instituto butantan: novos...

INSTITUTO BUTANTAN: NOVOS DESAFIOSNOVOS DESAFIOSPROF. JORGE KALIL

AAAAGENDAGENDA

OVERVIEW OF IMMUNIZATION PROGRAM IN BRAZIL ANDINSTITUTO BUTANTAN

BUTANTAN DEVELOPMENTS

Instituto Butantan | 1

AAAAGENDAGENDA




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


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


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


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


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


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


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


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,


(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




Instituto Butantan |From: dataSUS

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


time

Plasma Products Industry - Building


Plasma fractioning by h h

Plasma fractioning by h hchromatographychromatography

Plasma fractioning by chromatographychromatography


Processing – columns and tanksProcessing – columns and tanks


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


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


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


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


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


– 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


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


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


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


• 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 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


– BNDES / FAPESP

Av. Vital Brasil, 1500 - ButantãSão Paulo – SPZip Code - 05503-900


(+ 55 11) 3726.7222www.butantan.gov.br

instituto butantan: novos...

Documents