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