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Developing New Vaccine Adiuvants
Rino Rappuoli
Summer School on Influenza
Siena August 3 2011
When you run out of ideas…
From Sclavo to Sabinexploiting innovation to solve medical needs
Achille Sclavo
1904 I.S.V.T.
Istitu
to S
iero
tera
pic
o e
Vaccin
og
en
o T
oscan
o
Albert
Sabin
2006
The slow path to the development of vaccine adjuvants
1910s1920s1930s1940s1950s1960s1970s1980s1990s2000s
Aluminium Salts MF59
Many potent vaccine adjuvants have failed, due to safety concerns
MF59 was a key innovation, first novel adjuvant in 70 years
Alum and MPL (AS04®) are the only adjuvants currently approved in US
Fluad® (influenza
Fendrix ® (HBV)
Cervarix® (HPV)
Prepandrix®
(pandemic influenza)
MPL+Alum (ASO4)Cervarix
The Slow Pace of Adjuvant Development
1886
1911
Rabies vaccine introduced
1998 TLR shown to be LPS target
2005 Fendrix approved in EU. First approval of vaccine containing TLR agonist
2009 Cervarix approved in U.S.A. First FDA approval of vaccine containing TLR agonist
1997 Imiquimod therapy approved
1996 Toll receptors linked to innate immunity
Innate Response Activators and Vaccine Development
Pertussis (Pw) vaccine introduced
Influenza (whole cell) vaccine introduced
IPV vaccine introduced
JE vaccine introduced
Hep-A vaccine introduced
Typhoid vaccine introduced
1921 BCG vaccine introduced
ssRNA: TLR7/8
LPS, DNA: TLR 2,4,9
ssRNA: TLR7/8
ssRNA: TLR7/8
ssRNA: TLR7/8
Lipoprotein, DNA: TLR 2,9
LPS, DNA: TLR 2,4,5,9
Vaccines containing TLR-
agonists have been used
since 1885
History of Emulsions
Lipovaccines
Water/Oil
Emulsion
Oil/Water
Emulsion
1916: Le Moignac, Pinoy
1919: Whitmore
1937: Freund
1952: Salk (Flu – 900K doses in
U.K.)
1997: Seppic Montanide
1975: Ribi
1999: Allison
Approval of Oil/Water
Emulsion Products
1997: MF59 Fluad
(Novartis)
20__: Fluarix (GSK)
Prepandrix (GSK)
Adjuvants for influenza vaccines, an old solutionHennessy A,V, and Davenport F,M; Pub. Health Repts 76, 411-419, 1961
Polyvalent vaccines Test strain and antibody response1
Swine PR8 PR301
Aqueous; aqueous
Before second dose
After second dose
30
179
29
512
102
307
Adjuvant; adjuvant
Before second dose
After second dose
242
1,229
141
1,741
768
1,818
• “Mineral oil adjuvant vaccine is remarkably effective for stimulating high,
broad, uniform, and persistent antibody levels against prototype strains of
influenza A”
• “A phenomenal economy can be affected in the requirement of antigen”
for clinical studies
Too many Adjuvants for preclinical studies
very few for clinical studies
MF59: An established adjuvant in aEuropean-licensed seasonal trivalent vaccine
Oil-in-water emulsion adjuvant licensed for use in seasonal influenza vaccine FLUAD* since 1997
• More than 100 million commercial doses distributed
Adjuvanted vaccine provides heterologous responses to drifted strains
>120 Clinical studies, >200,000 subjects
• No safety signals in either pharmacovigilance database or meta-analysis of clinical trial database with6 month subject follow-up (filed with CBER)
Pediatric studies and efficacy trial in3,000 subjects
MF59 adjuvant emulsion
SPAN 85 TWEEN 80Antigens
160nm
