Prevention through vaccination

Transcription

1 Prevention through vaccination The Science of Rheumatic Fever Surveillance and Control Feb 4, 2013 Jonathan Carapetis Telethon Institute for Child Health Research Andrew Steer Centre for International Child Health, Melbourne

2 Group A streptococcal vaccines Given the global burden of GAS disease, including rheumatic heart disease, and the complexity of an effective population-level approach to preventing rheumatic fever, a GAS vaccine is clearly needed.

3 Priority GAS-vaccine preventable Superficial infection Pharyngitis Pyoderma diseases High and high-middle income countries Invasive diseases Septicaemia Pneumonia, osteomyelitis Necrotising fasciitis Toxin mediated diseases Scarlet fever Streptococcal toxic shock syndrome Low and low-middle income countries Post-streptococcal autoimmune sequelae Acute rheumatic fever / rheumatic heart disease **** Post-streptococcal glomerulonephritis? chronic renal impairment/failure

4 Susceptible host GAS vaccine GAS infection ARF No RHD RHD RHD morbidity (CCF, AF, IE, Stroke) Death

5 Michaud C, et al. In: Jamison DT, et al, eds. Disease control priorities in developing countries. Oxford: Oxford University Press, 1993: ; and Michaud C et al. In: Narula J et al, eds. Rheumatic fever. Washington, D.C.: American Registry of Pathology, 1999:

6 GAS vaccines

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8 VARIABLE REGION 1. Type-specific M-protein Basis of emm typing CONSERVED REGION

9 Human GAS immunisation Veldee et al Public Health Report 1940 Erythrogenic toxin n=41,109 children subjects Young et al Navy Bulletin 1945 Heat-killed or ultraviolet inactivated GAS n=7000 subjects

10 Human GAS immunisation Whole cell/toxin M protein Purified M protein

11 Human clinical trials of GAS vaccines (courtesy A Steer, adapted from Curr Opin Infect Dis Dec;22(6):544-52) Total 3905 vaccinated adults, 7365 vaccinated children

12 The Massell study 21 children who had a sibling with rheumatic fever Purified M protein vaccine Vaccinated weekly with increasing concentrations For weeks Reduction in number of GAS infections 3 vaccinees developed rheumatic fever Massell JAMA 1969;207:1115

13 ? Real risk of ARF following M protein vaccination Many problems with Massell study Multiple other studies with no reported cases HOWEVER Led to FDA 21 CFR in 1979 Group A streptococcus organisms and derivatives are prohibited from bacterial vaccines and bacterial antigens

14 2 deaths both in RSV immunised children

15 Revocation of 21 CFR Part 610 February The Food and Drug Administration (FDA) is removing the regulation applicable to the status of specific products; Group A streptococcus.

16 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 Serum opacity factor (Sof) Secreted Cell surface Cell surface Secreted Proteolysis of bact. and host proteins Opsonic epitopes 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

17 VARIABLE REGION emm CONSERVED REGION Well tolerated Good immune responses

18 New 30-Valent Vaccine Protein 1 M1 3.1 M6.4 M2 M18 M28 M12 SPA M (1-25)2 (1-25) Protein 2 M4 M5.14 M11 M75 M19 M29 M14.3 M24 M (1-25) (1-25) Protein 3 M77 M22 M73 M89 M58 M44 M78 M118 M Protein 4 M83.1 M82 M81 M87 M49 M92 M114 M

19 M1 M3 M6 M2 M18 M28 M12 SPA M4 M5 M11 M75 M19 M29 M14 M24 M77 M22 M73 M89 M58 *M44 *M78 *M118 *M83 M82 *M81 *M87 *M49 M92 M114 Mean ELISA Titer (Log 2 ) Geometric Mean Antibody Levels (Log 2 ) Evoked in Rabbits Immunized with 30-Valent Vaccine Dale et al

20 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 30-Valent Vaccine Against Vaccine Serotypes of GAS Dale et al

21 Others Number Cumulative % U.S. and Canadian GAS Pharyngitis emm Types Included in 30-Valent Vaccine (U.S. and Canada, Study Years 1-7, , N=8474) emm Type Number Cumulative % Dale et al + 5 emm types with <4 isolates each

22 Number Cumulative % StrepEuro Invasive emm Types Included in 30-Valent Vaccine (4,375 invasive isolates, ) emm Type Number Cumulative % Dale et al + 5 emm types with <4 isolates each

