INSTITUTO BUTANTAN: NOVOS DESAFIOS PROF. JORGE KALIL AGENDA

 OVERVIEW OF IMMUNIZATION PROGRAM IN AND INSTITUTO BUTANTAN

 BUTANTAN DEVELOPMENTS

Instituto Butantan | 1 AGENDA

 OVERVIEW OF IMMUNIZATION PROGRAM IN BRAZIL AND INSTITUTO BUTANTAN

 BUTANTAN DEVELOPMENTS

Instituto Butantan | 2 THE IMPACTS OF VACCINATION IN BRAZIL Children vaccination coverage by type of vaccination

Vaccination coverage in Brazil % (2000 to 2010) 120

110

100 Over 70 million

90 children successfully vaccitditinated in two

80 decades Implementation of the MMR and DTP + Hib vaccine 70 (tetravalent) in 100% municipalities 60

50 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

BCG MMR B Oral Polio Tetravalent (DTP+Hib) Rotavirus

Instituto Butantan | 3 THE IMPACTS OF VACCINATION IN BRAZIL Number of cases for – accidental and neonatal

Number of cases – Accidental and neonatal Tetanus

Accidental Neonatal (1990 – 2010) (1983 – 2010) Cases Cases 1. 800 0, 500 800 1.600 700 1.400 0,400 Elimination 600 Plan 1. 200 0,300 500 Strengthening 1.000 actions in areas 400 of potential risk 800 Emergency Plan for 0,200 300 600 high-risk counties 200 400 0,100 200 100 0 0,000 0 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 83 8485 86 8788 89 9091 92 9394 95 9697 9899 00 0102 03 0405 06 0708 09 10

Number of accidental tetanus per year Number of neonatal tetanus per year Incidence per 100K inhabitants

Source: Sinan/SVS/MS, data in 25/08/11Ministry of , Brazil , 2010. Instituto Butantan | 4 THE IMPACTS OF VACCINATION IN BRAZIL The number of severe cases and deaths due to influenza A H1N1 has been falling since March 2010

Number of severe cases and deaths due to influenza A H1N1 Brazil (2010)

80 79 12

70 65 65 10 59 Vaccination 60 campaign 8 50 47 47 ases 42 43 ss 40 6 34 Death

Severe C 30 27 4 21 19 20 19 20 15 17 17 17 13 10 10 10 11 10 2 10 8

1 1 0 0 0 Weeks * * epidemiological week of onset of symptoms

Severe h ospit a lize d cases o f pan dem ic in fluenza (H1N1) Deaths from pandemic influenza (H1N1)

Source: Sinan/SVS, Ministry of Health, Brazil , 2010. Instituto Butantan | 5 BRAZIL HAS BECOME AN INTERNATIONAL REFERENCE IN IMMUNIZATION

Strategy Brazil decided in the mid 80's to become self-sufficient in and immunization programs

Decision

This was a State decision rather than a government decision

Why

Too important to depend on availability and pricing

Instituto Butantan | 6 NATIONAL IMMUNIZATION PROGRAM (PNI) IN BRAZIL

PNI – Founded in 1973

PNI – General Information of Brazil (2011) . Smallpox Eradication . Poliomyelitis . 194 MM inhabitants . Measles (autocne transmission) . 43 types of immunobiological

 26 Vaccines  13 sera from animal . Neonatal tetanus  4 sera from human Under . Accidental tetanus Control . 77% produced in Brazil . . . ~ 300 MM doses of vaccines per year . Pertussis . 30 K vaccination rooms . Hepatite B . Influenza . Expansion of national self-sufficiency . Pneumococcus

Source: SVS/Ministry of Health, National Immunizatation Program, Brazil, 2011. Instituto Butantan | 7 WHAT DO WE ARE? BUTANTAN – A PUBLIC INSTITUTION OF THE STATE GOVERNMENT OF

 In 1901 Butantan was established to produce serum against the , the first director, investigated against bites

 Currently, Butantan is the main public producer of vaccines, antivenoms, antitoxins in  Fully dedicated to develop scientific research and production of immunobiological ppproducts for public health

Instituto Butantan | 8 RESEARCH & DEVELOPMENT LABORATORIES

. ~21 scientific labs

. ~180 Researchers  85% are PhD

. 1 Center  Multiple laboratories

. 1 Hospital (10 hospital beds)

. 1 Central Animal Facility

. Training programs (PAP)

. Gradtduatestditudies in TilToxicology

. Masters and PhDs Instituto Butantan | 9 INDUSTRIAL COMPLEX

. 7 Main Industrial Plants (Buildings)  Anaerobic vaccines (tetanus and botulinic ) and Anatoxin Purification  Biological control  Aerobic Vaccine (Diphtheria and Pertussis)  Hepatitis  IflInfluenza   Blood Products (under construction)  Control, Serums, Formulation and Filling