*FLUAD is a registered trademark of Novartis. FLUAD is not licensed in the Unites States. FLUAD is recommended for active prophylaxis of influenza in the elderly
oil
MF59 mechanism of action genes modulated by adjuvants at injection site
MF59 was the most potent activator of mouse transcriptome at injection site
All adjuvants tested modulate a common set of 168 “adjuvant core response genes”
Mosca et al. PNAS 2008
MF59 is a strong inducer of cytokines & cytokine receptor genes at injection site (mouse muscle)
Mosca et al. PNAS 2008
MF59 is a potent inducer of genes involved in leukocyte transendothelial migration at injection site
MF59 is the most potent
and rapid inducer of
Itgam/CD11b mRNA
Suggest a more rapid
recruitment of CD11b+
blood cells into the
muscle compared to CpG
and Alum Mosca et al. PNAS 2008
MF59 induces a rapid recruitmnent of CD11b+ blood cell injection site
Blue: Utrophin
Red: PI
Green: aCD11b
Mosca et al. PNAS 2008
Early reduction of macrophage and DCs in the muscle following MF59 injection
neutrophils
0
4000
8000
12000
n.t. MF59
cells
/ m
uscle
monocytes
0
100
200
300
400
n.t. MF59
cells
/ m
uscle
macrophages
0
1000
2000
3000
n.t. MF59
cells
/ m
uscle
mDC
0
200
400
600
n.t. MF59
cells
/ m
uscle
*
* *
Which cell type participates in adjuvant/antigen uptake and
transport?
1h
0
20000
40000
60000
80000
100000
120000
140000
0h 1h 3h 6h 16h 24h 48h 3d 5d 11d 20d 0h 3h 6h 24h 3d 5d 11d 20d
n.t. MF59
[# c
ells
]
neutrophilsinfl. monocyteseosinophilsmacrophagesmDCCD11blow DCCD11b neg DCTB
Non-treated muscle MF59-injected muscle
48h16h1h
Recruited cells/ muscle
Kinetic of cell recruitment induced by MF59 in mouse muscle
Neutrophil depletion does not affect recruitment of other
cell types and does not affect MF59 adjuvanticity
All CD11b+ cell types recruited in the muscle are MF59-Ag+
n.t. muscle MF59-DiO+OVA-AF647
DiO
OVA
DiO
OVA
23.8 58.6
16.8 0.8
5.1 4.0
90.6 0.2
CD11b- CD11b+CD11b- CD11b+
OVA-AF647
eosinophils macrophagesmonocytes mDCneutrophils
24h
OVA+ APC in the muscle found until 3 days post injection
MF59 promotes OVA uptake in LNs more efficiently than alum
0
500
1000
1500
2000
2500
treated untreated treated untreated treated untreated
MF59+OVA-AF647 alum+OVA-AF647 OVA-AF647
po
sit
ive c
ells p
er
10E
6 c
ells
OVA-positive cells
pos B cells
pos mDCs
pos CD11b low DCs
pos monocytes
pos neutrophils
pos pDCs
pos CD8+ DCs
24hOVA-AF647
OVA-AF647+Alum
OVA-AF647+MF59
Right Quadriceps
Right
Inguinal LNLeft
Inguinal LN
OVA positive cells
TREATED UNTREATED
Oil:
4.3% Squalene
Naturally present in human: component of cell membrane and synthetic
precursor of cholesterol
Surfactants:
0.5% Tween 80 (water-soluble)
0.5% Span 85 (oil-soluble)
Commonly used in other licensed pharmaceutical products
Water for injection
10 mM Na-citrate bufferH2O
H2O
OIL
H2OH2OH2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
MF59 oil-in-water emulsion adjuvantprogress on mechanism of action
- Squalene or surfactants alone no adjuvant activity
- does not signal via inflammasome
- does not signal via TLR
- requires MyD88
Complete MF59 emulsion is required for adjuvanticity
To
tal Ig
G t
ite
rs
Oil:
4.3% Squalene
Surfactants:
0.5% Polysorbate 8
0.5% Sorbitan Triolate
10 mM Na-citrate buffer
Which MF59 component has immunostimulatory activity?
