17/09/2014

1

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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2

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