Vaccine discovery in Australia: then and now -...
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Fighting Diseases of Global Impact Michael F Good Vaccine discovery in Australia: then and now
Transcript of Vaccine discovery in Australia: then and now -...
Fighting Diseases of Global Impact
Michael F Good
Vaccine discovery in Australia:
then and now
1993-2006
1997-2017
“Through partnership of industry and academia, to develop the science and technology needed to improve the efficacy of current vaccines and to assist in the design and construction of the next generation of medical and veterinary vaccines.”
Vaccine applications
EBV
Malaria
Streptococcus
Influenza
GI nematodes
Tick Fever
Core technologies
Induction of CTL immunity Delivery & directing the immune response Design of immunogens Mucosal immunity and non- parenteral vaccine delivery
Core partners
QIMR
WEHI
CSIRO
Uni Melbourne
CSL
Biotech Australia
QIMR WEHI CSIRO Uni of Melbourne CSL ARCBS Monash University La Trobe University
1993-2000 2000-2006
All programs (commercial and public benefit) had to have a “route to market” Vaccine Solutions Pty Ltd established
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Patents lodged
Sir Gustav Nossal AC Patron
Sir Brice Watson AC Chairman
Prof Anne Kelso AO Director, 2000-2006
Robin Anders Allan Saul
The malaria program
‘Whole parasite’ vaccines for malaria
Sporozoite stage Irradiated sporozoites (Hoffman et al, Sanaria)
‘CPS’ (chloroquine chemoprophylaxis with sporozoites)
Genetically attenuated
Blood stage Chemically attenuated parasites
Infection with chemoprophylaxis (CPS equivalent)
Killed adjuvanted (e.g liposomes)
Genetically attenuated
Chemically treated parasites induce immunity in normal (A/J) mice
Mice challenged 4 weeks after a single vaccination with 106 Centanamycin- attenuated parasites
Activation of human T cells following a single immunisation with chemically attenuated P. falciparum pRBC
The group A streptococcus
Diseases caused by group A streptococci
Non-invasive diseases
• Pharyngitis
• Impetigo
Invasive GAS diseases
• Necrotizing fasciitis
• Cellulitis
• Pneumonia
• Erysipelas
• Streptococcal bacteremia
• Osteomyelitis
• Otitis media
• Sinusitis
• Meningitis or brain abscess
• Puerperal sepsis
Autoimmune syndromes • Rheumatic fever/rheumatic heart disease • streptococcal glomerulonephritis • PANDAS
Toxin-mediated disease • Toxic shock syndrome • Scarlet fever
Diseases caused by group A streptococci
Non-invasive diseases
• Pharyngitis
• Impetigo
Invasive GAS diseases
• Necrotizing fasciitis
• Cellulitis
• Pneumonia
• Erysipelas
• Streptococcal bacteremia
• Osteomyelitis
• Otitis media
• Sinusitis
• Meningitis or brain abscess
• Puerperal sepsis
Autoimmune syndromes • Rheumatic fever/rheumatic heart disease • streptococcal glomerulonephritis • PANDAS
Toxin-mediated disease • Toxic shock syndrome • Scarlet fever
> 500,000 deaths per year
Prevalence of rheumatic heart disease in the Northern Territory of Australia, 2010
Report of the Australian Institute of Health and Welfare, 2013
1998 2000 2002 2004 2006 2008 2010 2012 2014 2016
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Incidence of invasive GAS disease in Alberta 1998-2016
Greg Tyrrell, Alberta Health Services
Genome of ~ 2,000,000 bps ~1800 protein-encoding genes ~40 virulence factors Responsible for more human diseases than any other bacterium 25
Group A streptococcus (GAS)
C1
C2
C3
NH2
COOH
amino terminus
(hypervariable)
carboxyl terminus
(conserved)
trans-membrane
region
type-specific
opsonic epitopes
“A”
repeat region
“B”
repeat region
“C”
repeat region
The M protein
(variable)
J8
From Cole, JN et al, Nat. Rev. Microbiol. 2011 27
Virulence factors upregulated by CovR/S mutations
J. Immunol. 2016
Peptide conjugates used in vaccine
CRM
J8
J8
J8
J8
J8
J8
J8
J8
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• diphtheria toxoid (DT) was used in early pre-clinical studies. GM diphtheria toxin (‘CRM197’) was used in later pre-clinical studies and will be used for proposed human vaccine trials
CRM
S2
S2
S2
S2
S2
S2
S2
S2
Pandey et al, Sci, Reports 2017
J8-CRM + S2-CRM protects mice from CovR/S wild type streptococci and from virulent CovR/S mutant types
J8-C
RM
J8-C
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K4S2-C
RM
