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TB Vaccine Development
in Indonesia
SEA-EU NET, 21-22 January 2014
Francisca S Tanoerahardjo
LOGO OUTLINE
TB Situation in Indonesia
On Going TB Vaccine research consortium
Challenges (Resources and Management)
LOGO Indonesia
Indonesia is an archipelago - 17,508 islands
Population over 238 million people
The 4th most populous country
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
LOGO TB Prevalence Survey 2013-2014
LOGO Result Dec 2014
LOGO Program 2011-2020
Ministry of Health
National Institute of Health Research and
Development
Ministry of Research and Technology
National Incentive Program
Collaborative Research
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)
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
LOGO History
Individual
Research
Working
Group
Research
Consortium
(8 Institutes)
Research
Consortium
(12 Institutes)
< 2011 2011 2012 2013
Research
Consortium
(12 Institutes)
2014
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
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
LOGO Adjuvant
LIPOTEK – Australia
base on Liposome – Antigens
Formulation & proof of concept
LOGO Immunogeniety Study
Subject
TB patients
Healthy but contact TB pos
Healthy without contact
Test
TST
CD4, CD8, IFNɣ, IL2
IL17
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
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%.
LOGO M.tuberculosis dorman
M.tuberculosis isolates
Sauton medium
Minimum Carbon source
M.tuberculosis from granuloma lung resection
Proteomics analysis
Re-culture
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
LOGO Problem
Data on BCG vaccination
Facilities -
Technology
Standarization
LOGO
Thank you
LOGO Roadmap International TB Research - 2011
Epidemiology Fundamental
Research
Diagnostics Operational
& 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
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
LOGO
PONTIANAK
MANADO
MAKASSAR
52,7
SURABAYA
BANDUNG
DKI AMBON
SERANG
PADANG
MATARAM
TJ.KARANG
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.
LOGO Keragaman genotipe Mtb di Indonesia
30,6
8,1
10
19,8
4,5
11,7
5,4
0,9 1,8
0,9
5,4
0,9
28,4
7,7
11,5
21,9
8,2
4,4
1 2,2
1
13,7
6,4
10
16,4
19,1
10,9 10
1,8 0,9 0,9
23,6
0
5
10
15
20
25
30
35
Wilayah Jawa Wilayah Sumatera Kalimantan wilayah Timur
LOGO Peta awal filogenetik Mtb di Indonesia: Menggambarkan diversitas bakteri yang bersirkulasi
Sum - Kal Jawa Wil. Timur
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
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
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
BIOFARMA,
LITBANGKES,
UNPAD, UGM,
UNAIR
BIO FARMA Institusi
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
Seed
Vacc
ine
Laboratorium
LOGO
TERIMA KASIH
LOGO HASIL PENELITIAN
Kegiatan Kemenristek (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 Imunogenitas Optimasi metode flowsitometri, dotblot, dan Elisa
Pembuatan isolat M.tb dorman in vitro
Pengamatan pertumbuhan koloni M.tb dorman dan identifikasi fenotipik
LOGO HASIL PENELITIAN
Kegiatan Kemenristek (1M) Kemenkes (3,1M)
Sekuensing BCG Total 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
LOGO HASIL PENELITIAN
Kegiatan Kemenristek (1M) Kemenkes (3,1M)
Sinergisme pemanfaatan sarana prasarana
Menggunakan isolat dan plasmid antar anggota
Pemanfaatan fasilitas Laboratorium Nasional di PBTDK oleh anggota Konsorsium
Training/Seminar Shortcourse Vaccinology for Clinical & Public Health Practice, Singapura Okt 2013
• 7th World Vaccine Congress Asia, Singapura Juni 2013 • Workshop Flowsitometri, Jakarta September 2013 • WS Imunologi, Jogja September 2013
Publikasi Poster Presentation, APFCB, Bali Oktober 2013
Draft: Whole Genome Sequence BCG
Presentasi/Sosialisasi EU TCF Workshop, Jakarta – Oktober 2013
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)
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
LOGO
TERIMA KASIH
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 II Phase III Phase IIb Phase 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
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