DEVELOPMENT OF ROTAVIRUS RV3BB VACCINE IN BIO FARMA

Erman Tritama, Ph.DPT. Biofarma (Persero)

2018

Bio Farma Overview

Established in August 6, 1890

State-owned Enterprise

The number of employees approx. 1200 people

Integrated Quality SystemcGMP, ISO 9001, ISO 14001, OHSAS 18001

Only manufacturer of vaccines and immunosera for human use in Indonesia

INTEGRATED MANAGEMENT SYSTEM

INTEGRATED SYSTEMIFRS

GMP

GLP

GCP

GDPISO

9001 ISO 14001

OHSAS 18001

GCG

ERM

CSR

LIST of ProductsWHO PQ Milestones

CURRENT STATUSBIO FARMA : State Owned Enterprise

Year Vaccine

1997 OPV, measles 10 ds

2001 DTP, DT, TT (vial)

2003 TT (Uniject)

2004 Hep B (Uniject)

2006 DTP/HepB, measles 20 ds

2009 mOPV1

2010 bOPV (1,3)

2011 Td

2014 Pentabio (DTP-HB-Hib Vaccine)

Global child death due to Rotavirus infection (2013)

• 215000 rotavirus deaths in children under 5 years of age globally.

• Rotavirus strain G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8] circulate world wide.

• Two available rotavirus vaccine, RotaTeq TM and Rotarix TM are developed based on these strains.

Source : WHO Data 2013 and Global Rotavirus Surveillance Data 2014

Distribution of Rotavirus Genotypes

Source : Global Rotavirus Information and Surveillance Bulletin Volume 4: October 2011

Graph 1. Global Distribution of Rotavirus Genotype

Table 1. Distribution of Uncommon Genotypes for Reporting WHO Regions, 2010

Source : Source : Dr. Duncan Steele presentation12thInternational Rotavirus Symposium.7-9 September, 2016. Melbourne, Australia

Source : Source : Dr. Duncan Steele presentation12thInternational Rotavirus Symposium.7-9 September, 2016. Melbourne, Australia

Challenging 1

Burden of Rotavirus in IndonesiaMeasles

Malnutrition TB

Tetanus

Sepsis

Congenital Heart Disease&

Hydrocephalus

Gastrointestinal disorders

Meningitis/Encephalitis

Pneumonia

Diarrhea

Other causes

Indonesia Basic Health Survey (Riskesdas),2017 :

31.4% of infant deaths were due to diarrhea

Surveillance to determine disease burden and epidemiology of rotavirus in Indonesia, 2004

36-61% of diarrhea cases among under five caused by rotavirus

Indonesian Rotavirus Surveillance Network, 2006 60% of diarrhea cases among under five caused by rotavirus,

children 6-24 mo were the most affected*Soenarto Y, Aman AT, Bakri A, Waluya H, et al. Burden of Severe Rotavirus Diarrhea in Indonesia. J of Infec Dis 2009; 200:S188-94.

ROTAVIRUS DIARRHEA IN HOSPITALIZED CHILDREN IN INDONESIA (2004-2016)

Palembang (2006) 64%

Bandung (2016) 58%

RV+ 2001-2008= 58%RV+ 2009-2011= 52%RV+ 2012-2016= 45%

Jakarta (2006) 67% Yogyakarta (2016)

38%

Surabaya (2016) 41%

Denpasar (2015) 40%

Mataram (2016) 41%

Timika (2016) 45%

Soenarto et all (2017), Underreview; Soenarto et all (2009)

Acceptability study in Yogyakarta, Indonesia

• As highlighted by the WHO, the vaccine is unlikely tobe introduced if the disease is not a public healthpriority.

• The Indonesian Rotavirus Surveillance Network(IRSN, 2008) has previously reported on theacceptability of rotavirus vaccine in four provincialteaching hospitals in Yogyakarta, Palembang,Denpasar and Mataram (unpublished data)

• We were unable to interview person in charge fromthe Ministry of Health because there was noresponse for in depth interview request

(Sitaresmi MN, et. al, 2015, Padmawati R.S. Et al , Seale et al 2015)

Primary care givers’ point of view

Their children were not susceptible of acquiring diarrhea

Diarrhea was not a high-priority health issue

Sanitation-hygiene behavior and breastfeeding were sufficient to protect against diarrhea

Very few had heard of rotavirus and none was aware of the availability of the rotavirus vaccine

Anti-vaccine group(Sitaresmi MN, et. al, 2015, , Simpson et al 2007 )

Case: Rotavirus 2006 & 2013

Religious leaders’ point of view

Fanatism in certain religious group

People can’t afford expensive vaccine

Vaccine can cause fever

Diarrhea is just a sign that children are growing up and smarter

Halal label is needed

(Sitaresmi MN, et. al, 2015, Padmawati R.S. Et al )

Healthcare providers’ point of view

Diarrhea is not an important problem, but can be serious if not properly treated

Few knew that a rotavirus vaccine was available

Rotavirus vaccine was not ranked as a priority as it is not listed on NIP (National Immunization Program)

Relatively high cost of the vaccine

(Sitaresmi MN, et. al, 2015, Seale et al 2015)

Development of Rotavirus RV3-BB Vaccine in Bio Farma

Area : 1.904.569 km2 (5 major islands and about 30 smaller groups )Population : 237,56 MillionBirth cohort : 5 MillionMore than 400 ethnics as well as languages diversity.Archipelago of 18.000 islands.Muslims : 88%Non-Muslims : 12%

Challenging 3

Development of Rotavirus RV3-BB Vaccine in Bio Farma

LAW NO. 33, 2014“HALAL PRODUCT GUARANTEE”

CLAUSE 4.Products import, circulating, and traded in Indonesian territory must be halal certified.

