DEVELOPMENT OF ROTAVIRUS RV3BB VACCINE IN BIO FARMA

Erman Tritama, Ph.D PT. Biofarma (Persero) 2018 Bio Farma Overview

Established in August 6, 1890

State-owned Enterprise

Only manufacturer of vaccines and immunosera for human use in Indonesia

The number of employees approx. 1200 people

Integrated Quality System cGMP, ISO 9001, ISO 14001, OHSAS 18001 CURRENT STATUS BIO FARMA : State Owned Enterprise LIST of Products INTEGRATED WHO PQ Milestones MANAGEMENT SYSTEM Year Vaccine ISO ISO 1997 OPV, measles 10 ds GDP 9001 14001 OHSAS GCP 2001 DTP, DT, TT (vial) 18001 2003 TT (Uniject) GLP GCG 2004 Hep B (Uniject) 2006 DTP/HepB, measles 20 ds GMP ERM 2009 mOPV1 2010 bOPV (1,3) INTEGRATED IFRS CSR SYSTEM 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

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

Graph 1. Global Distribution of Rotavirus Genotype

Source : Global Rotavirus Information and Surveillance Bulletin Volume 4: October 2011 Source : Source : Dr. Duncan Steele presentation 12thInternational Rotavirus Symposium.7-9 September, 2016. Melbourne, Australia Challenging 1

Source : Source : Dr. Duncan Steele presentation 12thInternational Rotavirus Symposium.7-9 September, 2016. Melbourne, Australia Burden of Rotavirus in Indonesia

Measles

Malnutrition TB Other causes Tetanus Indonesia Basic Health Diarrhea Sepsis Survey (Riskesdas),2017 :

Congenital Heart 31.4% of infant deaths Disease& Hydrocephalus were due to diarrhea

Gastrointestinal disorders Pneumonia

Meningitis/ Encephalitis 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) RV+ 2001-2008= 58% RV+ 2009-2011= 52% Timika (2016) Palembang (2006) RV+ 2012-2016= 45% 64% 45%

Surabaya (2016) Denpasar (2015) 41% 40%

Jakarta (2006) Yogyakarta (2016) 67% Mataram (2016) 38% 41% Bandung (2016) 58% Soenarto et all (2017), Underreview; Soenarto et all (2009) Acceptability study in Yogyakarta, Indonesia • As highlighted by the WHO, the vaccine is unlikely to be introduced if the disease is not a public health priority. • The Indonesian Rotavirus Surveillance Network (IRSN, 2008) has previously reported on the acceptability of rotavirus vaccine in four provincial teaching hospitals in Yogyakarta, Palembang, Denpasar and Mataram (unpublished data) • We were unable to interview person in charge from the Ministry of Health because there was no response 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

Case: Rotavirus 2006 & 2013

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 ) 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

Challenging 3

Area : 1.904.569 km2 (5 major islands and about 30 smaller groups ) Population : 237,56 Million Birth cohort : 5 Million More than 400 ethnics as well as languages diversity. Archipelago of 18.000 islands. Muslims : 88% Non-Muslims : 12% 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 Currently available live oral rotavirus vaccines

Rotarix® (GSK), RotaTeq® (Merck), ROTAVAC® (Bharat Higher efficacy in developed Biotech) and ROTASIL® (Serum countries (Jian, 2010) Institute of India)

Generally administered in Lower efficacy in high-burden infants, lack early low-income countries administration at birth (Bines, 2018)

Source : Jiang, Human Vaccines 6(7) (2010) 532-42 Bines, The New England journal of medicine 378(8) (2018) 719-30 RV3-BB (1)

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

Source : Bines, The New England journal of medicine 378(8) (2018) 719-30 RV3-BB (1)

1. Neonatal Strain suited for birth dose administration 2. Monovalent human neonatal rotavirus strain and simple manufacturing process should enable low manufacturing costs 3. Able to give heterotypic protection against other human rotavirus strain (G1, G2, G4).

Source : Bines Presentation Development of Rotavirus RV3-BB Vaccine in Bio Farma (2)

Rotavirus Working Virus Seed • Can be problematic to be used in some countries due to religion Activation by using trypsin (usually • Additional tests are needed to test the Porcine Trypsin) presence of virus related to porcine- derivate product (Porcine circovirus etc.) Activated Rotavirus

Indonesia government created a Law regarding product HALAL guarantee Infection to Vero Cell 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

Rotavirus Vaccine Under Development in Bio Farma

RV3-BB • Stable at -20 C • Frozen liquid Vaccine • Under Clinical Trial study (liquid Frozen)

• Developed by Kansas RV3-BB University, Batavia Bio Vaccine Science and Bio Farma with Funding from BMGF 2-8C • Stable at 2-8C • Formulated with Acid Neutralizing Agent (replacing antacid) Development of Rotavirus RV3-BB Vaccine in Bio Farma

RV3-BB Vaccine (liquid Frozen)

• 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 Development of Rotavirus RV3-BB Vaccine in Bio Farma

RV3-BB Vaccine (2-8C) • 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 Conclusion

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

DR. Duncan Steele DR. Carl Kirkwood Prof. Julie Bines Prof. Yati Soenarto Dr. Jarir At Thobari, Ph.D Thank you