TB Vaccine Development in Indonesia SEA-EU NET, 21-22 January 2014 Francisca S Tanoerahardjo.

Presentasi berjudul: "TB Vaccine Development in Indonesia SEA-EU NET, 21-22 January 2014 Francisca S Tanoerahardjo."— Transcript presentasi:

1 TB Vaccine Development in Indonesia SEA-EU NET, 21-22 January 2014 Francisca S Tanoerahardjo

2 LOGO OUTLINE  TB Situation in Indonesia  On Going TB Vaccine research consortium  Challenges (Resources and Management)

3 LOGO Indonesia  Indonesia is an archipelago - 17,508 islandsarchipelago17,508 islands  Population over 238 million people  The 4th most populous countrymost populous

4 LOGO TB Situation in Indonesia  22 TB High Burden Countries  TB Prevalence (estimated) WHO – NTP : 124/100.000 population  DOTS implementation  Distric Health Clinic (Goverment) - 90%  Hospital - 30-40%  Private Clinic – Public Private Mixed Program

5 LOGO TB Prevalence Survey 2013-2014

6 LOGO Result Dec 2014

7 LOGO Program 2011-2020  Ministry of Health  National Institute of Health Research and Development  Ministry of Research and Technology  National Incentive Program Collaborative Research

8 LOGO Goal of the Collaborative Research Focus on product : Health and Drug  Vaccine development  Drug discovery  Improvement of Health Technology Assesment  Saintifikasi jamu (Herbal) – Natural Product Priority :  Infectious diseases (Malaria, TB, HIV, Dengue, Influenza)  No infectious diseases (Cardiovascular & cancer)

9 LOGO On going TB Research  TB Vaccine Research :Collaborative Research, Academicy (13 University ) – Goverment (Ministry of Health, Ministry of Research & Technology)– Industry (PT. Bio Farma Tbk)  TB Prevalence Survey  TB Operational Research  Individual Research

10 LOGO History Individual Research Working Group Research Consortium (8 Institutes) Research Consortium (12 Institutes) < 2011201120122013 Research Consortium (12 Institutes) 2014

11 LOGO UNRAM UNEJ TB Vaccine Research Consortium NIHRD UNHAS UNBRAW UNAIR UGM ITB UNPAD UI Ministry of Health Ministry of Research & Technology 2012 Protein Rekombinan, Immunonicity test Preparation for M.tb dorman islate 2013 2014 2012 + Sekuensing BCG, BCG effectivity study 2013 + Sekuensing M.tb Beijing, proteomiks granuloma, adjuvan, PT Bio Farma LIPI UNIKA AJ

12 LOGO Protein Sub-Unit  Secreted protein  Esat6, Cfp10, Ag85, Ag38kD  Protein PE & PPE  PE17  PE41  Protein Rpf  Lipoprotein LipY 5 Institution: University of Indonesia Institute of Technology Bandung University of Hasanuddin University of Mataram Center of Biomedic and Tecnology Developemny NIHRD

13 LOGO Adjuvant  LIPOTEK – Australia  base on Liposome – Antigens  Formulation & proof of concept

14 LOGO Immunogeniety Study  Subject  TB patients  Healthy but contact TB pos  Healthy without contact  Test  TST  CD4, CD8, IFN ɣ, IL2  IL17

15 LOGO Kelom pok sampel Kelompok perlakuan [(rerata (SD)] Kontrol (tanpa perlakuan) Paparan Protein rekombinan 38 kDa Mtb 2 µg/ml Paparan PPD 2 µg/ml IL-2 (%)IFNg (%)IL-2 (%)IFNg (%)IL-2 (%)IFNg (%) Sehat 5,19 (0,54) 11,69 (1,52) 8,16 (0,55) 11,19 (0,33) 7,29 (0,44) 7,48 (0,17) Kontak TB 3,84 (0,39) 8,46 (0,58) 7,10 (1,72) 3,08 (0,14) 6,28 (0,95) 3,43 (1,72) Pasien TB 6,18 (1,89) 5,62 (2,89) 6,50 (2,67) 4,94 (1,32) 6,85 (2,73) 6,82 (4,13) Hasil pemeriksaan flowcytometry (SD) sitokin intraseluler IL-2 dan IFN- Ɣ in ach group

