Group A streptococcal vaccines:
challenges and progress
Florian Schödel
Philimmune LLC
Thanks to:
• 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
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
Summary of estimated global burden of GAS diseases
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
RHD-related infective
endocarditis
RHD-related stroke
1.88 million
188,000*
Acute post-streptococcal
glomerulonephritis
Invasive group A streptococcal
diseases
Total severe cases
18.1 million
Pyoderma
111 million
Pharyngitis
34,000
8,000
640,000
144,000
108,000
§
472,000
5,000
663,000
163,000
1.78 million
517,000
616 million
Lancet Infect Dis 2005;5:685-94
GBD 2010 estimates*
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
462,579
363,864
345,110
Deaths
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
Lancet 2012 and GBD website
Estimated global mortality from individual pathogens, 2002
Lancet Infect Dis
2005;5:685-94
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?
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)
Secreted
Proteolysis of bact. and host proteins
Group carbohydrate
Cell surface
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
Two clinically most advanced vaccine
candidates
• Recombinant
multivalent M protein
fusion peptides
• 30 valent
• Short conserved M
protein peptide
conjugate J8
30-Valent Vaccine (StreptAnova )
TM
Protein 1
M1
3.1
M6.4
M2
M18
M28
M12
SPA
M1
1-50
32-81
(1-25)2
(1-25)2
1-50
1-50
1-50
1-50
1-50
M4 M5.14 M11
M75
M19
1-50
1-50
(1-25)2
1-45
Protein 2
1-50
(1-25)2
M29 M14.3 M24
1-50
M4
1-50
1-50
Protein 3
M77
M22
M73
M89
M58
M44
1-50
1-50
1-50
1-50
1-50
1-50
M78 M118 M77
1-50
1-50
1-50
Protein 4
M83.1 M82
1-50
1-50
M81
M87
M49
1-50
1-50
1-50
M92 M114 M83.1
1-50
1-50
1-50
0
M1
M3
M6
M2
M18
M28
M12
M4
M5
M11
M75
M19
M29
M14
M24
M77
M22
M73
M89
M58
M44
M78
M118
M83
M82
M81
M87
M49
M92
M114
% Killing
Bactericidal Antibodies Evoked by 30Valent Vaccine
100
80
60
40
20
U.S. and Canadian GAS Pharyngitis emm Types Included in
30-Valent Vaccine (U.S. and Canada, Study Years 1-7, 2000-07,
1300
100
N=8474)
1200
90
1100
70
800
60
700
Number
Cumulative %
600
50
500
40
400
30
300
20
200
10
100
+5 emm
92
+Others
emm Type
114
29
18
11
5
22
77
89
75
6
2
3
28
4
0
1
0
12
Number
900
Cumulative %
80
1000
types with <4 isolates each
0
M8
M9
M15
M17
M25
M30
M33
M36
M40
M42
M43
M48
M51
M52
M53
M54
M55
M59
M60
M63
M64
M65
M66
M68
M70
M71
M76
M79
M80
M85
M94
M95
M97
M100
M102
M105
M109
M111
M116
M119
M122
M124
st1389
st1731
st2460
st4695
stXH1
% Killing
Bactericidal Antibodies Evoked by 30-Valent
Vaccine against Non-Vaccine Serotypes of GAS
100
80
60
40
20
Potential Coverage of 30-valent Vaccine against Invasive GAS in Europe
Based on Bactericidal Activity Observed against Vaccine and Non-vaccine
Serotypes (StrepEuro Data)
900
100
90
800
70
60
500
50
Vaccine serotype
Non-vaccine serotype
Cumulative %
400
300
40
30
200
20
100
10
VT Other
NVT Other
stNS1033
9
79
58
118
2
33
44/61
53
emm Type
73
11
78
82
43
75
22
18
6
5
77
81
4
83
12
89
87
0
3
0
1
28
Number of isolates
600
Cumulative % potential coverage
80
700
Potential Coverage of 30-valent Vaccine in
Bamako, Mali Based on Bactericidal Activity
Observed against Vaccine and Non-vaccine Serotypes
20
100
90
80
10
Vaccine serotype
Non-vaccine serotype
Cumulative %
60
50
40
30
5
20
10
0
0
18
25
65
28
58
77
81
109
42
64
74
85
89
4
11
75
95
123
19
118
st1731
st2904
8
63
79
82
97
stKNB
st1389
44
69
71
92
3
22
53
60
78
100
111
st2460
stXH1
st2911
114
Number of Isolates
70
Cumulative % of total isolates
15
Bactericidal Activity of 30-Valent Vaccine Antisera against
Cape Town Pharyngitis emm Types, N=118
(Vaccine and Non-vaccine Serotypes)
20
100
90
80
60
10
50
Vaccine serotype
Non-vaccine serotype
Cumulative %
40
30
5
20
10
st2002
7
64
58
43
33
28
15
92
77
53
44
87
8
6
3
116
82
80
2
9
75
1
89
22
94
4
0
12
0
48
Number of Isolates
70
Cumulative % of total isolates
15
Summary of Bactericidal Antibodies Evoked in Rabbits
by the 30-valent Vaccine Against Vaccine and NonVaccine 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
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 and Conclusions
• 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 crossopsonized 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)
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
p153
p154
J8
ELAKLRAGKASDSQTPDTKP
SDSQTPDTKPGNKAVPGKGQ
GNKAVPGKGQAPQAGTKPNQ……….
Courtesy Professor Michael Good, QIMR
CANVAS (Coalition to Accelerate New Vaccines
Against Streptococcus)
- aka the Trans-Tasman GAS vaccine initiative
• NZD 3 million first tranche in 2013-4 budgets
of NZ and Aust
• To evaluate up to three vaccines for proof of
principle (broadly cross-reacting functional
antibodies)
• ? Subsequent tranche of $30-40 million
• Awaiting response from NHMRC and NZ HRC
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