The Endgame: END RHD CRE and RF vaccines. Jonathan Carapetis

Transcription

1 The Endgame: END RHD CRE and RF vaccines Jonathan Carapetis

2 END RHD CRE D e v e loping a n endgame for r h e u matic h e a r t d isease in Australia

3 1953 Holmes et al A study of RF and streptococcal infection in different social groups in Melbourne 1954 Lupton J. Social factors in rheumatic heart disease 1940s 1950s Urban disease and rheumatic fever wards 1956 Powell ML Four faces of rheumatic heart disease in paediatrics

4 1990 ARF and RHD in a rural central Australian Aboriginal community. Retrospective case review of 976 clinical records from Australian Aboriginal community between s 1980s Case record reviews outside urban centers 1981 ARF in the West Kimberly. 60 case records of ARF admissions to Derby Regional Hospital RHD in Aboriginal children in the Northern Territory. Cases records of 33 children with RHD in Darwin over 4 years.

5 1993 Rheumatic fever and chronic RHD in Yarrabah Aboriginal community, North Queensland Mortality due to acute rheumatic fever and rheumatic heart disease in the Top End of Australia s Northern Territory 1999 Outcomes of cardiac valve replacement in for RHD in Aboriginal Australians 1999 ARF in the Kimberly region of Western Australia 1990s Evidence

6 1990s Action 1996 ARF notifiable in the Northern Territory 1997 Register based control program in the Top End of the Northern Territory begins 1999 National Health Priority Area Report on Cardiovascular Health Aim to reduce mortality from RHD by 50% by 2008

7 2006 Challenging perceptions of non-compliance with rheumatic fever prophylaxis in a remote Aboriginal community 2000s Evidence 2000 Cumulative incidence of RF in an endemic region: a guided to the susceptibility of the population 2005 Global Burden of Group A Streptococcal Diseases

8 2000 Central Australia RHD control program established 2000s Action 2010 Control programs in Western Australia and Queensland begin 2009 Commonwealth Rheumatic Fever Strategy announced

9 2010s Research

10 Unified RHD research and translation agenda

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14 We commit to identify a set of costed, stepwise interventions which are most likely to reduce the incidence of ARF and the prevalence of RHD for Indigenous Australians to the same level as non- Indigenous Australians. To eliminate RHD as a public health priority in Australia

15 Primary care Atlas of RHD Data linkage 1a. Burden of disease 1b. Burden of skin sore + throat 1. Epidemiology and Bioscience 1d. Vaccine 1c. Days at risk of RHD 2a. Primary care package 2. Implementation and Translation 2e. Tertiary outcomes 2b. Clinical guidelines 2c. Improved prophylaxis 2d. Echo 3a. Process and protocols 3. The RHD Community 3b. Telling the RHD Story 3c. Lifecourse approach

16 Preventing RHD GAS infection ARF Primordial prevention Primary prevention -Sore throat Rx -? Vaccine -? Skin sore Rx Often prolonged asymptomatic period of RHD Secondary prevention -Regular penicillin RHD Tertiary prevention -Heart failure medication -Surgery -Anticoagulation Cardiac surgery Stroke, endocarditis Death

17 Preventing RHD Only proven effective, and cost-effective intervention for preventing/controlling RHD Often prolonged asymptomatic period of RHD GAS infection ARF RHD Primordial prevention Primary prevention -Sore throat Rx -? Vaccine -? Skin sore Rx Secondary prevention -Regular penicillin Tertiary prevention -Heart failure medication -Surgery -Anticoagulation Cardiac surgery Stroke, endocarditis Death

18 Preventing RHD NZ RFPP may inform us as to whether sore throat intervention is effective and costeffective Often prolonged asymptomatic period of RHD GAS infection ARF RHD Primordial prevention Primary prevention -Sore throat Rx -? Vaccine -? Skin sore Rx Secondary prevention -Regular penicillin Tertiary prevention -Heart failure medication -Surgery -Anticoagulation Cardiac surgery Stroke, endocarditis Death

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

20 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

21 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

22 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

23 ? 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

24 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.