23 Established market economies Africa Pacific / Indigenous Australians

24 % Killing Bactericidal Antibodies Evoked by 30-Valent Vaccine Against Non-Vaccine Serotypes of GAS M15 M17 M30 M33 M36 M40 M42 M43 M48 M51 M52 M53 M54 M55 M59 M63 M64 M65 M66 M68 M70 M71 M76 M79 M8 M80 M85 M9 M94 M95 M97 M100 M102.2 M105 M109 M111 M116 M119 M122 M Dale et al

25 Summary of Bactericidal Antibodies Evoked by 30-Valent Vaccine Against Non-Vaccine Serotypes Bactericidal activity of >40% killing observed with 24/40 non-vaccine serotypes tested to date Of the 24 serotypes that displayed >40% killing, average bactericidal activity was 78% Average for all 40 serotypes tested was 54% killing

26 *other Number Cumulative % Cumulative Percentage of StrepEuro Invasive emm Types Opsonized by 30- Valent Vaccine Antiserum (4,375 invasive isolates, ) Vaccine serotype Non-vaccine serotype emm Type Number Cumulative % Dale et al

27 st2002 Number Cumulative % Bactericidal Activity of 30-Valent Vaccine Antisera against Cape Town Pharyngitis emm Types (Vaccine and Non-vaccine Serotypes) Vaccine serotype Non-vaccine serotype total isolates (28 emm types) 59% of all isolates represented in 30-valent vaccine Serotypes representing 90 % of all isolates opsonized by 30-valent antisera emm Type Number Cumulative % Dale et al

28 Number Cumulative % Bamako, Mali GAS Pharyngitis emm Types Included in 30- Valent Vaccine total isolates (74 emm types) Serotypes accounting for 44% of all isolates included in 30-valent vaccine Serotypes accounting for 68% of all isolates opsonized by 30-valent antisera (incomplete assessment) 15% of all isolates rheumatogenic types Number Cumulative % emm Type Dale et al

29 Other vaccine candidates Conserved region M protein vaccines OR Non M protein vaccines VARIABLE REGION CONSERVED REGION

30 New vaccine candidates Conserved M protein vaccines - The J8 vaccine Non M protein vaccines - C35a peptidase - GAS carbohydrate - Fibronectin binding proteins - Cysteine protease - Streptococcal pili - Genomic and proteomic fishing for vaccines

31 The J8 vaccine - Animal data encouraging - Adult vaccine phase I trials to start 2013 p145 LRRDLDASREAKKQVEKAL p146 AKKQVEKALEEANSKLAALE p147 EANSKLAALEKLNKELEESK p148 KLNKELEESKKLTEKEKAEL p149 KLTEKEKAELQAKLEAEAKA p150 QAKLEAEAKALKEQLAKQAE p151 LKEQLAKQAEELAKLRAGKA p152 ELAKLRAGKASDSQTPDTKP p153 SDSQTPDTKPGNKAVPGKGQ p154 GNKAVPGKGQAPQAGTKPNQ. J8 Courtesy Professor Michael Good, QIMR

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33 Big pharma Wyeth / Pfizer Merck GSK Novartis Intercell What are the obstacles? - Safety? - Market? - Other?

34 GAS vaccines current status M serotype specific vaccine 30 valent -? Significance of immunol cross reactivity Ready for clinical trials -?2013 J8-14 conjugate Clinical trials 2013 Novartis vaccine? Potential to enter clinical trials

35 10 next steps Update disease burden mortality, DALY Sentinel sites - disease burden / vaccine trials Global molecular epidemiology of GAS Improved tools for clinical testing including high throughput bactericidal assay Refine protocols for the testing of GAS vaccines Develop a Target Product Profile Explore collaborative approach - academia, industry, public health agencies/institutions Involve big pharma Develop a road-map for vaccine development Plan and coordinate large funding applications

36 Real next steps Get a vaccine into clinical trials ASAP for pharyngitis Find out from big pharma what the real reasons are for their reticence Two parallel and complementary aims: Encourage industry Long-term aim for a vaccine for the world

37 Summary Clear need for a GAS / RF vaccine A century of research, but recent progress Still concerted efforts needed to overcome real and perceived obstacles When available, still the challenges of provision to the populations that need it most