. 6 Pilot Plants  Dengue / Rotavírus (Under Construction)  Recombinant (BCG)  Monoclonal Antibodies  Influenza  Blood Products

Instituto Butantan | 10 WHAT DO WE DO? NATIONAL SUPPLIERS OF VACCINES FOR THE MINISTRY OF HEALTH

‘Market Share’ per Suppliers(1) Products (Vaccines) (2010)

FUNED 3% FAP 4% DTP DT dT

Butantan Biomanguinhos 51% 42% Rabies

Note: Part of Butantan’ s production was sent to other Institutes, Influenza such as Biomanguinhos. Not computed in the analysis (Flu)

1Source: Ministry of Health, 2010 Instituto Butantan | 11 WHAT DO WE DO? NATIONAL SUPPLIERS OF ANTIVENOMS AND ANTITOXINS FOR THE MINISTRY OF HEALTH

‘Market Share’ per Suppliers(1) Products (Sera) (2010)

Snakes AV

IVB 25%

Butantan AV AV Caterpillar AV 56% FUNED 19%

Tetanus AT Diphitheria AT AntiRabies

Note: Part of Butantan’ s production was sent to other Institutes, such as FUNED and CPPI. Not computed in the analysis AB & E

1Source: Ministry of Health, 2010 Instituto Butantan | 12 AGENDA

 OVERVIEW OF IMMUNIZATION PROGRAM IN BRAZIL AND INSTITUTO BUTANTAN

 BUTANTAN DEVELOPMENTS

Instituto Butantan | 13

From: dataSUS Instituto Butantan | Butantan Institute - Plasma fractionation plant based on chromatography

Impacts of chromatography  new plasma products Fractioning  better utilization of plasma

Flexibility in production  higher purity products  Lower index of contaminants Purification  Lower number of side effects for patients of operational costs  hihhigher tltolerance to inpu ts Process automation

Products with higher degree of safety Possibility of production of other Safety  removal products Chemical reagents removal

FiliiFacilitation of exper ience exc hange about Widespread medical practice Products with less side Technology Integration of health service providers in real effects time

Instituto Butantan | Plasma Products Industry - Building

Instituto Butantan | Plasma fractioning by chhhromatography

Plasma fractioning by chromatography

Instituto Butantan | Processing – columns and tanks

Instituto Butantan | VACCINES WITH EXTERNAL COOPERATION

Cooperation Projects NIH‐PATH Rotavirus (pentavalent) NIH‐DVI Dengue (tetravalent) Sabin Vaccine Institute ‐ George Washington University Necator ‐ Schistosoma

Children’s Hospital Harvard ‐ PATH Pneumococcus (cellular) Infectious Diseases Research Institute Visceral Leishmaniosis (for dogs) Ludwig Institute for Cancer Research Adjuvant for ovarian cancer BR Foods Lung SfttSurfactant Recombinant OncoBCG for bladder Universidade de São Paulo –Medical School cancer Institut Pasteur – / Novartis ‐ Siena / Recombinant BCG‐Pertussis Albert Einstein College of Medicine

Instituto Butantan | 20 WHAT DO WE WANT TO DO? Presentation and discussion of vaccines ppjrojects

Area Vaccines Projects 1

Vaccines - Research and . Pertussislow improvement . Adjuvant BpMPLA . Recombinant onco BCG . Silica nanostructure mesoporous – vaccine antigens encapsulated Vaccines - Collaborative . Rotavirus (pentavalent) development . Dengue (tetravalent) . Streptococcus pneumoniae (cellular - SPWCV) . BCG-Pertussis ViVaccines – Bas ics R&D . LtLeptospi ra

Techtransfer . Several vaccines under negociation

1 Not exhaustive

Instituto Butantan | 21 Pertussislow vaccine

Product - Pertussisllowow vaccine Butantan – . Composition . Challenges: – B.pertussis whole cell with lower content of – Scale-up LPS

. Production Technology . Objectives:

– Organic extraction of the cells to reduce LPS – To make available an alternative vaccine for content immunization of children, adolescent, pregnant women and adults  ~ 70% reduction of LPS

– “in line” process without additional costs

. Phase of Development

– Pre-clin ica l stditudies perfdformed iBttin Butantan and in the Netherlands Institute Vaccine (NIV)

– Phase I (2012) – Brazil

Instituto Butantan | 22 Pertussislow vaccine - technical and scientific aspects New developpppgpments in Pertussis Vaccines with Appropriate technologies

