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AAAAGENDAGENDA
OVERVIEW OF IMMUNIZATION PROGRAM IN BRAZIL ANDINSTITUTO BUTANTAN
BUTANTAN DEVELOPMENTS
Instituto Butantan | 1
AAAAGENDAGENDA
OVERVIEW OF IMMUNIZATION PROGRAM IN BRAZIL ANDINSTITUTO BUTANTAN
BUTANTAN DEVELOPMENTS
Instituto Butantan | 2
THE IMPACTS OF VACCINATION IN BRAZILChildren vaccination coverage by type of vaccination
%Vaccination coverage in Brazil
(2000 to 2010)
110
120(2000 to 2010)
90
100Over 70 million
children successfully i t d i t
70
80Implementation of the MMR
vaccine and DTP + Hib vaccine
vaccinated in two decades
60
70 vaccine and DTP Hib vaccine (tetravalent) in 100%
municipalities
502000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
BCG MMR Hepatitis B
Instituto Butantan |
BCGOral Polio
MMRTetravalent (DTP+Hib)
Hepatitis BRotavirus
3
THE IMPACTS OF VACCINATION IN BRAZILNumber of cases for tetanus – accidental and neonatal
Number of cases – Accidental and neonatal Tetanus
0 5001 800Cases
Accidental(1990 – 2010)
Neonatal(1983 – 2010)
Cases
0,400
0,500
1 200
1.400
1.600
1.800
600
700
800
EliminationPlan
0,200
0,300
600
800
1.000
1.200
300
400
500
Emergency Plan for high-risk counties
Strengthening actions in areas of potential risk
0,000
0,100
0
200
400
600
0
100
200
8384858687888990919293949596979899000102030405060708091090 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10
Incidence per 100K inhabitantsNumber of accidental tetanus per year
Number of neonatal tetanus per year
83848586878889909192939495969798990001020304050607080910
Instituto Butantan | 4
Incidence per 100K inhabitants
Source: Sinan/SVS/MS, data in 25/08/11Ministry of Health, Brazil , 2010.
THE IMPACTS OF VACCINATION IN BRAZILThe 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 H1N1Brazil (2010)
since March 2010
65
79
65 10
12
70
80
47
59
4742 43
8
10
50
60
sases
Vaccinationcampaign
27
21
34
42 43
4
6
30
40
Dea
ths
Seve
re C
15 20 1721 19
13
19
10
17 17
10 10 11 10
1
8
1
210
20
1 1 000
S h it li d f d i i fl (H1N1)
Weeks ** epidemiological week of onset of symptoms
Instituto Butantan | 5
Deaths from pandemic influenza (H1N1)Severe hospitalized cases of pandemic influenza (H1N1)
Source: Sinan/SVS, Ministry of Health, Brazil , 2010.
BRAZIL HAS BECOME AN INTERNATIONAL REFERENCE IN IMMUNIZATION
StrategyBrazil 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
Wh
Too important to depend on availability and pricing
Why
Instituto Butantan | 6
NATIONAL IMMUNIZATION PROGRAM (PNI) IN BRAZIL
PNI – Founded in 1973
Eradication 194 MM inhabitants
PNI – General Information of Brazil (2011) Smallpox
PoliomyelitisEradication 194 MM inhabitants
43 types of immunobiological
26 Vaccines
Poliomyelitis
Measles (autocne transmission)
Neonatal tetanus Accidental tetanusUnder
26 Vaccines 13 sera from animal 4 sera from human
Accidental tetanus Tuberculosis Diphtheria
Pert ssis
UnderControl 77% produced in Brazil
~ 300 MM doses of vaccines per year Pertussis Hepatite B Influenza
P
30 K vaccination rooms
Expansion of national self-sufficiency
Instituto Butantan | 7
Pneumococcus
Source: SVS/Ministry of Health, National Immunizatation Program, Brazil, 2011.
