MVA and (mainly) Malaria
Adrian Hill
The Jenner Institute, Oxford University
MVA: A Growing Safety Database
• 120,000 MVA vaccines during 1970s
• Poxvirus boosting for T cell response amplification
discovered in malaria
– Vaccinia then MVA (1996)
• First clinical trial of MVA boosting in 1999
• Since then over 100 clinical trials
– 46 in malaria (six inserts), 35 in TB, HIV, influenza, HCV
– >1000 vaccinees in malaria, > 2000 in TB, > 1000 others
– Therapy: melanoma, renal cancer, prostate cancer, HIV,
HCV, HPV (over 500 cancer patients for Trovax alone)
– No myocarditis issue
MVA: some updates
• BAC recombineering technology has accelerated vector
construction (Cottingham et al PLoS One, 2008)
–
–
–
–
as have flow sorting methods
Attempts to enhance immunogenicity further: limited success
Immunogenicity dependent on cross-presentation
Vector genetic and thermo-stability generally excellent
• Some differences from NYVAC reported
– But appear minor
• Orthopox vectors being developed for diverse species
– e.g. cattle (TB) and chickens (influenza)
– Multiple avipox vectors widely used as veterinary vaccines
Malaria
A Complex Parasite Life-Cycle
The MeTRAP Vaccine Insert
Targets the Liver-Stage of Plasmodium falciparum
A Polyepitope-Protein Vaccine Construct
ME: Multiple malaria epitopes
TRAP: ThrombospondinRelated Adhesion Protein
TRAP strain is T9/96
in this vaccine
Why Use Viral Vectors
in Prime-Boost Regimes?
•
Best means of safely inducing T cells in humans
•
7 vaccines have induced >1500 SFU/ml
–
–
•
in malaria (x 3), HCV, HIV, tuberculosis and influenza
all used MVA viral vector boosting
Adenovirus – MVA is the most potent approach
–
–
better than DNA – Adenovirus
better than Adenovirus - Heterologous Ad
8 weeks
Adenovirus Prime
MVA Boost
ME-TRAP T Cell Immunogenicity
in the Clinic
VACCINE
T CELL RESPONSE
ANTIGEN
mean cells/ million PBMCs
DNA x 3
48
ME-TRAP
Fowlpox x 2
50
ME-TRAP
MVA x 3
41
ME-TRAP
ChAd63 x 1
850
ME-TRAP
DNA x 2 - MVA
430
ME-TRAP
Fowlpox x 2 - MVA
475
ME-TRAP
ChAd63-MVA
2800
ME-TRAP
Viral Vector Vaccines
to Maximise Cellular Immunogenicity
8 weeks
Adenovirus Prime
MVA Boost
Malaria, HCV, HIV, influenza, TB...
MVA Can Re-Boost at One Year
Gambian Data: FFM and DDM
800
DNA/MVA
700
FP9/MVA
SFCs / MILLION PBMCs
600
500
400
300
200
100
0
1
2
Pre- d7
MVA
3
d28
4
d56
5
6
7
d360 d367
MVA
Moorthy et al. 2004 J Inf Dis
ChAd-MVA Responses
are Durable and Can Be Re-Boosted
at 6-30 Months Post-MVA
O’Hara et al. 2012 J Inf Dis
ChAd63-MVA MeTRAP Efficacy
correlates with CD8+ T cells
57% (8/14) of volunteers show vaccine efficacy
21% (3/14) show sterile protection
3/3 showed efficacy at 8 months
CD8+ T cells correlate with efficacy
specifically g -interferon +ve cells
Ewer et al. submitted
40
Anti-MS
Anti-MS
Anti-MS
20
10
10
MVA Boosts MSP1 & AMA1 Antibodies
1
0
80
60
20 120
40 140
60 160
80
100
1
100 120 140
160 40
0
20
1
0
80
60
20 120
40 140
60 160
80 100 120 140 160
100
Time (d)
Time (d)trials
ChAd63-MVA
Phase Ia clinical
Time (d)
C
AdCh63-MVA MSP1
AdCh63
100000MSP1
IFN-g SFU / Million PBMCs
0
10
100
10
10
1
1