J8-C
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CRM
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Pe
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** ** ****
** **
A
J8-C
RM
J8-C
RM
+S2-CRM
K4S2-C
RM
J8-C
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+K4S2-CRM
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Pe
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-burd
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Day 3 Day 6
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** **
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J8-C
RM
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K4S2-CRM
J8-C
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+K4S2-
CRM
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Perc
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ion in
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S s
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io-b
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Day 3 Day 6
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** **** ** **C
J8-C
RM
J8-C
RM
+S2-CRM
K4S2-C
RM
J8-C
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+K4S2-
CRM
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Pe
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Day 3 Day 6
** ** ****
** **
A
J8-C
RM
J8-C
RM
+S2-CRM
K4S2-C
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J8-C
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+K4S2-CRM
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Pe
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** ** ****
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B
J8-C
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K4S2-CRM
J8-C
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+K4S2-CRM
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Perc
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Day 3 Day 6
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** **** ** **C
J8-C
RM
J8-C
RM
+S2-CRM
K4S
2-CRM
J8-C
RM
+K4S2-
CRM
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Pe
rce
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ctio
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GA
S s
kin
bio
-bu
rde
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Day 3 Day 6
** ** ****
** **
A
J8-C
RM
J8-C
RM
+S2-C
RM
K4S
2-CRM
J8-C
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+K4S
2-CRM
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Pe
rce
nt re
du
ctio
n in
GA
S b
lood
bio
-burd
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Day 3 Day 6
** ** ****
** **
B
J8-C
RM
J8-C
RM
+S2-CRM
K4S2-C
RM
J8-C
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+K4S2-
CRM
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Perc
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GA
S s
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io-b
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Day 3 Day 6
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** **** ** **C
J8-C
RM
J8-C
RM
+S2-CRM
K4S
2-CRM
J8-C
RM
+K4S2-
CRM
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Pe
rce
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kin
bio
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Day 3 Day 6
** ** ****
** **
A
J8-C
RM
J8-C
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+S2-C
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K4S
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J8-C
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+K4S
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Pe
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B
J8-C
RM
J8-C
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+S2-CRM
K4S2-C
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J8-C
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+K4S2-
CRM
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Perc
ent re
duct
ion in
GA
S s
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en b
io-b
urd
en
Day 3 Day 6
**
** **** ** **C
J8-C
RM
J8-C
RM
+S2-C
RM
K4S2-C
RM
J8-C
RM
+K4S
2-CRM
0
20
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Pe
rce
nt re
du
ctio
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GA
S s
kin
bio
-bu
rde
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Day 3 Day 6
** **
*
**
D
