Download - Development of the ASO Adjuvant series
2
GSK Biologicals vaccine design principle
Vaccine
Antigen Adjuvant
Specificity of the immune
response
ADJUVANT SYSTEMS
Combination of different adjuvants to allow tailoring of the immune response to
achieve enhanced and sustained protection
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Adjuvant approach
New adjuvants need to induce a response:–
Tailored to the pathogens or pathogenesis
–
Tailored to the populations
Only the right match of protective Antigen(s) and Adjuvant
System can help to mobilize the effective immunological pathways to enable enhanced and sustained protection
Two critical concepts
AS04
AS03
AS02
AS01AS15
HPV, HBV, HSV
(pre) pandemic
Influenza
Malaria
Malaria, TB, HIV
Antigen-Specific
Cancer Immunotherapy
(ASCI)
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GSK Biologicals Adjuvant Systems
Tailored combinations of two or more immuno- enhancers: aluminum salts, o/w
emulsion, liposome,
MPL, QS21, CpG, α-tocopherol
MPL QS21
Principle
CpG
α-tocopherol
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GSK Bio Adjuvant Systems at work:
Immunogenicity, efficacy
Malaria vaccine
Pandemic
Influenza vaccine
HIV vaccine
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Malaria vaccine
Vaccine composition
RTS,S malaria vaccine candidate
Adjuvant System 02 (AS02)
ImmunoenhancersMPLQS21
Proprietaryo/w
emulsion
HBsAg
HBsAg
R T S
+ S
RTS,S Particle
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Malaria vaccine
Proof of concept in human
Similar antibody responses in o/w-based Adjuvant SystemsIncreased frequency of IFN-γ responders with AS02Cellular response is associated with protective efficacy
Stoute et al. NEJM 1997, 336: 86–91
P<0.02
lgG
Ant
ibod
y (μ
g/m
l)
0 14Day of Study
0.1
1
10
100
P<0.02
IgG CS Repeats
30 44 150 194 220
RTS,S/AS02RTS,S/AS03
RTS,S/AS04
RTS,S/AS04 RTS,S/AS03 RTS,S/AS02
Pre
Post
Subjects
Num
ber o
f ELI
SPO
Ts/1
06ce
ll s20
00
400
600
Sun et al. J Immunol 2003, 171: 6961-7
CMI (IFN-γ
Elispot) Protected
Unprotected
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Malaria vaccine
Can we improve vaccine efficacy through alternative formulation ?
AS01: MPL, QS21, liposome based Adjuvant System
RTS,S/AS01
is
promising in preclinical immunogenicity studies in mice and in monkeys
Phase I/IIa
challenge study to compare safety, immunogenicity and efficacy of RTS,S/AS02 vs
RTS,S/AS01
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Malaria
Can we improve vaccine efficacy through alternative formulation ?
Kester et al. manuscript in preparation
p = 0.008
0
50
100
150
200
250
300
Pre M1 M2 DOC Pre M1 M2 DOC
GM
C (µ
g/m
l), 9
5% C
I
RTS,S/AS02 RTS,S/AS01
0
200
400
600
800
1000
1200
1400
1600
Pre Post II DOC Pre Post II DOC
dCD
4+ T
cel
ls/m
illio
n C
D4
+ T
cells
Q3
Median
Q1
p = 0.07
RTS,S/AS02 RTS,S/AS01
IgG CS Repeats Double pos. CD4+
cells for CD40L, IL2, TNF-α, or IFN-γ
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Malaria
Can we improve vaccine efficacy through alternative formulation ?