1000
100
10
10000
1000
100
100
100
1000
1000
Anti-AMA1 (3D7) ELISA units
100
MSP119 ELISA units (QKNG)
1000
MSP119 ELISA units (QKNG)
MSP119 ELISA units (QKNG)
Anti-MSP119 ELISA units
1000
100000
2000
10000
AdCh63-MVA AMA1
AdCh63 AMA1
1000
1000
10000
100
100
100000
1000
0
10000
1000
100
10
100000
80MSP1100
120
140
MSP119 ELISA units (ETSR)
unitsMSP1
(ETSR)
SP11940
ELISA60
units (ETSR)
19 ELISA
19 ELISA units (ETSR)
0
1
Time
(d)
rs = 0.87
60
60
40
40
20
20
00
3D7
80
60
40
20
1B
1B
FVO
Group 1
120
120
(g/ml)
IgG (g/ml)
Anti-AMA1 IgG
Anti-AMA1
100
100
100
0
2B
2B
3D7
20
40
r = 0.90
120 Ps140
< 0.0001
60
1
1B
1B
FVO
Group
Group
Group
Group
2 1
80
100 120 140
Time
0 (d)20
40
60
80
100
120
140
Time (d)
Time (d)
MSP1
D
80
80
r = 0.90
s
20 P < 40
100
0.000160 P <80
0.0001
120
120
Anti-MSP142 IgG (g/mL)
Anti-AMA1
(g/ml)
IgG (g/ml)
Anti-AMA1 IgG
rs = 0.87
P < 0.0001 0
Time (d)
3000
d28 vs QKNG
/ dC-1
d28
/ dC-1
d84 MSP1d84
ETSR
vs QKNG
MSP1d84
ETSR
vs QKNG
10000
d28 MSP1 ETSRd84
8 MSP1 ETSR
vs QKNG
10000
10
Group 2B+C
Group 2B+C
AMA1
ChAd63 prime = 5 x 1010 vp (i.m.)
100
100
MVA boost = 1.25 - 5 x 108 pfu (i.m.)
80
80
60
60
40
40
20
20
00
2B
2B
3D7 1B
1B FVO2B
2B
Group 2
1B
1B
Group
Group
Sheehy SH et al. (2011) Mol Ther 19:2269-76
Sheehy SH et al. (2012) PLoS ONE 7:e31208
2B
2B
Sukuta Vaccine Clinic
The Gambia
MVA: Immunogenicity Summary
• MVA is a poor priming vector
– but it remains the best boosting vector
• Generally MVA boosts what is primed
– responses appear to broaden
• Mixtures of different vectors (Ad mixed with MVA)
– are more potent than the individual vectors
– both pre-clinically and clinically (Reyes-Sandoval et al. Mol Therapy 2012)
• Many adjuvants reduce MVA immunogenicity
– IMX313 increases it as a carrier protein (Spencer et al. PLoS One 2012)
• Late re-boosting should be explored further
Why Might You Not Use MVA?
Three potential concerns
1. Cost of scale-up
Use cell lines (EB66, AGE1.CR)
2. Instability
Use the right promoter
3. IP
No longer an issue
3 Take Home Messages
• In nearly all cases MVA boosts pre-existing T cell
responses by about 5 to 10 fold
– to 1,000 - 10,000 SFU / million
– significant efficacy in 6 phase II malaria trials required MVA
boosting
– also good antibody boosting, by about a 10 fold
• Safety has been very good in thousands of vaccinees
– Malaria, TB, HIV, cancer, flu, HCV:- > 4000 subjects
– Europe, Africa, US
• Re-boosting with MVA vector after 6 months works
– in mice and in humans
Malaria Acknowledgements
Malaria Pre-Clinical
Simon Draper
Arturo Reyes-Sandoval
Alex Spencer
Migena Bregu
Matt Cottingham
Sarah Gilbert
The Gambia
Kalifa Bojang
Katie Flanagan
Muhammed Afolabi
Jenny Mueller
Britta Urban
European Vaccine Initiative
Egeruan Imoukhuede
BioManufacturing
Sarah Moyle
Eleanor Berrie
Alfredo Nicosia
Stefano Colloca
Riccardo Cortese
Kilifi, Kenya
Roma Chilengi
Caroline Ogwang
Clinical Trials
Geraldine O’Hara
Susanne Sheehy
Chris Duncan
Nick Anagnostou
Katharine Collins
Katherine Gantlett
Ian Poulton
Sean Elias
Nick Edwards
Alison Lawrie
Katie Ewer
Bob Sinden
WRAIR
Jitta Murphy