J8-C
RM
J8-C
RM
+S2-
CRM
K4S2-CRM
J8-C
RM
+K4S
2-CRM
0
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Pe
rce
nt re
du
ctio
n in
GA
S b
loo
d b
io-b
urd
en
Day 3 Day 6
** ** ****
E
J8-C
RM
J8-C
RM
+S2-CRM
K4S
2-CRM
J8-C
RM
+K4S2-CRM
0
20
40
60
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100
Pe
rce
nt re
du
ctio
n in
GA
S s
ple
en
bio
-bu
rde
n
Day 3 Day 6
**** ****F
J8-C
RM
J8-C
RM
+S2-C
RM
K4S2-C
RM
J8-C
RM
+K4S
2-CRM
0
20
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Pe
rce
nt re
du
ctio
n in
GA
S s
kin
bio
-bu
rde
n
Day 3 Day 6
** **
*
**
D
J8-C
RM
J8-C
RM
+S2-
CRM
K4S2-CRM
J8-C
RM
+K4S
2-CRM
0
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Pe
rce
nt re
du
ctio
n in
GA
S b
loo
d b
io-b
urd
en
Day 3 Day 6
** ** ****
E
J8-C
RM
J8-C
RM
+S2-CRM
K4S
2-CRM
J8-C
RM
+K4S2-CRM
0
20
40
60
80
100
Pe
rce
nt re
du
ctio
n in
GA
S s
ple
en
bio
-bu
rde
n
Day 3 Day 6
**** ****F
J8-C
RM
J8-C
RM
+S2-
CRM
K4S2-
CRM
J8-C
RM
+K4S
2-CRM
0
20
40
60
80
100
Pe
rce
nt re
du
ctio
n in
GA
S s
kin
bio
-bu
rde
n
Day 3 Day 6
** **
*
**
D
J8-C
RM
J8-C
RM
+S2-
CRM
K4S2-
CRM
J8-C
RM
+K4S
2-CRM
0
20
40
60
80
100
Pe
rce
nt re
du
ctio
n in
GA
S b
loo
d b
io-b
urd
en
Day 3 Day 6
** ** ****
E
J8-C
RM
J8-C
RM
+S2-CRM
K4S
2-CRM
J8-C
RM
+K4S2-CRM
0
20
40
60
80
100
Pe
rce
nt re
du
ctio
n in
GA
S s
ple
en
bio
-bu
rde
n
Day 3 Day 6
**** ****F
J8-C
RM
J8-C
RM
+S2-
CRM
K4S2-C
RM
J8-C
RM
+K4S
2-CRM
0
20
40
60
80
100
Pe
rce
nt re
du
ctio
n in
GA
S s
kin
bio
-bu
rde
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Day 3 Day 6
** **
*
**
D
J8-C
RM
J8-C
RM
+S2-
CRM
K4S2-
CRM
J8-C
RM
+K4S
2-CRM
0
20
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60
80
100
Pe
rce
nt re
du
ctio
n in
GA
S b
loo
d b
io-b
urd
en
Day 3 Day 6
** ** ****
E
J8-C
RM
J8-C
RM
+S2-CRM
K4S
2-CRM
J8-C
RM
+K4S2-CRM
0
20
40
60
80
100
Pe
rce
nt re
du
ctio
n in
GA
S s
ple
en
bio
-bu
rde
n
Day 3 Day 6
**** ****F
J8-C
RM
J8-C
RM
+S2-
CRM
K4S
2-CRM
J8-C
RM
+K4S
2-CRM
0
20
40
60
80
100
Pe
rce
nt re
du
ctio
n in
GA
S s
kin
bio
-bu
rde
n
Day 3 Day 6
** ** ****
** **
A
J8-C
RM
J8-C
RM
+S2-
CRM
K4S
2-CRM
J8-C
RM
+K4S
2-CRM
0
20
40
60
80
100
Pe
rce
nt re
du
ctio
n in
GA
S b
lood
bio
-burd
en
Day 3 Day 6
** ** ****
** **
B
J8-C
RM
J8-C
RM
+S2-
CRM
K4S
2-CRM
J8-C
RM
+K4S
2-CRM
0
20
40
60
80
100
Perc
ent re
ductio
n in
GA
S s
ple
en b
io-b
urd
en
Day 3 Day 6
**
** **** ** **CNS1 (wild type)
NS88.2 (mutant type)
Skin bioburden Blood bioburden
** Significantly different compared to PBS-immunized group
Control Vaccinated
Protection from skin disease following immunization
Immunogenicity of J8-DT/Alum in pilot study in 10 human volunteers*
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• Volunteers received a single dose of 50ug of J8-DT/Alum. There were no adverse events. Data is being prepared for publication.
‘J8-Lipo-DT’ – a vaccine to induce mucosal immunity
Immunogenicity of J8-Lipo-DT delivered intra-nasally
Zaman et al, Sci Reports 2016
J8-Lipo-DT protects against GAS URT infection (GAS colonies in throat swabs post challenge)
J8-Lipo-DT protects against GAS URT infection (GAS colonies in NALT day 3 post challenge)
Acknowledgments – Malaria team Institute for Glycomics Gold Coast Hospital Sanaria
Danielle Stanisic John Gerrard Steve Hoffman
Xue Liu James Fink Kim Lee Sim
Bibiana Rodriguez Johanna Mayer Tao Li
Jolien Pingnet Lana Sundac
Jessica Powell Sarah Coghill
Nicole Willemsen Letitia Gore
Mei-Fong Ho
Ibrahim El-Deeb Burnet Institute Mater Hospital
Tanya Forbes James Beeson Paul Griffin
Nicola Cocroft Jo-Anne Chan
Chris Davis Christine Langer
Michael Batzloff
Silvana Sekuloski Australian Army Malaria Institute
Judy Coote Dennis Shanks, Qin Cheng
Maryna Martin Marina Chavchich
QIMR Berghofer Institute Bio21
for Medical Research Eric Hansen
James McCarthy
Silvana Sekuloski Georgia State University
Katharine Trenholme Moses Lee
Funding: NHMRC and National Heart Foundation of Australia
Institute for Glycomics, Griffith University
Manisha Pandey Victoria Ozberk Ainslie Calcutt Jessica Powell Emma Langshaw Tania Hernandez Zak Phillips Mei Fong Ho Mehfuz Zaman Michael R Batzloff Griffith Medical school, Griffith University Alfred Lam
RCH, Melbourne Pierre Smeesters Andrew Steer
QIMR, Berghofer MRI, Brisbane Sri Sriprakash Michelle Wykes
Acknowledgments – Streptococcus team
