Adjuvant Systems for Vaccines From Concept To Clinical Evidence

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

3

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)

4

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

6

GSK Bio Adjuvant Systems at work:

Immunogenicity, efficacy

Malaria vaccine

Pandemic

Influenza vaccine

HIV vaccine

7

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

9

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

10

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

11

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

12

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

13

Pandemic Influenza vaccine

15

Pandemic Influenza vaccine

Vaccine Composition

Pandemic influenza vaccine

AS03GSK proprietary o/w

emulsionSplit prepandemic influenza strain

16

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

18

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

19

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

22

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

23

Conclusions

24

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)