H2O
H2O
OIL
H2OH2OH2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
0
20000
40000
60000
Singlets
0
10000
20000
30000
Neutrophils
0
200
400
600
800
1000
DC
0
2000
4000
6000
8000
Monocytes
0
200
400
600
800
Eosinophils
0
20
40
60
80
Macrophages
+OVA-A647 +OVA-A647 +OVA-A647
Num
ber
of
cells
Only complete MF59 emulsion induces cell migration events in mouse muscle
6h
MF59 Surfact. Squalene Citrate untreated
OVA-A647
SS
Cmo
DCs
0
5000
10000
15000
20000
25000
30000
35000
0
50000
100000
150000
200000
250000
MF
59
Su
rfa
c.
Squale
ne
Citra
te
Un
tre
ate
d
OV
A-
MF
I
Monocytes
DCs
Only complete MF59 emulsion increase OVA uptake by monocytes at injection site
OVA –A647
OVA –A647
6h
MF
I
CD14 MHC class II CD86
MF
59
Span
+
Tw
een
Squa
lene
Citra
te
buffer
FSC
SS
C
MF
59
Span
+
Tw
een
Squa
lene
Citra
te
buffer
MF
59
Span
+
Tw
een
Squa
lene
Citra
te
buffer
MF59 Surfactants Squalene Citrate untreated
Only complete MF59 emulsion changes morphology and differentiation state of human monocytes in vitro
Mouse BMDC
MF59 does not activate Nalp3 in vitro in LPS primed BMDC
or PBMCs
MF59 does not activate Nalp3 in vitro
38
28
17
Adjuvant: - Alum 400 ug/ml
LPS:
MF59 1:100 MF59 1:1000
Pro-IL1b
IL1b
10/ 1/ 0.1 ng/ml
0
500
1000
1500
2000
2500
3000
w/o 400 40 1:10 1:100 1:1000
Alum MF59
[pg
/ml]
IL-1b
LPS 10 ng/ml
LPS 1 ng/ml
LPS 0.1 ng/ml
w/o
0
100
200
300
400
500
600
700
alum MF59 alum MF59
wt Nalp3-/-
[pg
/ml]
IL-1b
Human PBMCsMouse BMDC
LPS alone
LPS + adjuvant
MF59 adjuvanticity is Nalp3-independent
WT and Nalp3 KO mice have been imunized i.p. with 3 MenB antigens alone or
adjuvanted with alum, MF59 and CFA
Cell recruitment and cytokine production in the peritoneum are not affected in Nalp3 KO
Adjuvanticity to three different MenB Ags is Nalp3-independent (IgG and BCA titers)
Nalp3 mutation affects the response to all non-adjuvanted antigens in the plain vaccine
10
100
1000
10000
100000
0h 4h
cells/
10E
6
macrophages MenB wt
MenB Nalp3-/-
MenB+alum wt
MenB+alum Nalp3-/-
MenB+MF59 wt
MenB+MF59 Nalp3-/-MenB+CFA wt
MenB+CFA Nalp3-/-
plain wt
Nalp3-/-
alumwt
Nalp3-/-
MF59wt
Nalp3-/-
CFAwt
Nalp3-/-10
100
1000
10000
0h 24h
cells
/ 1
0E6
monocytes
*
* P<0,05
** P<0,01
IgG against MenB 287-953
3
3.5
4
4.5
5
5.5
6
6.5
7
wt Nalp3-/- wt Nalp3-/- wt Nalp3-/- wt Nalp3-/-
plain alum MF59 CFA
GM
T
******
MF59 is not a TLR Agonist in Vitro
MF59-adjuvanticity depends on the adaptor molecule MyD88
3
4
5
6
7
wt
MyD
88-/
-
wt
MyD
88-/
-
wt
MyD
88-/
-
wt
MyD
88-/
-
-- Alum MF59 CFA
Log10 titers
********
a-FH-BP (total IgG)
WT
MyD
88-/
-
WT
MyD
88-
/-
WT
MyD
88-
/-
WT
MyD
88-
/-
Alum MF59 CFA--
1
2
3
4
5
6
wt
MyD
88-/
-
wt
MyD
88-/
-
wt
MyD
88-/
-
wt
MyD
88-/
-
-- Alum MF59 CFA
Log10 titers
*******
a-NadA (total IgG)
WT
MyD
88-/
-
WT
MyD
88-
/-
WT
MyD
88-
/-
WT
MyD
88-
/-
Alum MF59 CFA--
A
3
4
5
6
7w
t
MyD
88-/
-
wt
MyD
88-/
-
wt
MyD
88-/
-
wt
MyD
88-/
-
-- Alum MF59 CFA
Log10 titers
********
a-NHBA (total IgG)
WT
MyD
88-/
-
WT
MyD
88-
/-
WT
MyD
88-
/-
WT
MyD
88-
/-
Alum MF59 CFA--
vaccinate (i.p.)
