ID93/GLA-SE TB Vaccine Candidate
TB Vaccines Global Forum
Cape Town, 26 March 2013
CONFIDENTIAL
1
ID93 – Stable Emulsion (SE)
100 nm oil droplets stabilized by emulsifiers in a bulk aqueous phase
- Manufactured by high-shear homogenization
- Pre-formed emulsion added to antigen before injection
-Antigen or additional immunostimulant may be localized in oil phase, aqueous
phase, or at the interface
ID93
Emulsion components
Oil :
squalene
Emulsifier:
phosphatidylcholine
Cosurfactant:
Pluronic F68
Isotonicity
agent:
glycerol
buffer:
ammonium
phosphate, pH 5.1
Rv3619 Rv1813 Rv3620
Rv2608
Pluronic F68
squalene
oil
droplet
phosphatidylcholine
2
3
Enabling Roles of Adjuvants
T cell vaccines
Antibody Response Broadening
Antigen Dose Sparing
Immune Response Durability
Vaccine Dosage Sparing
Immune Senescence
Vaccine Therapy
CONFIDENTIAL
4
Adjuvant Platforms in Approved
Vaccines
– Alum
• Alum alone
• Alum/MPL (AS04)
– Emulsions
• MF59, AF03
– Virosomes
– (Liposomes..coming soon?)
CONFIDENTIAL
5
ID93-virosome particle architecture
Neuraminidase
Hemagglutinin
GLA integrated into bilayer
ID93 is anchored in virosome
membrane via lipid anchor
The integration occurs at the time
of particle assembly
6
Adjuvants in TB Vaccine
Candidates
AS01 (M72); MPL, QS21, Liposomal (TLR4)
CAF01 (H1) Liposome
IC31 (H1,H56,H4) (TLR9)
GLA-SE (ID93) (TLR4)
CONFIDENTIAL
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Next Generation Adjuvant: GLA
GLA Based; Synthetic TLR 4 Agonist
Proven Mechanism of Action: Based on MPL
Several Formulations Have Been Prepared
Clinical Stage (Five Trials Completed; Six More in Progress)
Scaled Production, Low COG
CONFIDENTIAL
8
Rational Design of TLR 4 Ligands
PO4 interfaces
with TLR-4
chain 1
Acyl interface
with TLR-4
chain 2
Synthetic TLR-4 agonist
Lipid
“sandwich” in
MD2
CONFIDENTIAL
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Optimizing Adjuvant Activity
CONFIDENTIAL
10
Increased Purity= Increased
Potency
CONFIDENTIAL
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TLR4 Agonists: Designer
Adjuvants
CONFIDENTIAL
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Significance of GLA Purity,
Potency
Lowest Doses of Any TLR Agonist in Clinic (5ug or less)
Favorable COG
CONFIDENTIAL
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TLR Agonist to Adjuvant
Micelle
• Nanomicellar GLA
Emulsified
• GLA-SE
Small
Particle
• GLA/Alum
CONFIDENTIAL
Liposome
• GLA-LI
14
Adjuvant Formulation Library
GLA
•
•
•
•
•
Aqueous suspension
Alum-adsorbed
Liposome
Niosome
Emulsion
•
•
R848
•
•
•
Aqueous solution
Liposome
Emulsion
•
QS21
•
•
•
Aqueous solution
Liposome
Emulsion
•
•
Aqueous solution
Emulsion
•
GLA + QS21
– Aqueous suspension
– Liposome
– Emulsion
GLA + R848
– Aqueous suspension
– Liposome
– Emulsion
GLA + CpG
– Aqueous suspension
– Emulsion
GLA + Poly (I:C)
– Aqueous suspension
– Emulsion
CpG
CONFIDENTIAL
15
IFN-
25000
20000
15000
0
• GLA-SE enhances Th1 responses
83
ID +G ID8
8 L 3
ID 3+G A-S +S
83 L E E
+G A- 1u
LA S E g
-S 5 u
E g
20
ug
ID
83
ID +G ID8
8 L 3
ID 3+G A-S +S
83 L E E
+G A- 1u
LA S E g
-S 5 u
E g
20
ug
30000
ID
3
ID +G ID8
8 L 3
ID 3+G A-S +SE
83 L E
+G A- 1u
LA S E g
-S 5u
E g
20
ug
ID
83
ID +G ID8
8 L 3
ID 3+G A-S +S
83 L E E
+G A- 1u
LA S E g
-S 5u
E g
20
ug
ID
8
Cytokine (pg/ml)
Importance of Adjuvant Selection
Th1400
Th2
TNF
800
700
300
600
200
10000
5000
100
0
IL-5
800
700
500
500
400
400
300
300
200
200
100
100
0
0
IL-13
600
while SE promotes Th2 cytokines
Adjuvant Selection: A Matter of Life
or Death
100
Guinea Pig Survival (%)
90
80
70
60
50
40
30
20
10
0
0
50
100
150
Days post challenge (d)
Saline
BCG
ID93/SE
ID93/GLA-SE
ID93/GLA-SE confers protection against Mtb in guinea pigs. Guinea pigs were injected with saline or were immunized with
BCG, ID93/SE, or ID93/GLA-SE. The data is represented as percentage survival of guinea pigs over time following
infection with Mtb. Log-rank test was used for statistical comparisons of median guinea pig survival among the
experimental groups. p values 0.05 were considered significant.
