Immunoinformatics prebuilt!!
• Vaccine design algorithms
• Vaccine Production
• Delivery device Pilot
program
Funded
by
DARPA
• Animal safety/tox/immunogenicity/validation
• Deployment by established distribution systems
27
28. 20
hours
-‐
April
05
–
April
06
2013
Extremely
Rapid
H7N9
Vaccine
Design
April
05,
2013:
Obtain
H7N9
Sequences
(4
human-‐sourced;
GISAID)
Obtain
all
available
H7N9
sequences
EpiMatrix
Analysis:
IdenMficaMon
of
H7N9
Class
I
and
Class
II
Epitopes
Compare
with
previous
epitopes
(IEDB)
And
other
H7N9
strains;
create
final
list
20
hours
(Logged).
101
H7N9
ICS*
Class
II
Epitopes
+
586
Class
I
Epitopes
Eliminate
Epitopes
highly
conserved
with
Human
Design
vaccine:
12
hours
(Logged).
April
06,
2013:
H7N9
Vaccine:
Two
Constructs,
Class
I
and
Class
II
29. Predic?ng
Epitopes
that
Drive
Immune
Response
is
our
Exper?se
HLA (Human MHC), are comprised of
MHC II Pocket a limited number of pockets.
EpiMatrix predicts how well a side
chain will bind to a specific pocket.
MHC II Peptide
Epitope 8 class II Archetype matrices which
taken together incorporate 95% of
human populations (and pockets)
Mature worldwide.
APC
Each 9-mer/10-mer is analyzed for
binding potential to each of those 8
allele matrices.
The
EpiMatrix
Score
describes
how
well
.
Southwood et al. J. Immunology 1998 the
pepMde
“fits”
into
the
pockets
Sturniolo et al. Nature Biotechnology, 1999
EpiVax
30. Published
Benchmark
2009
De
Groot
and
MarMn.
Reducing
risk,
improving
outcomes:
Bioengineering
less
immunogenic
protein
therapeuMcs.
Clinical
Immunology
2009.
131,
189-‐201.
31. Epitope
Clusters
=
Immunogenic
• A Key Discovery – Epitopes are Clustered in Protein Sequences
DRB1*0101
DRB1*0301
DRB1*0401
DRB1*0701
DRB1*0801
DRB1*1101
DRB1*1301
DRB1*1501
• T-cell epitope clusters make excellent vaccine candidates:
– compact; relatively easy to deliver as peptides; highly reactive in-vivo
31
32. Building
ICSs
EpiAssembler
–
Final
Immunogenic
Consensus
Sequence
STRAIN 01 Q X S W P K V E Q F W A K H X W N X I S X I Q Y L
STRAIN 02 Q A S W P K V E X F W A K H M W N F I S G I Q Y L
STRAIN 03 Q X S W P K X E Q F W A K H M W N F I S G I Q Y X
STRAIN 04 Q A S W X K V E Q F W A K H M W N F X S X I Q Y L
STRAIN 05 Q X S W P K V E Q F W A K H M W N F I S G I Q Y L
STRAIN 06 Q A S W P K X E Q F W A X H M W N F I S G I Q Y X
STRAIN 07 Q X S W P K V E Q F W A K H M X N F I S G I Q Y L
STRAIN 08 Q A S W X K V E Q F W A K H M W N F I S G I Q Y L
STRAIN 09 Q X S W P K X E Q F W A K H M W N F X S X I X Y X
STRAIN 10 Q A S W P x
R V E Q F W A K H M W N F I X G I Q Y L
STRAIN 11 Q A S W P K V E Q F W A K H M W N F I S G I Q Y L
STRAIN 12 Q A S W X K V E Q F W A X H M W N F I S G I Q Y X
STRAIN 13 Q A S W P K V E Q F W A K H M W N F I S G I Q Y L
STRAIN 14 Q A S W X K X E Q F W A K H M W N F I S X I Q Y L
STRAIN 15 Q A S W P K V E X F W X K H M W N F I S G I Q Y L
STRAIN 16 Q X S W P K V E Q F W A K H M W N F I X G I Q Y L
STRAIN 17 X A S W X K V E Q F W A K H M W N F I S G I Q Y X
STRAIN 18 Q X S W P K X E Q F W A K H M W N X I S G I Q Y L
STRAIN 19 Q A S W X K V E Q F W A K H M W N F I S X I Q Y L
STRAIN 20 Q A S W P K V E Q F W A X H M W N F I S G I Q Y L
F W A K H M W N F
W P K V E Q F W A M W N F I S G I Q
Q A S W P K V E Q N F I S G I Q Y L
Q A S W P K V E Q F W A K H M W N F I S G I Q Y L
33. Building
ICSs
EpiAssembler
–
Final
Immunogenic
Consensus
Sequence
Balance
Score+Conserva?on:
Highest
conserved
epitopes
Selec?on
for
score
Best
Op?on
are
poorly
immunogenic
37. GD-‐IDV
FormulaMons
(plaporm
independent)
DNA
–
chain
of
epitopes,
or
ICS-‐opMmized
whole
proteins
ICS-‐opMmized
proteins
in
VLP
pepMde
in
liposomes
38. EpiVax
is
eager
to
help
• Seasoned
Research
Team
• Validated
Vaccine
Design
Tools
• H7N9
Analysis/Vaccine
design
complete
• Constructs
sent
for
producMon
• Other
services:
– Analyze
exisMng
H7
vaccines
for
conservaMon
– Advise
on
vaccine
design
EpiVax
Contacts:
Anthony
Marcello,
BDA,
amarcello@epivax.com
Anne
S.
De
Groot
CEO/CSO
annied@epivax.com
39. Ac?ve
Collaborators
/
Vaccines
Alan
Rothman
Bill
MarMn
Carey
Medin
Ted
Ross
Lenny
Moise
Andres
GuiMerrez
Frances
Terry
Danielle
Aguirre
Leslie
Cousens
Joe
Desrosiers
Ryan
Tassone
Thomas
Mather
Don
Drake,
Brian
Schanen
Howie
LaMmer
Wendy
Coy
David
Weiner
Mindy
Cote
Loren
Fast
Lauren
Levitz
ChrisMne
Boyle
Hardy
Kornfeld
Connie
Schmaljohn
Jinhee
Lee
Lesley
C.
Dupuy
Mark
Poznansky
Sharon
Frey
Tim
Brauns
Liisa
Selin
Mark
Buller
Pierre
LeBlanc
Jill
Schreiwer
40. EpiVax:
Four
Core
Strengths
Media
Contact:
Anthony
Marcello,
BDA,
amarcello@epivax.com
40
ConfidenMal