210 49 serum35Day:
AS059
8 C57B6 WT or KO/group
14
Seubert et al. PNAS 2011
Signaling pathways required for MF59 action
IL-1R IL-18R ST2/IL1R AcP
DAMPs(damage-associated
molecular patterns)
Pro-caspase-
1
Caspase-1
MyD88
PAMPs(pathogen-associated
molecular patterns)
IL-18
Asc
Nlrp3
crystals, lysosomal
damage, ROS,....
B cell
APC, epithelial cells,...
Target cells:
T, B, NK, MPh,....
TACI
IL-1β
TLR
H2O
H2O
OIL
H2OH2OH2O
H2O
H2OH2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
Release of
endogenous
TLR
agonists?
MF59
MyD88MyD88
Pro-IL-
18IL-18
Pro-IL-
1βIL-1β
IL-
33
IL-33
MyD88
NF-κB
The MF59 adjuvant
makes the old
immune system to
behave like a young
one !!!!
young
old + MF59old
Preclinical studies show that MF59 nanoparticles are the strongest adjuvant for subunit flu vaccine
0
500
1000
1500
2000
2500
3000
Se
um
HI
tite
rs
post-1 post-2
H3N2
0
200
400
600
800
post-1 post-2
H1N1
PLGCAPCpG
MF59Alumnil
0
50
100
150
200
250
300
350
post-1 post-2
B
FCC given at 0.1 micrograms/dose
Se
rum
HI a
ntib
od
y tite
rs
FLUAD Immunogenicity Meta-Analysis - All Subjects
Superior Immune Response Against Conventional Vaccines
0.0
0.5
1.0
1.5
2.0
3.0
5.0
B A/H3N2 A/H1N1
FLUAD/Comparator Post-Immunization GMT Ratio
1st immunisation
2st immunisation
3st immunisation
Fluad® safety meta-analysis: no severe reactions
0%
10%
20%
30%
40%
50%
Pa
in
Ery
the
ma
Ind
ura
tio
n
Ma
lais
e
He
ad
ac
he
My
alg
ia
Fe
ve
r (>
=3
8°C
)
Pa
in
Ery
the
ma
Ind
ura
tio
n
Ma
lais
e
He
ad
ac
he
My
alg
ia
Fe
ve
r (>
=3
8°C
)
Control Severe
Reaction (n= 1437)
Control Mild/Mod.
Reaction (n= 1437)
FLUAD Severe
Reaction (n= 2112)
FLUAD Mild/Mod.
