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Vaccine Technology IV Proceedings
Spring 5-21-2012 111 years producing immunobiologicals: New challenges Jorge Kalil Instituto Butantan
Follow this and additional works at: http://dc.engconfintl.org/vaccine_iv Part of the Biomedical Engineering and Bioengineering Commons
Recommended Citation Jorge Kalil, "111 years producing immunobiologicals: New challenges" in "Vaccine Technology IV", B. Buckland, University College London, UK; J. Aunins, Janis Biologics, LLC; P. Alves , ITQB/IBET; K. Jansen, Wyeth Vaccine Research Eds, ECI Symposium Series, (2013). http://dc.engconfintl.org/vaccine_iv/6
This Conference Proceeding is brought to you for free and open access by the Proceedings at ECI Digital Archives. It has been accepted for inclusion in Vaccine Technology IV by an authorized administrator of ECI Digital Archives. For more information, please contact [email protected]. THE EFFORTS OF A PUBLIC INSTITUTE TO DEVELOP NEW VACCINES PROF . J ORGE KALIL
PORTUGAL , 2012 AAGENDA
OVERVIEW OF IMMUNIZATION PROGRAM IN BRAZIL AND INSTITUTO BUTANTAN
BUTANTAN DEVELOPMENTS
Instituto Butantan | 1 AAGENDA
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 vaccinated 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 400 800 of potential risk 0.200 Emergency Plan for 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 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 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 42 43 40 6 34 Deaths Deaths
Severe Cases Cases Severe Severe 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 hospitalized cases of pandemic influenza (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 P UBLIC 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 products 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)
Graduate studies in Toxicology
Masters and PhDs Instituto Butantan | 9 SCREENING OF BIOACTIVE COMPOUNDS OF ANIMAL VENOMS
Pharmacological Activities
ANALGESIC ANTIINFLAMATORY ANTI -MICROBIOLOGICAL ANTI-COAGULANT ANTI-TUMORAL NERVOUS SYSTEM ACTION ANTI-VENOMS REACTIVITY ANTI-HYPERTENSION
Venom Composition by Transcriptomics and Proteomics
Instituto Butantan | Plasma fractioning by chromatography
Plasma fractioning by chromatography
Instituto Butantan | INDUSTRIAL COMPLEX
7 Main Industrial Plants (Buildings) Anaerobic vaccines ( tetanus and botulinic ) and Anatoxin Purification Biological control Aerobic Vaccine (Diphtheria and Pertussis ) Hepatitis Influenza 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 | 12 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 Influenza Institutes, such as Biomanguinhos. Not computed in the (Flu) analysis
1Source: Ministry of Health, 2010 Instituto Butantan | 13 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 | 14 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 Surfactant 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 | 15 AAGENDA
OVERVIEW OF IMMUNIZATION PROGRAM IN BRAZIL AND INSTITUTO BUTANTAN
BUTANTAN DEVELOPMENTS
Instituto Butantan | 16 WHAT DO WE WANT TO DO ? Presentation and discussion of vaccines projects
Area Vaccines Projects 1
Vaccines - Research and Pertussis low improvemen t Adjuvant Bp MPLA Recombinant onco BCG Silica nanostructure mesoporous – vaccine antigens encapsulated Vaccines - Collaborative Rotavirus (pentavalent) development Dengue (tetravalent) Streptococcus pneumoniae (cellular - SPWCV) BCG-Pertussis Vaccines – Basics R&D Leptospira
Techtransfer Several vaccines under negociation
1 Not exhaustive
Instituto Butantan | 17 Pertussis low vaccine
Product - Pertussis low 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-clinical studies performed in Butantan and in the Netherlands Institute Vaccine (NIV)
– Phase I (2012) – Brazil
Instituto Butantan | 18 Pertussis low vaccine - technical and scientific aspects New developments in Pertussis Vaccines with Appropriate technologies
® = Patents Whole Cell Pertussis Vaccine
Whole Cell Pertussis ~ 70% reduction of LPS Less reactogenic Low LPS content Low cost
B. pertussis WCP WCP ® fermentation low Tangential Organic filtration extraction
Instituto Butantan | Adjuvant – Monophosphoryl lipid A ( Bp MPLA)
Product - Monophosphoryl lipid A ( Bp MPLA) Butantan –
Composition Challenges: – Bp MPLA 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 exisiting and new vaccines Phase of Development – To increase production capacity
– Scale-up Bp MPLA – Clinical trial Pandemic H1N1 + BpMPLA – Pre-clinical Human rabies – Animal Study Dog Leishimania – In development Hepatites B + BpMPLA Seazonal Influenza + BpMPLA
Instituto Butantan | 20 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 gene 1 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
Nota: 1 Auxotrofic strain for lysine is complemented with a plasmid that expresses the deleted gene plus the heterologous gene – S1PT
Instituto Butantan | 21 Recombinant BCG-Pertussis - technical and scientific aspects Protection of neonate mice immunized with rBCG-S1PT against intracerebral challenge with B. pertussis
ONE DOSE AT DAY 5
100 Saline 100 Saline DPT BCG 80 80 BCG rBCG-S1PT rBCG-S1PT 60 60
40 40 % Survival Survival % % % Survival Survival % %
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: 10 6 CFU Challenge dose at day 21: 3x10 7 CFU
Source: Microbes Infect.10:198-202 (2008) Instituto Butantan | 22 Silica (SBA-15) Immunogenic complex formed by vaccinal antigens encapsulated by nanostructured mesoporous silica
Features The SBA-15 possesses hexagonal porous uniformity (3.1 – 6.5 nm) Thermal and hydrothermal stability Exhibits potential applications for selective adsorption and catalysis
Instituto Butantan | 23 Rotavirus Vaccine
Product – Pentavelent Rotavirus Vaccine Butantan –
Composition Challenges:
– Attenutated virus – To perform Phase II and III - non-inferiority study – 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 | 24 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 produced: 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 | 25 [email protected] Obrigado Thank you
Av. Vital Brasil, 1500 - Butantã São Paulo – SP Zip Code - 05503-900 (+ 55 11) 3726.7222 www.butantan.gov.br
Instituto Butantan | 26