25 Types of vaccines M protein based vaccine Multi-valent M protein vaccine VARIABLE REGION CONSERVED REGION

26 Other vaccine types Conserved region M protein vaccines OR Non M protein vaccines VARIABLE REGION CONSERVED REGION

27 Current leading vaccine candidates Griffith University J8-DT/Alum Conserved M protein vaccine (Brisbane, Australia) PI: Michael Good StreptInCor C-terminal portion of M protein (Heart Institute, São Paulo) PI: Luiza Guilherme PREVENT 30-Valent M protein based Vaccine (Tennessee, USA Saskatchewan, Canada) PI: James Dale GSK 4-component non M protein vaccine (Siena, Italy, now GSK)

28 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

29 Established market economies Africa Pacific / Indigenous Australians

30 Bactericidal Antibodies Evoked by 30-Valent Vaccine Against Non-Vaccine Serotypes of GAS Dale, Vaccine 2013

31 Big pharma Wyeth / Pfizer Merck GSK Novartis Intercell What are the obstacles? - Safety? - Market? -Technical? - Other? Risk/profit balance

32 Coalition to Advance New Vaccines for Group A Streptococcus A trans-tasman initiative to combat rheumatic fever

33 Conversation between Prime Minister John Key and Dean of Auckland Medical School, Professor John Fraser Prime Ministers of NZL and AUS investigate possible joint support towards a program Partnership with Professor Jonathan Carapetis, Director of Telethon Kids Institute Program commissioned through Australian NHMRC and NZ HRC Discussions with vaccine developers, local and international experts, stakeholders Government s Chief Science Advisors oversee proposal development and initial peer review

34 CANVAS Stage 1 Selection of representative panel of GAS strains Evaluation of potential protection against the panel Develop immunological assay Economic analysis Making the case for investment in a GAS vaccine in Aust/NZ

35 Strain selection, bioinformatics and lead candidate selection Andrew Steer, Pierre Smeesters, Deborah Williamson, Steven Tong, Mark Davies, Nikki Moreland, Mark Walker, Thomas Proft

36 Number of isolates Other clinical manifestations (impetigo, pharyngitis, ) in ANZ, the Pacific and worldwide igas worldwide ARF worldwide igas in ANZ and Pacific ARF in ANZ and Pacific

37 Global collection (n=1579) CANVAS core collection (n= ) CANVAS minimal set (n=20-40)

38 Development of candidate evaluation assays For assessing the efficacy of GAS vaccine candidates Current gold standard - Lancefield bactericidal assay Methodology established decades ago and unsuitable for use in contemporary clinical trials Uses whole blood from human donors Whole blood causes large variance between experiments Some GAS strains do not grown in whole human blood Relies on data from a single serum dilution (1:5) 50% killing considered protective

39 NIH-PA Author Manuscript NIH-PA Author Manuscript Lancefield Assay Data Example 30-valent antisera against non-vaccine M-types (Dale JB et al., (2011) Vaccine) Dale et al. Page 9 Protected 50% Not-Protected Fig. 3. Bactericidal antibodies evoked by 30-valent vaccine against non-vaccine serotypes of GAS.

40 Group A Strep OPK Modelled opsonisation killing assays (OPK) from assays developed for S. Pneumo Use HL60 cells (neutrophil cell line), not whole blood Robust assessment of killing; generate titration curve and calculate opsonisation index (OI) Goldblatt Laboratory, University College London WHO reference laboratory for Pneumococcal serology Leading expertise in HL60 cell differentiation and OPK methodology David Goldblatt

41 CANVAS Economic Outcomes Is preventing GAS disease by vaccination an economically viable strategy? 1. Cost of GAS infections and health burden 2. Economic evaluations of other (non-vaccination) GAS prevention programmes. - Primary prevention of ARF - Secondary prevention of recurrent ARF, and RHD 3. Determine the cost-effective price of a vaccine - Govt subsidisation

42 Clinical Development Plan Developing a road map for clinical development of GAS vaccines

43 Summary Major technical and safety challenges to GAS vaccine development are surmountable CANVAS initiative should de-risk early stage clinical development An RF vaccine is a realistic possibility in the medium term

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