Reaction (n= 2112)
Podda, Vaccine 19: 2673-80, 2001
Enhancement of adjuvant effect in elderly with low pre-immunization titer
0%
5%
10%
15%
20%
Rela
tive incre
ase in %
with 4
-fold
incre
ase
B A/H3N2 A/H1N1
Pretiter <=20
Pretiter>40
0%
5%
10%
15%
20%
Rela
tive incre
ase in %
with H
I T
itre
>=
160
B A/H3N2 A/H1N1
A) Proportion of subjects with 4-fold
increase or seroconversion
B) Proportion of subjects
with HI Titre >= 160
** **
**
**
**
** Pretiter 20 vs Pretiter >40, P<0.01
MF59-adjuvanted vaccine in childrenSeroprotection rates after one and two doses
H3N2 H1N1 B
0
10
20
30
40
50
60
70
80
90
100
0
10
20
30
40
50
60
70
80
90
100
0
10
20
30
40
50
60
70
80
90
100
%%
%
DAY 1 DAY 1 DAY 1DAY 29 DAY 29 DAY 29 DAY 50DAY 50DAY 50
0
10
20
30
40
50
60
70
80
90
100
0
10
20
30
40
50
60
70
80
90
100
0
10
20
30
40
50
60
70
80
90
100
0
10
20
30
40
50
60
70
80
90
100
0
10
20
30
40
50
60
70
80
90
100
%%
%
DAY 1 DAY 1 DAY 1DAY 29 DAY 29 DAY 29 DAY 50DAY 50DAY 50
FLUAD
Vaxigrip
The risk of subjects ≥65 years of age developing an unsolicited reaction was similar for MF59- and non-adjuvanted vaccinesGreen indicates statistical evidence of a decreased risk with MF59-adjuvanted vaccine;
red indicates statistical evidence of an increased risk with MF59-adjuvanted vaccine. Significance claimed if 95% CI excluded 1.
* Compared to non-adjuvanted vaccine; † includes or ‡ excludes study V7P35 (ClinicalTrials.gov Identifier: NCT00481065).
Risk ratio: risk of developing a disease after exposure to a vaccine.
Pellegrini M. et al. Vaccine 2009; 27:6959–6965.
Relative risk of adverse events following vaccination with MF59-adjuvanted or non-adjuvanted vaccines
Pooled analysis of 38 randomized, controlled influenza trials, subjects ≥65 years of age
1.0 1.2 1.4 1.6 1.8 2.00.0 0.2 0.4 0.6 0.8
All unsolicited adverse events‡
Including:
Solicited local reactions
• Cardiovascular diseases‡
• New onset of chronic diseases§
• Deaths§
• Serious adverse events§
• Hospitalizations§
Solicited systemic reactions
Lower risk with
MF59-adjuvanted*
Higher risk with
MF59-adjuvanted*
Risk ratios
MF59-adjuvanted vaccine is safe in children (6-36 mo-old)Summary of Post-injection Reactogenicity After Any Vaccination
0% 10% 20% 30% 40% 50%
ECCHYMOSIS
ERYTHEMA
INDURATION
SWELLING
TENDERNESS
CHANGE IN HABITS
SLEEPINESS
UNUSUAL CRYING
IRRITABILITY
VOMITING
DIARRHEA
FEVER
P=0.033
Local and systemic reactions were mild or moderate and transient, and comparable to those induced by the
control vaccine with the exception of site injection swelling (12% vs 5% p=0.033).