16 LOGO IL-4 dan IL-10  Rerata limfosit (CD3) yang menghasilkan IL- 4 pada masing-masing kelompok adalah sbb: Pasien: PK: 23,87%; PP: 25,50%; PA: 37,96%. Kontak: KK: 28,98%; KP: 16,80%; KA: 16,19%. Sehat: SK: 40,82%; SP: 22,71%; SA: 22,55%.  Rerata limfosit (CD3) yang menghasilkan IL- 10 pada masing-masing kelompok adalah sbb: Pasien: PK: 25,96%; PP: 18,73%; PA: 8,94%. Kontak: KK: 40,64%; KP: 34,48%; KA: 32,19%. Sehat: SK: 52,47%; SP: 37,58%; SA: 33,49%.

17 LOGO M.tuberculosis dorman  M.tuberculosis isolates  Sauton medium  Minimum Carbon source  M.tuberculosis from granuloma lung resection  Proteomics analysis  Re-culture

18 LOGO BCG Effectivity- baseline data (2014)  Community Study (+200 houses @ 4 person)  East Java (rural area)  Jakarta (urban area)  Quesionairre –  BCG vaccination  TB cases  Environment  TST & IGRA  HLA

19 LOGO Problem  Data on BCG vaccination  Facilities -  Technology  Standarization

20 LOGO  Thank you

21 LOGO Roadmap International TB Research - 2011 EpidemiologyFundamental Research DiagnosticsOperational & PH Research Vaccine Treatment Characterized Human TB Host- pathogen interaction identification of the causes of low rate case detection & cure transmission host– pathogen Interaction: mechanisms leading to persistence M. tb with the immune system host’s immune system identification of biomarkers of patients at each stage. evaluation of biomarkers identified in fundamental studies for use as diagnostic tools - validation of novel simple tools for diagnosis at points of care design target drug discovery for TB active & TB persistence identifi cation of the mechanism s of action of current and newly developed anti-TB drugs immuno dominant antigens protec tive immunity after vaccinati on prepara tion of clinical trial TB case-fi nding, in HIV- infected expanded access to treatment for Vulnerable diagnosis of & access to treatment for MDR-TB and XDRTB

22 LOGO TB Research 2009 – 2009 – Mapping the problem & Burden of diseases: 1Case Detection Rate / Cure Rate 2Retro study: hosp-based DOT’s : related mortality & Morbidity 3Prescription Study Risk factors: 1.Immunocellular host 2.Environment 3. Co-infection 4. Biosafety & Biosecurity Non-pharmaceutical Preventions: 1. Behavior change studies Health Economics: 1. Cost & benefits studies of TB Case management & prevention Early detection: 1. Rapid Diagnostic Test (RDT) (new tool / new method ) 2. Optimized DOT’s programs at peripheral lab. 3. Optimized Operational Research Outbreak Investigation: 1. Mapping genotype & strain 2. Environment investigation 3. Peripheral Lab. investigation Case Identification: 1. Diagnosis of new case 2. Diagnosis of MDR/XDR 3. Diagnosis of nonTB / MOTT 4. Diagnosis of co-infection Development of candidate vaccine/new drugs/new diagtoctic test: 1. Identification of major / specific Mtb in Indonesia; Mtb sequencing; selection of candidate vaccine (primer/ species specific); selection of drugs delivery system (DDS) or vaccine model; pharmacology / bioavailability-bioequivalence (BA/BE) 2. Identification of specific plant for TB in Indonesia; pre clinic study (phase I – III); BA/BE 3. Selection of RDT method Case diagnosis & management: 1. Case studies for MDR / XDR – MOTT; co-infection 2. Case management studies: DOT’s & other (Operational Research) 3. Development & testing of rapid D/& other D/methods 4. Development of new vaccine & new drugs Genetics: 1. Human genetic immunocellular 2. Genotype & phenotype of Mtb (Mycobact. tuberculosis) : inventory strain 3. Rapid Diagnostic Test (tool & method) 4. DOT’s drugs resistant (susceptibility of Mtb / MODS – Mycobacterium Observation of Drugs Susceptibility) Clinico-pathogenesis, Immunity: 1. TB related Immunity studies (incl. co-infection studies) Clinical trials: Colab.w/existing vacc./ new drugs / new diagnostic kit procedures (Phase IV) OBJECTIVES: 1. Epidemiology: Burden of disease, mapping & early detection system 2. Mtb characterization & Mapping 3. Human susceptibility & pathogenesis 4. Prevention of Risk factors, Therapy & Case management 5. BIO-banking 6. Selections of vaccine / new drugs / new diagnostic test for TB; Production of Vaccine, Diagnostic Tests, Drugs, etc. GOALS: 1TB prevention 2Early detection system 3Disease reduction 4Production of vaccine, dew drugs, rapid diagnostic test, etc