CLAUSE 17 (1)The material used in product process halal consists of raw materials, processed materials, supplementary materials, and auxiliary materials.

CLAUSE 17 (2)The materials mentioned in clause 17 point 1 can be sourced from ; animals, plants, microbial or processed materials from chemical, biological or genetic engineering process

CLAUSE 18 (1)The materials from animal which under HARAM criteria are : carcass, blood, porcine, or other animal which do not slaughter following Islamic doctrine

Development of Rotavirus RV3-BB Vaccine in Bio Farma

Rotarix® (GSK), RotaTeq® (Merck), ROTAVAC® (Bharat Biotech) and ROTASIL® (Serum Institute of India)

Higher efficacy in developed countries (Jian, 2010)

Lower efficacy in high-burden low-income countries

Generally administered in infants, lack early administration at birth (Bines, 2018)

Currently available live oral rotavirus vaccines

Source : Jiang, Human Vaccines 6(7) (2010) 532-42Bines, The New England journal of medicine 378(8) (2018) 719-30

Need for highly efficacious and affordable neonatal rotavirus vaccine targeting early prevention of rotavirus gastroenteritis

• An oral human neonatal rotavirus vaccine candidate (RV3-BB) has been developed by MCRI from the human neonatal rotavirus strain RV3 (G3P[6]) 3

• RV3-BB was safe and immunogenic in neonates and infants in Phase 2a clinical trials 3,4

• The vaccine was found to be efficacious under low resource settings in Phase 2b clinical trials 3

RV3-BB (1)

Source : Bines, The New England journal of medicine 378(8) (2018) 719-30

RV3-BB (1)

1. Neonatal Strain suited for birth dose administration2. Monovalent human neonatal rotavirus strain and simple manufacturing

process should enable low manufacturing costs3. Able to give heterotypic protection against other human rotavirus strain (G1, G2, G4).

Source : Bines Presentation

Rotavirus Working Virus Seed

Activated Rotavirus

Infection to Vero Cell

Activation by using trypsin (usually Porcine Trypsin)

• Can be problematic to be used in some countries due to religion

• Additional tests are needed to test the presence of virus related to porcine-derivate product (Porcine circovirus etc.)

Indonesia government created a Law regarding product HALAL guarantee

Bio Farma develop all new vaccine to meet with halal

requirements

Development of Rotavirus RV3-BB Vaccine in Bio Farma (2)

• Trypsin Bovine Recombinant can be used as alternative trypsin for rotavirus activation.

• Using this trypsin in cultivation RV3 giving comparable results to trypsin porcine recombinant although slight lower than trypsin porcine.

• Bio Forma using trypsin bovine recombinant in order to be admitted in global market and limiting the raw materials from animal.

Development of Rotavirus RV3-BB Vaccine in Bio Farma (2)

Development of Rotavirus RV3-BB Vaccine in Bio Farma

• Stable at -20 C• Frozen liquid• Under Clinical Trial study

RV3-BB Vaccine (liquid Frozen)

• Developed by Kansas University, Batavia Bio Science and Bio Farmawith Funding from BMGF

• Stable at 2-8C• Formulated with Acid

Neutralizing Agent (replacing antacid)

RV3-BB Vaccine

2-8C

Rotavirus Vaccine Under Development in Bio Farma

Development of Rotavirus RV3-BB Vaccine in Bio Farma

• 1mL Frozen-Liquid.

• Stable up to 2 years in -20 C.

• Glass vial format, similar with OPV, make it familiar to be used by program personnel.

• Currently under clinical trial in Indonesia

RV3-BB Vaccine (liquid Frozen)

Development of Rotavirus RV3-BB Vaccine in Bio Farma

• 1-2mL Liquid Vaccine.

• Several excipient already screening and combination among excipient already studied

• Several candidate formulation already evaluated

• Buffer capacity in neutralizing acid already evaluated using Baby Rossette Rice Assay

• Effect of Matrix on RV3 potency test already evaluated

• Next step, deciding formula candidate based on clinical trial RV3-BB Vaccine Frozen Liquid in Indonesia

RV3-BB Vaccine (2-8C)

• Innovative approach Rotavirus Vaccine (RV3BB): • Affordable • Safe and Immunogenic in neonates• Halal certification

Conclusion

DR. Duncan SteeleDR. Carl KirkwoodProf. Julie BinesProf. Yati SoenartoDr. Jarir At Thobari, Ph.D

Acknowledgement

Thank you