90
178
0
20
40
60
80
100
120
140
160
180
GMTs
90
178
0
20
40
60
80
100
120
140
160
180
GMTs
FLUAD
Vaxigrip
Priming with H5N3
In 2006 we vaccinated with clade 1 H5N1 vaccine those people that had been vaccinated with clade 0 H5N1 in 1999
1
10
100
1000
10000Homologous H5N1 –
Clade 1
Heterologous H5N1 –
Clade 2.2
Heterologous H5N1 –
Clade 2.3
Heterologous H5N1 –
Clade 2.1
Days
Boost with H5N1
clade 1 with MF59
6-8
years
Months
Protective
titer (1:40)
With MF59
w/o MF59
By day 7 post-boost most of
subjects have already
protective neutralizing
antibody titers against all
virus strains
Priming with H5N3
Memory T cells are induced first Memory B cells are more abundant following adjuvant priming
1
10
100
1000
10000Homologous H5N1 –
Clade 1
Heterologous H5N1 –
Clade 2.2
Heterologous H5N1 –
Clade 2.3
Heterologous H5N1 –
Clade 2.1
Days
Boost with H5N1
clade 1 with MF59
6-8
years
Months
Protective
titer (1:40)
With MF59
w/o MF59
0
100
200
300
400
500
Pre Post-1 Post-2
Mean IL-2+/ IFN-- cells (x 10 6)
MF59 / 15 ug
MF59 / 7.5 ug
nil / 15 ug
Mean T
cells
x 1
06
0
5
10
15
20
25
30
p<0.05
n=17
day 22
n=6 n=7
p<0.05
plain-H5N3 primed
unprimed
MF59-H5N3 primed
Vaccination with adjuvant: more CD4+ T cells, more
antibodies....... a different game
Non-Adj-15
MF59-7.5
MF59-15
10
100
1000
1 22 130 202 223 38243
A/V
N/1
11
94
/04
MN
-G
MT
*
*
*
*
*
1:40
Galli et al, Proc Natl Acad Sci USA 2009
H5-C
D4
+(i
n 1
06
tot
CD
4)
days
*
0
250
500
750
1000
1 22 130 202 223 38243
* *
*
0
5
10
15
20
0 22 43 2020
5
10
15
20
0 22 43 2020
5
10
15
20
0 22 43 202
MF59-H5N3 primedH5N3 primedUnprimed
Memory B cells are present only in those primed with
adjuvanted H5N1vaccine
1.20.80.7
12
3.6
2.4
3.63.0 3.6
2.9
9.2
4.1
Galli et al, Proc Natl Acad Sci USA 106 (19): 7962-7967, 2009
Pe
rce
nta
ge
of
me
mo
ry B
ce
lls
Adjiuvant
No adjuvant Protective titer
It is all about Memory
CD4 T cells
Memory B cells
Antibody titer
MF59 works against drifetd viruses Fujan example
Immunogenicity (haemagglutination inhibiting antibody titers) of 3 Chiron Vaccines
inactivated influenza vaccines against H3N2 homologous vaccine strain (A/Panama) and
against H3N2 heterovariant strain (A/Wyoming)
Agrippal™ subunit
vaccine
(n = 29)
Begrivac™ split
vaccine
(n = 30)
Fluad™ adjuvanted
subunit vaccine (n =
30)
A/Panama
(H3N2)
A/Wyoming@
(H3N2)
A/Panama
(H3N2)
A/Wyoming
(H3N2)
A/Panama
(H3N2)
A/Wyoming
(H3N2)
Pre-
vaccination
GMT 95% CI
87.2 56.4-
134.8
52 31.9-85
48.1 32.8-70.6
20.3 13.9-29.6
65.2 42.2-
100.9
40.2 25.5-63.1
Seroprotection
rate§ No/Total (%)
23/29 (79.3%)
19/29 (65.5%)
22/30 (73.3%)
11/30 (36.7%)
21/30 (70%)
16/30 (53.3%)
Post-
vaccination
GMT 95% CI
174 1118.3-
255.9
122.3 77.3-193.6
141.2 100.4-
198.5
82.2 52.6-128.5
248.7 177.5-
348.5
176.9 122.6-
255.3
Seroprotection
rate§ No/Total (%)
28/29 (96.5%)
22/29 (75.9%)
29/30 (96.7%)
24/30 (80%)
30/30
(100%)
30/30
(100%)
§ Seroprotection rate: proportion of subjects with a protective HI titre 40
@ A/Wyoming /3/2003 is an A/Fujian/411/2002-like strain.
* GMR: geometrical mean ratio (post-vaccination GMT / pre-vaccination GMT)
Efficacy in the elderly 10-year study, 713,872 person-seasons, average age 73
MF 59 can address low vaccine
efficacy due to antigenic drift
Influenza Vaccines
past futuretoday
From June to December 20093 H1N1 vaccines were:
Developed
Tested in clinical trials
Licensed
180 million doses produced
The race to make vaccines
The Infleunza Hemagglutinin
Structure of the antibody binding site on the stem of HA
F16, a truly universal antibody against influenza
F16 recognizes a flat surface on the stem of HA
5-15 mg/Kg of F 16 are necessary for protection
MF59 induces a more broad recognition of H5N1 epitopes covering neutralizing regions of HA
Data obtained through a
CRADA with Hana Golding
CBER Khurana et al. Sci Trans. Med. 2010
Toll-like receptor (TLRs) recognize microbial structures
TLRs on the plasma
membrane recognize
bacterial products
TLRs in the endosome
recognize microbial nucleic
acids
TLRs trigger different
signal transduction pathways
TLRs are differentially
expressed in immune cells
All TLRs are
validated targets for
vaccine adjuvants.