Protected Infected VE
RTS,S/AS02 14 30 32%
(95% CI: 20; 47)
RTS,S/AS01 18 18 50%
(95% CI: 35; 66)
VE AS01 vs
VE AS02: p = 0.11
RTS,S/AS01 being
introduced into the clinical development plan
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Pandemic Influenza vaccine
Vaccine Composition
Pandemic influenza vaccine
AS03GSK proprietary o/w
emulsionSplit prepandemic influenza strain
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Pandemic/Prepandemic Influenza vaccine
1.Leroux-Roels et al. Lancet 2007 ; 370: 580-892.Leroux-Roels et al. International Conference on Avian Influenza, Bangkok, Thailand, 23–25 Jan 2008.3.Leroux-Roels et al. PLoS One 2008; 3: e1665 (doi:10.1371/journal.pone.0001665)
All CHMP criteria were metAdjuvantation confers
antigen-sparing
Vaccinated cohort = 50 per group
A/Vietnam/1194/04Clade 1
Homologous immune response1,2
0
20
40
60
80
100
SCR
(%)
3.75 µg
7.5 µg 3.75 µg AS03
7.5 µgAS03
Split H5N1HA
Day 21
Day 180Day 42Neutralizing antibodies –Seroconversion rate (%)
induces a broad and persistent cross-reactive humoral immunity against several substantially drifted clade 2
strains
0
20
40
60
80
100
SCR
(%)
20 subjects
per group
3.75µg 3.75µgAS03
3.75µg 3.75µgAS03
3.75µg 3.75µgAS03
A/Indonesia/5/05Clade 2.1
A/turkey/Turkey/1/05Clade 2.2
A/Anhui/1/05Clade 2.3
Cross-reactive (heterologous) immune response3
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GSK Biologicals’
HIV vaccine candidate F4/AS01
Antigen F4–
Recombinant fusion protein
–
Expressed in E. coli–
Consisting of p24-RT-Nef-p17
Adjuvant System AS01GSK Biologicals’
proprietary liposome-based Adjuvant System containing
–
QS21: Quillaja
Saponaria
Molina, fraction 21
(Antigenics, New York, NY, USA)
–
MPL: 3-O-desacyl-4’-
monophosphoryl
lipid A
Vaccine Composition
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CD4+
T cell
response
to fusion protein
F4
•
Very high frequency and persistence of specific CD4+
T cells•
Highest responses induced by the 10 µg F4/AS01 dose (p < 0.0001 at 2 weeks post dose II)
•
Very low responses observed in non-adjuvanted groups
% C
D4+
T ce
lls e
xpre
ssin
g IL
-2
and
at le
ast a
noth
er m
arke
r(m
edia
n)
10 30 90 10 30 90 10 30 90 10 30 900.0
0.5
1.0
1.5
2.0
3.0
4.0 Pre 2 weeks post II
Max
Min
Q1
Q3
Median
Water AS01 Water AS01
Dose of F4 (µg) Time (days)
0 50 100 150 200 250 300 3500.0
0.2
0.4
0.6
0.8
1.0
1.2
10 µg F4/AS0130 µg F4/AS0190 µg F4/AS01
21
10 µg F4/AS01
group
%*
Month
6 Month
12
1.42 0.580.650.95
1 Cytokine2 Cytokines3 Cytokines
* Sum
of % CD4+CD40L+
T cells
expressing
1, 2, or 3 cytokines (means)
Cytokine co-expression profile of F4-specific CD4+CD40L+
T cells
•
Cytokine co-expression profile maintained
up to month
12
2 weekspost II
1 monthpost II
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Study
conclusions
F4/AS01-adjuvanted HIV vaccine candidate exhibited
an acceptable safety
and reactogenicity profile in HIV-
seronegative
volunteers
High F4-specific CD4+ T cell
responses
induced
by F4/AS01-adjuvanted HIV vaccine candidate, no CD8+
T
cells
detected−
CD4+ T cell
responses
only
in adjuvanted groups
−
High responder
rates and elevated
frequencies
against
the four antigens
−
Polyfunctional
profile and good
persistence
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Adjuvant approach
New adjuvants need to induce a response:–
Tailored to the pathogens or pathogenesis
–
Tailored to the populations
Only the right match of protective Antigen(s) and Adjuvant
System can help to mobilize the effective immunological pathways to enable enhanced and sustained protection
Two critical concepts
AS04
AS03
AS02
AS01AS15
HPV, HBV, HSV
(pre) pandemic
Influenza
Malaria
Malaria, TB, HIV
Antigen-Specific
Cancer Immunotherapy
(ASCI)