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 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 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 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 –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 . 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 toxin 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 Dengue Vaccine
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