23 LOGO PONTIANAK MANADO MAKASSAR 52,7 SURABAYA PALEMBANG BANDUNG DKI AMBON SERANG BANJARMASIN PADANG MATARAM TJ.KARANG P.BARU SORONG 49,8 MEDAN DATA SURVEILANS EPIDEMIOLOGI MOLEKULAR HASIL PENELITIAN 2008-2010 Sampel : 404 spesimen dahak BTA positif pasien TB dari 16 ibu kota provinsi di Indonesia.

24 LOGO Keragaman genotipe Mtb di Indonesia

25 LOGO Peta awal filogenetik Mtb di Indonesia: Menggambarkan diversitas bakteri yang bersirkulasi Sum - KalJawaWil. Timur

26 LOGO Hasil Pengembangan Kit Diagnostik  Diagnostik molekuler – deteksi DNA M.tb  Metode Loop-Mediated Isothermal Amplification (LAMP), yang di modifikasi menggunakan primer sesuai isolat Indonesia yang telah dilakukan genotyping  Kit Diagnostik  Sederhana  Memungkinkan untuk dilaksanakan pada Laboratorium RS  Uji klinik skala kecil telah dilaksanakan  In house

27 LOGO KONSORSIUM RISET VAKSIN TB UNRAM UNEJ PBTDK UNHAS UNBRAW UNAIR UGM ITB UNPAD UI PBTDK-BALITBANGKES KEMENKES Insentif SINas KEMENRISTEK 2012 Protein Rekombinan, Uji Imunogenitas Penyiapan isolat M.tb dorman 2013 2014 2012 + Sekuensing BCG, efektivitas BCG 2012 + Sekuensing M.tb Beijing, proteomiks granuloma, peran Treg, adjuvan PT Bio Farma LIPI

28 LOGO Penyiapan Kandidat antigen: 1.Mencegah infeksi 2.Mencegah TB primer 3.Mencegah infeksi laten 4. Mencegah reaktivasi laten Uji Imunogeni sitas Formulasi Kandidat Vaksin Uji Preliminary pada Hewan Coba Pembuatan experiment al lot Pembuatan clinical lot Preclinical trial Clinical trial Basic Research 2012 - 2015 Pre Development 2014 - 2017 Development 2017 - 2019 Production 2020 Launching Product Produksi rutin Tahapan pembuatan vaksin Tujuan tahapan pembuata n vaksin ROADMAP VAKSIN TB SUB-UNIT LITBANGKES, ITB, UI, UGM, UNPAD, UNAIR, UNHAS BIO FARMA, LITBANGKES, UNPAD, UGM, UNAIR BIO FARMA Institusi

29 LOGO Genomics Analysis Antigen & Epitop Selection Protective Immunity Community Study Tahapan pembuatan vaksin Tujuan tahapan pembuatan vaksin (Basic Research) BASIC RESEARCH Laboratorium Laboratorium Hewan Coba Studi lapangan & Laboratorium Fasilitas Institusi Genome Sequence, Computer Analysis Antigen Selection / Productio n, B&T Cell Epitope Animal Protective Immunity Epid Molecular & Uji Diagnostik Seed Vacc ine Laboratorium

30 LOGO TERIMA KASIH

31 LOGO HASIL PENELITIAN KegiatanKemenristek (1M)Kemenkes (3,1M) Identifikasi Isolat Klinik M.tb sbg templat Antigen 19 isolat: 33% Beijing, 66% Non Beijing, 1% tak teridentifikasi Pembuatan Antigen kandidat vaksin Siap uji imunogenitas: RV1734, Rv2430, fusi Esat6-Mtb32c Perlu optimasi: Ag85B, Rv2660c, PG14 Esat6 & Cfp10 (selanjutnya digunakan sebagai kontrol) Uji ImunogenitasOptimasi metode flowsitometri, dotblot, dan Elisa Pembuatan isolat M.tb dorman in vitro Pengamatan pertumbuhan koloni M.tb dorman dan identifikasi fenotipik

