Group A streptococcal vaccines - WHO · 17/09/2014 3 GBD 2010 estimates* Compared to previous 2005...
Transcript of Group A streptococcal vaccines - WHO · 17/09/2014 3 GBD 2010 estimates* Compared to previous 2005...
17/09/2014
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Group A streptococcal vaccines
Florian Schödel
Philimmune LLC
Thanks to:
• Andrew Steer, Royal Children’s Hospital, AU
• Jonathan Carapetis, Telethon Institute for Child Health Res., West Perth, AU
• James Dale, Univ. Memphis TN
• John Fraser, Univ. Auckland, NZ
• Michael Good, Queensland Inst. Med. Res., NZ
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Group A streptococcal diseases
• Superficial infection – Pharyngitis – Pyoderma
• Invasive diseases
– Septicaemia – Pneumonia, osteomyelitis… – Necrotising fasciitis
• Toxin mediated diseases
– Scarlet fever – Streptococcal toxic shock syndrome
• Post-streptococcal autoimmune sequelae
– Acute rheumatic fever / rheumatic heart disease
– Post-streptococcal glomerulonephritis
Disease Number of
existing cases
Number of new
cases each year
Number of
deaths each year
Rheumatic heart disease 15.6 million 282,000* 233,000†
History of acute rheumatic fever
without carditis, requiring
secondary prophylaxis
1.88 million 188,000*
RHD-related infective
endocarditis
34,000 8,000
RHD-related stroke 640,000 144,000 108,000
Acute post-streptococcal
glomerulonephritis
§ 472,000 5,000
Invasive group A streptococcal
diseases
663,000 163,000
Total severe cases 18.1 million 1.78 million 517,000
Pyoderma 111 million
Pharyngitis 616 million
Summary of estimated global burden of GAS diseases
Lancet Infect Dis 2005;5:685-94
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GBD 2010 estimates*
Compared to previous 2005 publication:
15.6 million cases
233,000 deaths
NOTE: Modelling still needs work – 2010 estimates should be updated
during 2014, but are unlikely to fall
1990 2005 2010
Prevalence 29,172,383 33,468,203 34,232,795
YLL 13,267,810 9,670,605 8,720,292
YLD 1,150,422 1,365,502 1,429,575
DALY 14,418,232 11,036,107 10,149,867
Deaths 462,579 363,864 345,110
Lancet 2012 and GBD website
Estimated global mortality from individual pathogens, 2002
Lancet Infect Dis
2005;5:685-94
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Existing Prevention and Control measures
• GAS remains Penicillin sensitive – Resource intensive
– No evidence that disease burden has decreased
– ARF without symptomatic disease
– Role of skin infections?
– Secondary prophylaxis after ARF works, but resource intensive
• Serious GAS disease decreases in richer countries
Priority public health needs
• Prevent ARF/RHD
– Prevention of strep throat may be a first indication (antibiotic use) and may as a consequence also lead to prevention of ARF/RHD
• Prevent PSGN
• Prevent invasive disease, septic shock
• Some agreement on first priority, little agreement on path
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Challenges
• Attributable burden of disease – more information available, but gaps remain
• Safety perceptions due to one historical study – largely resolved, CFR changed – more clinical safety data will accrue with development of new candidates
• Serotype diversity – see below
• Commercial interest? Strep throat viable commercial target?
Development activity resources applied
• Two vaccine candidates in early clinical development – without current major pharma support, both based on M protein
• Numerous pre-clinical candidates, little commercial engagement
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Models, Assays, Endpoints
• No reliable animal model • However: frequency declines with age and
immunity and bactericidal antibodies likely predictive of protection as in other streptococcal diseases
• Strep throat frequent and easily tested clinically: could be used as endpoint for first indication and to triage candidates
• Prevention of ARF/RHD and PSGN more challenging due to time lag and frequency – similar to cancer indications for HBV or HPV
GAS Vaccine Candidate Antigens with in vivo Evidence of Protection
Antigen Location Function
Type-specific M peptides Cell surface Opsonic epitopes
