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MVA and (mainly) Malaria Adrian Hill The Jenner Institute, Oxford University
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MVA and (mainly) Malaria - who.int · – 46 in malaria (six inserts), 35 in TB, HIV, ... d28 d84 / dC -1 d28 MSP1 ETSR vs QKNG 1 10 100 1000 1 10 100 ... Muhammed Afolabi Roma Chilengi

Feb 15, 2019

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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

ME: Multiple malaria epitopes

TRAP: Thrombospondin-

Related Adhesion Protein

TRAP strain is T9/96

in this vaccine

A Polyepitope-Protein Vaccine Construct

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

Adenovirus Prime MVA Boost

8 weeks

ME-TRAP T Cell Immunogenicity in the Clinic

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

VACCINE T CELL RESPONSE mean cells/ million PBMCs

ANTIGEN

Viral Vector Vaccines to Maximise Cellular Immunogenicity

Adenovirus Prime MVA Boost

8 weeks

-

Malaria, HCV, HIV, influenza, TB...

0

100

200

300

400

500

600

700

800

1 2 3 4 5 6 7

SF

Cs / M

ILL

ION

PB

MC

s

DNA/MVA

FP9/MVA

MVA Can Re-Boost at One Year Gambian Data: FFM and DDM

Pre- d7 d28 d56 d360 d367 Moorthy et al. 2004 J Inf Dis MVA MVA

ChAd-MVA Responses

are Durable and Can Be Re-Boosted at 6-30 Months Post-MVA

OHara et al. 2012 J Inf Dis

ChAd63-MVA MeTRAP Efficacy correlates with CD8+ T cells

CD8+ T cells correlate with efficacy specifically g -interferon +ve cells

Ewer et al. submitted

57% (8/14) of volunteers show vaccine efficacy 21% (3/14) show sterile protection

3/3 showed efficacy at 8 months

0 20 40 60 80 100 120 1401

10

100

1000

10000

Time (d)

An

ti-A

MA

1 (

3D

7)

EL

ISA

un

its

0 20 40 60 80 100 120 1401

10

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10000

Time (d)

An

ti-M

SP

11

9 E

LIS

A u

nit

s

0 20 40 60 80 100 120 1400

1000

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AdCh63-MVA MSP1

AdCh63 MSP1

Time (d)

IFN

- g S

FU

/ M

illi

on

PB

MC

s

0 20 40 60 80 100 120 140

0

1000

2000

3000

AdCh63 AMA1

AdCh63-MVA AMA1

Time (d)

IFN

- g S

FU

/ M

illi

on

PB

MC

s

MVA Boosts MSP1 & AMA1 Antibodies ChAd63-MVA Phase Ia clinical trials

Sheehy SH et al. (2011) Mol Ther 19:2269-76

Sheehy SH et al. (2012) PLoS ONE 7:e31208

ChAd63 prime = 5 x 1010 vp (i.m.)

MVA boost = 1.25 - 5 x 108 pfu (i.m.)

MSP1

0 20 40 60 80 100 120 140 1601

10

100

1000

10000

Group 2A

Group 1A

Time (d)

An

ti-M

SP

11

9 E

LIS

A u

nit

s0 20 40 60 80 100 120 140 160

1

10

100

1000

10000

Group 2B+C

Group 1B

Time (d)

An

ti-M

SP

11

9 E

LIS

A u

nit

s

A B

C

Figure 5

3D7 FVO 3D7 FVO

0

20

40

60

80

100

An

ti-M

SP

14

2 I

gG

(

g/m

L)

D

Group 1 Group 2

rs = 0.87P < 0.0001

rs = 0.90P < 0.0001

d28 d84 / dC-1d28 MSP1 ETSR vs QKNG

1 10 100 10001

10

100

1000

MSP119 ELISA units (ETSR)

MS

P1

19 E

LIS

A u

nit

s (

QK

NG

)

d84 MSP1 ETSR vs QKNG

100 1000 10000 100000100

1000

10000

100000

MSP119 ELISA units (ETSR)

MS

P1

19 E

LIS

A u

nit

s (

QK

NG

)

0 20 40 60 80 100 120 140 1601

10

100

1000

10000

Group 2A

Group 1A

Time (d)

An

ti-M

SP

11

9 E

LIS

A u

nit

s

0 20 40 60 80 100 120 140 1601

10

100

1000

10000

Group 2B+C

Group 1B

Time (d)

An

ti-M

SP

11

9 E

LIS

A u

nit

s

A B

C

Figure 5

3D7 FVO 3D7 FVO

0

20

40

60

80

100

An

ti-M

SP

14

2 I

gG

(

g/m

L)

D

Group 1 Group 2

rs = 0.87P < 0.0001

rs = 0.90P < 0.0001

d28 d84 / dC-1d28 MSP1 ETSR vs QKNG

1 10 100 10001

10

100

1000

MSP119 ELISA units (ETSR)

MS

P1

19 E

LIS

A u

nit

s (

QK

NG

)

d84 MSP1 ETSR vs QKNG

100 1000 10000 100000100

1000

10000

100000

MSP119 ELISA units (ETSR)

MS

P1

19 E

LIS

A u

nit

s (

QK

NG

)

1B 2B 1B 2B

0

20

40

60

80

100

120

Group

An

ti-A

MA

1 Ig

G (

g/m

l)

1B 2B 1B 2B

0

20

40

60

80

100

120

Group

An

ti-A

MA

1 Ig

G (

g/m

l)

AMA1

1B 2B 1B 2B

0

20

40

60

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120

Group

An

ti-A

MA

1 Ig

G (

g/m

l)

1B 2B 1B 2B

0

20

40

60

80

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120

Group

An

ti-A

MA

1 Ig

G (

g/m

l)

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

2. Instability

3. IP

Use cell lines (EB66, AGE1.CR)

Use the right promoter

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 BioManufacturing Clinical Trials Simon Draper Sarah Moyle Geraldine OHara

Arturo Reyes-Sandoval Eleanor Berrie Susanne Sheehy

Alex Spencer Chris Duncan

Migena Bregu Nick Anagnostou

Matt Cottingham Katharine Collins

Sarah Gilbert Alfredo Nicosia Katherine Gantlett

Stefano Colloca Ian Poulton

The Gambia Riccardo Cortese Sean Elias

Kalifa Bojang Nick Edwards

Katie Flanagan Kilifi, Kenya Alison Lawrie

Muhammed Afolabi Roma Chilengi Katie Ewer

Jenny Mueller Caroline Ogwang Bob Sinden

Britta Urban

European Vaccine Initiative WRAIR

Egeruan Imoukhuede Jitta Murphy