32 LOGO HASIL PENELITIAN KegiatanKemenristek (1M)Kemenkes (3,1M) Sekuensing BCGTotal genom M.bovis BCG (vaksin produksi PT BioFarma), 6 isolat. M.tb H37Rv, 7 isolat. Uji efektivitas BCG Data kasus TB di lapangan (data sekunder dari Dinkes Kab) Model uji efektivitas BCG di masyarakat Diskusi perencanaan, evaluasi, laporan semua anggota Konsorsium Diskusi interaktif, persamaan persepsi, saling tukar informasi dan membangun kepercayaan

33 LOGO HASIL PENELITIAN KegiatanKemenristek (1M)Kemenkes (3,1M) Sinergisme pemanfaatan sarana prasarana Menggunakan isolat dan plasmid antar anggota Pemanfaatan fasilitas Laboratorium Nasional di PBTDK oleh anggota Konsorsium Training/SeminarShortcourse Vaccinology for Clinical & Public Health Practice, Singapura Okt 2013 7 th World Vaccine Congress Asia, Singapura Juni 2013 Workshop Flowsitometri, Jakarta September 2013 WS Imunologi, Jogja September 2013 PublikasiPoster Presentation, APFCB, Bali Oktober 2013 Draft: Whole Genome Sequence BCG Presentasi/SosialisasiEU TCF Workshop, Jakarta – Oktober 2013

34 LOGO RENCANA TINDAK LANJUT  Keberlanjutan: (?)  Jaminan pendanaan & program & institusi yang mengawal kegiatan Konsorsium  Bedah Buku Konsorsium Riset Vaksin:  Cerita kebutuhan keberlanjutan Riset Vaksin sebagai salah satu riset yang berorientasi pada PRODUK yang akan diproduksi oleh Industri.  Merupakan riset jangka panjang yang merupakan kebijakan TOPDOWN (tidak kompetitif)

35 LOGO RENCANA TINDAK LANJUT  Sumber Pendanaan:  Kemenkes – DIPA (multi years sampai 2020)  Kemenristek – INSINas (?) – dpt TOP DOWN?  Kemendikbud – in kind Universitas (sarpras & SDM)  Kemen BUMN – Industri  Bappenas --  Kemenkeu –  Sosialisasi - Kolaborasi Riset dengan LN  ASEAN-European Union Meeting, Bangkok Januari 2014  TBVI (TuBerculosis Vaccine Initiative) dengan sumber pendanaan Bill Gate Foundation

36 LOGO TERIMA KASIH

37 LOGO AdAg85A McMaster University Hybrid-I+CAF01 SSI, TBVI H56+IC31 SSI, Aeras, Intercell Hyvac 4/ AERAS-404 +IC31 SSI, sanofi-pasteur, Aeras, Intercell ID93/GLA-SE IDRI, Aeras M72+AS01 GSK, Aeras VPM 1002 Max Planck, Vakzine Projekt Mgmt, TBVI Hybrid-1+IC31 SSI, TBVI, EDCTP, Intercell RUTI Archivel Farma, S.L. MVA85A/ AERAS-485 Oxford-Emergent Tuberculosis Consortium (OETC), Aeras, EDCTP, Wellcome Trust AERAS-402/ Crucell Ad35 Crucell, Aeras, EDCTP, NIH Mw [M. indicus pranii (MIP)] Dept of Biotechnology (India), M/s. Cadila Phase IIPhase IIIPhase IIbPhase I Source: Tuberculosis Vaccine Candidates – 2011 Prime Boost Post-infection Immunotherapy TB Vaccine Types Viral-vectored: MVA85A, AERAS-402, AdAg85A Protein/adjuvant: M72, Hybrid-1, Hyvac 4, H56 rBCG: VPM 1002, ID93/GLA-SE Killed WC or Extract: Mw, RUTI Global TB Vaccine Pipeline