C-repeat M peptides Cell surface Opsonic epitopes
M-related proteins (Mrp) Cell surface Opsonic epitopes
C5a peptidase (SCPA) Secreted Cleaves C5a
Pili (T antigen) Cell surface Adhesion
Serine protease (ScpC) Secreted Cleaves IL-8 and other chemokines
Serine esterase (Sse) Secreted Tissue invasion
Cysteine protease (SpeB)
Group carbohydrate
Secreted
Cell surface
Proteolysis of bact. and host proteins
Opsonic epitopes
Serum opacity factor (Sof) Cell surface Secreted
Opsonic epitopes/Fn binding
FBP54 Cell surface Adhesin/Fn binding
Sfb1 Cell surface Adhesin/Fn binding
GAS 40 Cell surface Unknown/opsonic epitopes
Nine common antigens Unknown
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Two clinically most advanced vaccine candidates
• Recombinant multivalent M protein fusion peptides
• 30 valent
• Short conserved M protein peptide conjugate J8
30-Valent Vaccine (StreptAnovaTM)
Protein 1
M1 3.1 M6.4 M2 M18 M28 M12 SPA M1
M4 M5.14 M11 M75 M19 M29 M14.3 M24 M4
M77 M22 M73 M89 M58 M44 M78 M118 M77
M83.1 M82 M81 M87 M49 M92 M114 M83.1
Protein 2
Protein 3
Protein 4
1-50 32-81 (1-25)2 (1-25)2 1-50 1-50 1-50 1-50 1-50
1-50 (1-25)2 1-50 1-50 (1-25)2 1-45 1-50 1-50 1-50
1-50 1-50 1-50 1-50 1-50 1-50 1-50 1-50 1-50
1-50 1-50 1-50 1-50 1-50 1-50 1-50 1-50
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Bactericidal Antibodies Evoked by 30-
Valent Vaccine
0
20
40
60
80
100
% K
illin
g
M1
M3
M6
M2
M4
M5
M8
2
M8
7
M1
8
M2
8
M1
2
M5
M1
1
M7
5
M1
9
M2
9
M1
4
M2
4
M7
7
M2
2
M7
3
M8
9
M5
8
M4
4
M7
8
M1
18
M8
3
M8
1
M4
9
M9
2
M1
14
M1
8
M2
8
M1
2
M5
M1
1
M7
5
M1
9
M2
9
M1
4
M2
4
M7
7
M8
9
M4
4
M7
8
M1
18
M8
3
M8
1
M4
9
M9
2
M2
8
M1
2
M5
M1
1
M7
5
M1
9
M2
9
M1
4
M2
4
M7
7
M8
9
M4
4
M7
8
M1
18
M8
1
M4
9
M9
2
U.S. and Canadian GAS Pharyngitis emm Types Included in
30-Valent Vaccine (U.S. and Canada, Study Years 1-7, 2000-07,
N=8474)
+5 emm types with <4 isolates each
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
12 1 4
28 3 2 6
75
89
77
22 5
11
18
29
11
4
92
+O
the
rs
emm Type
Nu
mb
er
0
10
20
30
40
50
60
70
80
90
100
Cu
mu
lati
ve
%
Number
Cumulative %
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Bactericidal Antibodies Evoked by 30-Valent
Vaccine against Non-Vaccine Serotypes of GAS
0
20
40
60
80
100
M8
M
9
M1
5
M1
7
M2
5
M3
0
M3
3
M3
6
M4
0
M4
2
M4
3
M4
8
M5
1
M5
2
M5
3
M5
4
M5
5
M5
9
M6
0
M6
3
M6
4
M6
5
M6
6
M6
8
M7
0
M7
1
M7
6
M7
9
M8
0
M8
5
M9
4
M9
5
M9
7
M1
00
M
10
2
M1
05
M
10
9
M1
11
M
11
6
M1
19
M
12
2
M1
24
st
13
89
st
17
31
st
24
60
st
46
95
st
XH
1
% K
illin
g
Potential Coverage of 30-valent Vaccine against Invasive GAS in Europe
Based on Bactericidal Activity Observed against Vaccine and Non-vaccine
Serotypes (StrepEuro Data)
emm Type
0
100
200
300
400
500
600
700
800
900
1
28
3
89
87
12
4
83
81
5
77
6
22
18
75
82
43
11
78
73
2
33
11
8
44
/61
53
58
9
79
stN
S10
33
VT
Oth
er
NV
T O
the
r
Nu
mb
er
of
iso
late
s
0
10
20
30
40
50
60
70
80
90
100
Cu
mu
lati
ve %
po
ten
tial
co
vera
ge
Vaccine serotype
Cumulative %
Non-vaccine serotype
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Potential Coverage of 30-valent Vaccine in
Bamako, Mali Based on Bactericidal Activity
Observed against Vaccine and Non-vaccine Serotypes
Vaccine serotype
Cumulative %
Non-vaccine serotype
0
5
10
15
20 1
8
25
6
5
28
5
8
77
8
1
10
9
42
6
4
74
8
5
89
4
11
7
5
95
1
23
1
9
11
8
st1
73
1
st2
90
4 8
63
7
9
82
9
7
stK
NB
st
13
89
4
4
69
7
1
92
3
22
5
3
60
7
8
10
0
11
1
st2
46
0
stX
H1
st
29
11
1
14
Nu
mb
er
of
Iso
late
s
0
10
20
30
40
50
60
70
80
90
100
Cu
mu
lati
ve %
of
tota
l iso
late
s
Bactericidal Activity of 30-Valent Vaccine Antisera against
Cape Town Pharyngitis emm Types, N=118
(Vaccine and Non-vaccine Serotypes)
Vaccine serotype
Cumulative %
Non-vaccine serotype
0
5
10
15
20
48
12
4
94
22
89
1
75
9
2
80
82
11
6 3
6
8
87
44
53
77
92
15
28
33
43
58
64
7
st2
00
2
Nu
mb
er
of
Iso
late
s
0
10
20
30
40
50
60
70
80
90
100
Cu
mu
lati
ve %
of
tota
l iso
late
s
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Summary of Bactericidal Antibodies Evoked in Rabbits
by the 30-valent Vaccine Against Vaccine and Non-
Vaccine Serotypes
• Total emm-types tested: 83
• Vaccine types + non-vaccine types >50%
killing: 73 (88%)