Adjuvant
development
Lead candidates
for advancement
In vitro
HitsConfirmed
hits
Secondary
screens
Novel
adjuvant
candidates
Formulation
and
delivery
In vivo
In vivo
immunogenicity
evaluation
TLR
Screens
Focused or
diverse
libraries
Hit to lead
optimization
Structure
activity
assessment
Adjuvant Discovery: High Throughput Screening for Small Molecule Immune Potentiators (SMIPs)
TLR7 agonists enhances breadth of antibody response in mice against Men B (>MF59)
Alu
m M
enB
Alu
m M
enB 1
/4 O
MV
MF59
Alu
m M
enB IC
31
Super
Alu
m M
enB
0
20
40
60
80
100
perc
en
tag
e o
f co
vera
ge
Percent coverage (15 MenB strains) for serum
bactericidal titers greater than 4096
TLR7 agonist
Picking the WinnersDefining the optimal PK/PD profile for adjuvant safety and efficacy
0
500
1000
1500
2000
2500
base SMIP-1 SMIP-2 SMIP-3
SB
A T
ite
rs
0
25
50
75
100
SMIP-1 SMIP-2 SMIP-3
% c
yto
kin
e r
ele
ase
re
lative
to
R8
48
(2
5u
g)
IFNg
IL-12t
IL-6
IL-10
TNFa
Peak CytokinesSBA titer level of Mice dosed IM
with 3MenB antigen + SMIP
Wasted Inflammation!
Clinical correlate for protection (titer ≥ 1024)
Systemic exposure is detrimental to efficacy
Adjuvant ( MF59 )
Toll-like receptors ( TLRs )
Acknowledgement (II)The SMIP Team
Immunology
Andy Miller
Ann Herman
Alejandra Rocha
Bill Wacknov
Bishnu Nayak
Christophe Filippi
De Shon Hall
Janice Hampton
Jillian Rojek
Joe Cahiwat
Jonathan Deane
Kelly-Anne Masterman
Laura Boase
Maureen Ibanez
Michael Cooke
Peggy Hedden
Tamar Tomassian
Tami Annable
Chemistry
Alex Cortez
Allan Pan
Chun Li (DMPK)
Kathy Yue
Michael Shapiro (DMPK)
Porino Va
Tim Hoffman
Tom Wu
Xiaoyue Zhang
Xuebin Liao
Yefen Zou
Yongkai Li
Protein expression
Mark Knuth
Sarah Cox
Benjamin Bohl
DMP
Greg Michaud
John Tallarico
Joshua Schustak
Qian Huang
Xinming Cai
Lisa Welch
Rekha Panchal
Sina Bavari
Travis Warren
Immunology
Anne-Marie Pulichino
Alessandro Muzzi
Carla Russo
Carlo Iavarone
Christine Dong Lee
Christine Shaw
Diego Piccioli
Elaine Tritto
Elena Caproni
Elisabetta Monaci
Elisabetta Soldaini
Ennio De Gregorio
Flaviana Mosca
Gillis Otten
Igor Leykin
Jason Debasitis
Lamine Mbow
Mary Schaefer
Michaela Brazzoli
Nick Valiante
Rocco Cantisani
Sara Valentini
Susanna Aprea
Ugo D’Oro
Valerie Pasquetto
Genomics
Loren Miraglia
Raquel Vega
Richard Glynne
Jody Puglisi
Tinghe Wu
Ana Avalos
Hidde Ploegh
5
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