Do We Need A New TB Vaccine?
Boosting BCG
Therapeutic Vaccination
CONFIDENTIAL
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ID93/GLA-SE, ID83/GLA-SE:
Protection in BCG primed Guinea Pigs
Percent survival
100
Saline
BCG' Saline Boost
BCG' ID83+GLA-SE
BCG' ID93+GLA-SE
*
*
75
50
25
0
0
100
200
300
400
500
Days
19
Do We Need A New TB Vaccine?
Boosting BCG
Therapeutic Vaccination
CONFIDENTIAL
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TB: Infection PrimeVaccine Boost
100
Percent survival
80
60
40
Rx+ID93+GLA-SE (DTT)
Rx+ID93+GLA-SE (PTT)
Rx d15-105
Saline
20
0
0
50
100
150
200
250
300
350
400
Days p.i.
Mice were infected with LDA of Mtb. Fifteen days later mice were treated for 90 days with
a combination of antibiotics. A subset of mice in each group were immunized three times,
three weeks apart with the candidate fusion vaccine one day after chemotherapy was
completed. Protection was assessed by monitoring animal survival.
21
ID93/GLA-SE: Summary, Status
Protection Mouse Models
Prophylactic
Therapeutic
Protection in Disease Models
Guinea Pigs
NHP
Clinical Trials
1. U. S. Phase I (Ongoing)
2ug vs. 5ug GLA-SE; 2 vs. 10 ug Ag
2. S.A. Phase I (Planned)
CONFIDENTIAL
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Therapeutic Vaccination: Lessons
Learned
• Safe in Infected, Diseased Individuals
• Applications for Post Exposure Prophylaxis and
Therapy
• Human Leishmaniasis: Strong Immune Responses,
but Weak Responses to Vaccine Antigens Prior to
Vaccination
• Strong Ag-Specific Responses Induced Post-Vaccine
• Immune Response Can Be Re-Directed With
Protein/Adjuvant
CONFIDENTIAL
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Vaccine Optimization
Future Directions:
Adjuvant Formulation, TLR Combinations
ID Delivery
CONFIDENTIAL
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TLR Agonist Synergy
(TLR4/TLR7/8): Human DC
CONFIDENTIAL
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TB Protection: TLRL Synergy
4/8/2015
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Intra-dermal Delivery
Sanofi has demonstrated advantages of ID delivery (Fluzone)
BCG Delivered ID
Targeting dermal dendritic cells (DDC)
TLR 4 expressed on DDC
No adjuvants for ID delivery have been developed
GLA formulations are safe and effective ID adjuvants
Clinical Trial of ID GLA Ongoing
Dendritic Cells in Human Skin
Langerhans cells
CD1a
•
•
•
•
CD1a
Langerin (CD207)
Birbeck granules
E-cadherin
Dermal dendritic cells
• CD1b
• DC-SIGN (CD209)
• FXIIIa
DC-SIGN
Intra-dermal Delivery
Microneedles
Combined with
Adjuvant
Cross Cutting Lessons to
Accelerate Clinical Development
• Common Platforms Useful For Multiple Vaccine Candidates
• Adjuvant/Formulation Selection is Critical
• More Adjuvant is Not Better
• MPL; 40ug vs. 10ug
• GLA Formulations: 2ug < 5ug > 20ug
• Lowering Development Hurdles
• Build on Known Adjuvants When Possible
• Use Minimal Amounts
CONFIDENTIAL
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Funding Development
BMGF
BARDA
DARPA
NIAID
Murdock Trust
CONFIDENTIAL
ALM
31
Acknowledgments
• IDRI
Rhea Coler
Sylvie Bertholet
Susan Baldwin
Mark Orr
Tom Vedvick
Chris Fox
Darrick Carter
Greg Ireton
• WHO
Martin Friede
www.pbs.org/nationalparks