• Bactericidal killing of >50% observed with
43/53 (81%) non-vaccine serotypes
• Of the 43 serotypes that displayed >50%
killing, average bactericidal activity was 80%
Potential Coverage of 30-Valent Vaccine Based on
Vaccine Types and Cross-Opsonized
Non-vaccine Types
% Total isolates (cases)
VT only
VT + NVT
(cross-opsonized)
Pharyngitis-NA 98 98
Invasive Disease-US 90 93
Invasive Disease-Europe 78 97
Pharyngitis-Bamako 40 84
Pharyngitis-Cape Town 59 90
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Future of the 30-Valent Vaccine
• Basic pre-clinical work completed
• Comprehensive assessment of cross-opsonic antibodies with GAS isolates from developing countries is ongoing
• Vaxent has entered into a license agreement/collaboration with the Pan-Provincial Vaccine Enterprise Inc. (PREVENT) of Canada
• PREVENT and Vaxent will jointly develop the 30-valent vaccine
• GMP manufacturing is underway
• Next steps include pre-clinical toxicology studies and a phase 1 clinical trial in Halifax (Scott Halperin, PI)
Summary 30 valent
• Recombinant multivalent M protein-based vaccines have been well-tolerated and highly immunogenic in early phase clinical trials
• A new 30-valent vaccine in pre-clinical development evokes bactericidal antibodies against all 30 vaccine serotypes of GAS and is free of tissue cross-reactive epitopes
• Immunity against GAS may not be as “type-specific” as once thought; the 30-valent vaccine antisera cross-opsonized 81% of the non-vaccine serotypes tested to date
• M protein-based vaccines may provide coverage sufficient for developed and developing countries (more data are required)
• M related proteins may add cross-protection
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The J8 vaccine - Animal data encouraging - Adult vaccine phase I trials underway in 2013 – single dose safe and immunogenic in 6 6 volunteers
p145 LRRDLDASREAKKQVEKAL
p146 AKKQVEKALEEANSKLAALE
p147 EANSKLAALEKLNKELEESK
p148 KLNKELEESKKLTEKEKAEL
p149 KLTEKEKAELQAKLEAEAKA
p150 QAKLEAEAKALKEQLAKQAE
p151 LKEQLAKQAEELAKLRAGKA
p152 ELAKLRAGKASDSQTPDTKP
p153 SDSQTPDTKPGNKAVPGKGQ
p154 GNKAVPGKGQAPQAGTKPNQ……….
Courtesy Professor Michael Good, QIMR J8
Weaknesses of current pipeline
• Lack of commercial interest
• Lack of public awareness and support
• Consequence – very likely vaccine preventable disease burden remains high
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Likelihood of Vaccine emerging
• High POS – good clinical endpoint for triage and functional relevance with strep throat
• Biological plausibility: Inverse correlation of increased age and acquired immunity and disease frequency, protection against human challenge after M protein immunization shown
• Functional assays available to de-risk – similar to the successful development of conjugate vaccines for other streptococci
• Advanced vaccine candidates available
Potential WHO role
• Prioritize GAS prevention • Raise public awareness of high disease burden of a
preventable disease • Endorse staged clinical development from strep throat to
ARF and RHD (roadmap) • Consensus on clinical endpoints
– NIH criteria for diagnosis or ARF and RHD available, may need some updating
– Recent publication of new criteria for echocardiographic diagnosis (2012)
• Endorse further disease burden research and functional assays – as supported by the governments of NZ and AUS (CANVAS)
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Coalition to Advance New Vaccines against group A Streptococcus
• Collaborative project between New Zealand and Australian
governments
• Initial funding for the following three key exercises:
– Economic analysis of GAS vaccine impact
– Strain selection strategy
– Evaluation pathway for vaccine candidates including
immunoassay development
• If first phase successful, further funding application for
support of leading candidate/s
Summary
• Clear need for a GAS / RF vaccine
• A century of research, but recent progress
• A commercially viable vaccine to prevent strep throat might be first step
• Test and make available for high disease burden areas
• Concerted efforts needed to overcome real and perceived obstacles – Potential for Trans-Tasman Initiative