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 immunobiologicalproducts for public healthp p
Instituto Butantan | 8
RESEARCH & DEVELOPMENT LABORATORIES
~21 scientific labs
~180 Researchers 180 Researchers 85% are PhD
1 Biotechnology Center Multiple laboratoriesMultiple laboratories
1 Hospital (10 hospital beds)
1 Central Animal Facility
Training programs (PAP)
G d t t di i T i l
Instituto Butantan | 9
Graduate studies in Toxicology
Masters and PhDs
INDUSTRIAL COMPLEX
7 Main Industrial Plants (Buildings) Anaerobic vaccines (tetanus and botulinic )Anaerobic vaccines (tetanus and botulinic )
and Anatoxin Purification Biological control Aerobic Vaccine (Diphtheria and Pertussis) Hepatitis I fl Influenza Rabies Blood Products (under construction) Control, Serums, Formulation and Filling
6 Pilot Plants Dengue / Rotavírus (Under Construction) Recombinant (BCG) Monoclonal Antibodies
Instituto Butantan | 10
Monoclonal Antibodies Influenza Blood Products
WHAT DO WE DO?NATIONAL SUPPLIERS OF VACCINES FOR THE MINISTRY OF HEALTH
‘Market Share’ per Suppliers(1)
(2010) Products (Vaccines)(2010)
FAP
FUNED3%
DTP DT dTFAP4%
Butantan 51%Biomanguinhos
42%Rabies Hepatitis B
42%
InfluenzaNote: Part of Butantan’s production was sent to other Institutes,
Instituto Butantan |
(Flu)
111Source: Ministry of Health, 2010
Note: Part of Butantan s production was sent to other Institutes, such as Biomanguinhos. Not computed in the analysis
WHAT DO WE DO?NATIONAL SUPPLIERS OF ANTIVENOMS AND ANTITOXINS FOR THE MINISTRY OF HEALTH
‘Market Share’ per Suppliers(1)
(2010) Products (Sera)(2010)
Snakes AV
IVB25%
Butantan 56%
Scorpion AV Spider AV Caterpillar AV
FUNED19%
Tetanus AT Diphitheria AT AntiRabies
Note: Part of Butantan’s production was sent to other
Instituto Butantan |1Source: Ministry of Health, 2010
Botulism AB & E
12
Note: Part of Butantan s production was sent to other Institutes, such as FUNED and CPPI. Not computed in the analysis
AAAAGENDAGENDA
OVERVIEW OF IMMUNIZATION PROGRAM IN BRAZIL ANDINSTITUTO BUTANTAN
BUTANTAN DEVELOPMENTS
Instituto Butantan | 13
Butantan Institute - Plasma fractionation plant based on chromatography
new plasma products Impacts of chromatography
plant based on chromatography
Fractioning better utilization of plasma
Flexibility in production
Purification
higher purity products Lower index of contaminants Lower number of side effects for patients hi h t l t i t
Flexibility in production
of operational costs higher tolerance to inputs
Products with higher degree of safetyVi l
Process automation
Possibility of production of otherSafety Virus removal
Chemical reagents removal
F ili i f i h b
Biopharmaceutical products
WidespreadTechnology
Facilitation of experience exchange about medical practiceIntegration of health service providers in real time
Products with less side effects
Instituto Butantan |
time
Plasma fractioning by h h
Plasma fractioning by h hchromatographychromatography
Plasma fractioning by chromatographychromatography
Instituto Butantan |
VACCINES WITH EXTERNAL COOPERATION
Cooperation ProjectsCooperation 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
L S f t tBR Foods Lung Surfactant
Universidade de São Paulo – Medical SchoolRecombinant OncoBCG for bladder cancer
Institut Pasteur – Paris / Novartis ‐ Siena / Albert Einstein College of Medicine
Recombinant BCG‐Pertussis
Instituto Butantan | 20
WHAT DO WE WANT TO DO?Presentation and discussion of vaccines projects
Area Vaccines Projects 1
p j
Area Vaccines Projects 1
Vaccines - Research and improvement
Pertussislow
Adjuvant BpMPLA Recombinant onco BCG Silica nanostructure mesoporous – vaccine
antigens encapsulatedantigens encapsulated
Vaccines - Collaborative development
Rotavirus (pentavalent) Dengue (tetravalent) Streptococcus pneumoniae (cellular - SPWCV) BCG-Pertussis
V i B i R&D L t iVaccines – Basics R&D Leptospira
Techtransfer Several vaccines under negociation
Instituto Butantan | 21
1 Not exhaustive
Pertussislow vaccine
Product - Pertussislow vaccine Butantan –
Composition
– B.pertussis whole cell with lower content ofLPS
low
Challenges:
– Scale-up
LPS
Production Technology
Organic extraction of the cells to reduce LPS
Objectives:
– To make available an alternative vaccine for– Organic extraction of the cells to reduce LPS content
~ 70% reduction of LPS
To make available an alternative vaccine for immunization of children, adolescent, pregnant women and adults
– “in line” process without additional costs
Phase of Development
P li i l t di f d i B t t d– Pre-clinical studies performed in Butantan andin the Netherlands Institute Vaccine (NIV)