® = Patents Whole Cell Pertussis ViVaccine

Whole Cell Pertussis . ~ 70% reduction of LPS . Less reactogenic Low LPS content . Low cost

B. pertussis WCP WCP ® fermentation low Tangential Organic filtration extraction

Pertussis vaccine before and after organic extration of LPS (PLow) Chromatography Before After Acellular ® ® MPLA Pertussis Adjuvant Vaccine

Recombinant BCG-Pertussis Neonatal immunization

Instituto Butantan | 23 Adjuvant – Monophosphoryl lipid A (BpMPLA)

Product - Monophosphoryl lipid A (BpMPLA) Butantan –

. Composition . Challenges: – BpMPLA derived from LPS of B.pertussis – Scale-up

. Production Technology . Objectives: – Purification of B.pertussis followed by LPS – To optimize immunolgical response of pre- hydrolises exiitiisiting and new vaccines . Phase of Development – To increase production capacity

– Scale-up BpMPLA – Clinical trial  Pandemic H1N1 + BpMPLA – Pre-clinical  Human rabies – Animal Study  Dog Leishimania – In development  HtitB+Hepatites B + BMPLABpMPLA  Seazonal Influenza + BpMPLA

Instituto Butantan | 24 Recombinant BCG-Pertussis Neonate vaccine / Onco BCG for Bladder cancer

Product - Recombinant BCG – Pertussis Butantan –

. Composition . Challenges:

– Recombinant BCG strain expressing the S1 – To produce the vaccine by fermentation or subunit 1 of Pertussis static culture

– To perform the clinical trials . Production Technology

– The rBCG-Pertussis strain was produced without antibiotic resistance gene1 . Objectives:  Appropriate for use in humans – To immunize infants 0 – 2 months of age . Phase of Development – To make available a new vaccine for bladder – Production of GMP lots cancer

NtNota: 1 AtfiAuxotroficstiftrain for l liysine is comp lemen tdithlted with a plasm idthtid that expresses the deleted gene plus the heterologous gene – S1PT

Instituto Butantan | 25 Recombinant BCG-Pertussis - technical and scientific aspects Protection of neonate mice immunized with rBCG-S1PT against intracerebral chllhallenge w ith BtiB. pertussis

ONE DOSE AT DAY 5

100 Saline 100 SliSaline DPT BCG 80 80 BCG rBCG-S1PT rBCG-S1PT ival

vival 60 vv 60 rr

40 40 % Su % Sur

20 20

0 0 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Days after Challenge Days after Challenge

Challenge dose at day 21: 106 CFU Challenge dose at day 21: 3x107 CFU

Source: Microbes Infect.10:198-202 (2008) Instituto Butantan | 26 Silica (SBA-15) Immunogenic complex formed by vaccinal antigens encapsulated by nanostructured mesoporous silica

FtFeatures  The SBA-15 possesses hexagonal porous uniformity (3.1 – 6.5 nm)  Thermal and hyyydrothermal stability  Exhibits potential applications for selective adsorption and catalysis

Instituto Butantan | 27 Rotavirus Vaccine

Product – Pentavelent Rotavirus Vaccine Butantan –

. Composition . Challenges:

– Attenutated virus – To perform Phase II and III - non-inferiority stdtudy – Sorotypes: G1, G2, G3, G4 e G9 – To find funding for: . Technology of Production  Clinical Trial and laboratory assay – Phase II / III – Cell substrate: Vero cells – Reassortment – Human/bovine . Objective: – Nº lots produced: 09 (6 K doses) – Pentavalent low cost vaccine . Phase of Development – Phase I: 2010  Results: safe and immunogenic – Phase II: 2013

• Partnership – NIH / PATH / BNDES

Instituto Butantan | 28

Product – Tetravalent Dengue Vaccine Butantan –

. Composition . Challenges:

– Attenuated virus – To speed up Phase I, II, and III – (to avoid – Sorotypes: DEN1, DEN2, DEN3, DEN4 non-inferiority study)

. Technology of Production – To find funding for:  Clinical Trial and Laboratory assay – Phase III – Cell substrate: Vero cells  Equipment – Recombinant DNA technology  Plant – Chimeric  Maintenance of “The Global Solutions for – Nº lots pp(roduced: 06 (17 K doses) Infectious Disease” support – To define target population for immunization . Phase of Development – Production capacity x national and – Phase I and II: 2012/2013 international demand . Objective: • Partnership – NIH - DVI (Dr. Steve Whitehead) – Tetravalent low cost vaccine – BNDES / FAPESP

Instituto Butantan | 29 Av. Vital Brasil, 1500 - Butantã São Paulo – SP Zip Code - 05503-900 (+ 55 11) 3726.7222 www.butantan.gov.br

Instituto Butantan | 30