INSTITUTO BUTANTAN: NOVOS DESAFIOS PROF. JORGE KALIL AGENDA OVERVIEW OF IMMUNIZATION PROGRAM IN BRAZIL 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 vaccine and DTP + Hib vaccine 70 (tetravalent) in 100% municipalities 60 50 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 BCG MMR Hepatitis B Oral Polio Tetravalent (DTP+Hib) Rotavirus Instituto Butantan | 3 THE IMPACTS OF VACCINATION IN BRAZIL Number of cases for tetanus – 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 Health, 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 hosp ita 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 vaccines 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 . Tuberculosis . Diphtheria . ~ 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 SÃO PAULO In 1901 Butantan was established to produce serum against the bubonic plague Vital Brazil, the first director, investigated antivenoms against snake bites Currently, Butantan is the main public producer of vaccines, antivenoms, antitoxins in Latin America 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 Biotechnology 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 Rabies 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 Hepatitis B 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 Scorpion AV Spider 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 Botulism 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 Virus removal Biopharmaceutical products Chemical reagents removal FiliiFacilitation of experience exchange 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 –Paris / 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 . LtLeptosp ira 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 toxin static culture – To perform the clinical trials . Production Technology – The rBCG-Pertussis strain was produced without