– Phase I (2012) – Brazil
Instituto Butantan | 22
Pertussislow vaccine - technical and scientific aspects New developments in Pertussis Vaccines with Appropriate technologiesp pp p g
Whole Cell PertussisV i
® = Patents
Vaccine
Whole Cell Pertussis Low LPS content
~ 70% reduction of LPS Less reactogenic Low cost
B. pertussisfermentation
Tangential filtration
WCPOrganic
extraction
WCPlow®
filtration extraction
ChromatographyPertussis vaccine before and after organic extration of
LPS (PLow)
AcellularPertussisVaccine
MPLAAdjuvant
®®Before After
Recombinant BCG-PertussisNeonatal immunization
Instituto Butantan | 23
Neonatal immunization
Adjuvant – Monophosphoryl lipid A (BpMPLA)
Product - Monophosphoryl lipid A (BpMPLA) Butantan –
Composition
– BpMPLA derived from LPS of B.pertussis
Challenges:
– Scale-up
Production Technology– Purification of B.pertussis followed by LPS
hydrolises
Objectives:
– To optimize immunolgical response of pre-i iti d i
y
Phase of Development
– Scale-up
exisiting and new vaccines
– To increase production capacity
BpMPLAp– Clinical trial Pandemic H1N1 + BpMPLA
– Pre-clinical Human rabies Human rabies
– Animal Study Dog Leishimania
– In development H tit B + B MPLA
Instituto Butantan |
Hepatites B + BpMPLA Seazonal Influenza + BpMPLA
24
Recombinant BCG-Pertussis Neonate vaccine / Onco BCG for Bladder cancer
Product - Recombinant BCG – Pertussis Butantan –
Composition
– Recombinant BCG strain expressing the S1 subunit 1 of Pertussis toxin
Challenges:
– To produce the vaccine by fermentation or static culturesubunit 1 of Pertussis toxin
Production Technology
– The rBCG-Pertussis strain was produced
static culture
– To perform the clinical trials
– The rBCG-Pertussis strain was produced without antibiotic resistance gene1
Appropriate for use in humans Objectives:
– To immunize infants 0 – 2 months of age Phase of Development
– Production of GMP lots
To immunize infants 0 2 months of age
– To make available a new vaccine for bladder cancer
N t 1 A t fi t i f l i i l t d ith l id th t
Instituto Butantan | 25
Nota: 1 Auxotrofic strain for lysine is complemented with a plasmid that expresses the deleted gene plus the heterologous gene – S1PT
Recombinant BCG-Pertussis - technical and scientific aspectsProtection of neonate mice immunized with rBCG-S1PT against intracerebralh ll ith B t ichallenge with B. pertussis
ONE DOSE AT DAY 5
100 Saline 100 S li
60
80
100 Saline
DPT
BCG
rBCG-S1PT
rviv
al
60
80
100 Saline
BCG
rBCG-S1PT
viva
l
20
40% S
ur
20
40% S
urv
0 2 4 6 8 10 120
Days after Challenge0 2 4 6 8 10 12
0
Days after Challenge
Challenge dose at day 21: 106 CFU Challenge dose at day 21: 3x107 CFU
Instituto Butantan | 26Source: Microbes Infect.10:198-202 (2008)
Silica (SBA-15)Immunogenic complex formed by vaccinal antigens encapsulated by nanostructured mesoporous silicananostructured mesoporous silica
F t
The SBA-15 possesses hexagonal porous uniformity (3.1 – 6.5 nm) Thermal and hydrothermal stability
Features
Instituto Butantan | 27
y y Exhibits potential applications for selective adsorption and catalysis
Rotavirus Vaccine
Product – Pentavelent Rotavirus Vaccine Butantan –
Composition
– Attenutated virus
Challenges:
– To perform Phase II and III - non-inferiority t d– Sorotypes: G1, G2, G3, G4 e G9
Technology of Production
study
– To find funding for: Clinical Trial and laboratory assay – Phase II / III
– Cell substrate: Vero cells
– Reassortment – Human/bovine
– Nº lots produced: 09 (6 K doses) Objective:
N lots produced: 09 (6 K doses)
Phase of Development– Phase I: 2010
– Pentavalent low cost vaccine
Results: safe and immunogenic
– Phase II: 2013
• Partnership
Instituto Butantan | 28
• Partnership
– NIH / PATH / BNDES
Dengue Vaccine
Product – Tetravalent Dengue Vaccine Butantan –
Composition
– Attenuated virusSorotypes: DEN1 DEN2 DEN3 DEN4
Challenges:
– To speed up Phase I, II, and III – (to avoid non inferiority study)– Sorotypes: DEN1, DEN2, DEN3, DEN4
Technology of Production– Cell substrate: Vero cells
non-inferiority study)
– To find funding for: Clinical Trial and Laboratory assay – Phase III
– Recombinant DNA technology– Chimeric– Nº lots produced: 06 (17 K doses)
Equipment
Plant
Maintenance of “The Global Solutions for Infectious Disease” supportp ( )
Phase of Development
– Phase I and II: 2012/2013
pp
– To define target population for immunization– Production capacity x national and
international demand
• Partnership– NIH - DVI (Dr. Steve Whitehead)
Objective:
– Tetravalent low cost vaccine
Instituto Butantan | 29
– BNDES / FAPESP