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The Oswaldo Cruz Foundation - FiocruzMinistry of Health - Brazil
Technology Transfer
Hib GSK to Bio-Manguinhos/Fiocruz
Dr. Akira Homma
Bio-Manguinhos/Fiocruz
WHO Headquaters
30 November-01 December
2010
VaccineVaccine productionproduction -- intense science & technology basis ––must do tecnologyecnology innovationinnovation
� The vaccine development is very complex: takes long time, multi-disciplinary teams, highcost and the return of investiment is uncertain;
� Requires specilized Human Resources, specialfacilities and equipments, experienced teamand proper management;
BioBio--ManguinhosManguinhos -- StrategyStrategy for for TecnologyTecnologyInnovationInnovation
a) a) SelfSelf developmentdevelopment projectsprojects
b) b) JointJoint TechnologicalTechnological DevelopmentDevelopmentprojectsprojects
c) c) TransferTransfer of of TechnologyTechnology AgreementsAgreements
a) SELF DEVELOPMENT PROJECTSa) SELF DEVELOPMENT PROJECTS
�� MeningoccalMeningoccal serogroupserogroup C C conjugatedconjugated ––ClinicalClinical studystudy -- phasephase 2;2;
�� MeningococcalMeningococcal serogroupserogroup B B –– OMV OMV –– ClinicalClinicalstudystudy phasephase 2;2;
�� PneumococcalPneumococcal –– commoncommon proteinprotein; ; conjugationconjugation;;
�� Dengue Dengue chimerachimera –– 17D as 17D as backbonebackbone;;
�� Malaria Malaria chimerachimera –– 17 D as 17 D as backbonebackbone;;
�� YellowYellow FeverFever inactivatedinactivated
b) JOINT DEVELOPMENT PROJECTSb) JOINT DEVELOPMENT PROJECTS
�� PentavalentPentavalent DTP/HBV+HibDTP/HBV+Hib –– ButantanButantanInstituteInstitute
�� LeptospiralLeptospiral recombinantrecombinant –– proofproof of of conceptconcept, , IPqGMIPqGM;;
�� LeishmaninaLeishmanina recombinantrecombinant –– proofproof of of conceptconcept, , IPqGMIPqGM; ;
�� Dengue Dengue inactivatedinactivated -- GSKGSK
�� Objective = collaborative development of a dengue vaccine Objective = collaborative development of a dengue vaccine that will offer sustainable control of dengue in Brazil and restthat will offer sustainable control of dengue in Brazil and restof the worldof the world
�� Contribution of both GSK & FIOCRUZ => all steps of the Contribution of both GSK & FIOCRUZ => all steps of the vaccine vaccine devtdevt, including R&D & Clinical , including R&D & Clinical devtdevt
�� Considering the epidemiological situation in Brazil, we will Considering the epidemiological situation in Brazil, we will play key role in the clinical development of the dengue play key role in the clinical development of the dengue vaccinevaccine
�� Production in Brazil of the dengue vaccine for Production in Brazil of the dengue vaccine for MercosulMercosul
GSK/FIOCRUZ dengue inactivated GSK/FIOCRUZ dengue inactivated
vaccine developmentvaccine development
�� GSK/FIOCRUZ dengue inactivated vaccine developmentGSK/FIOCRUZ dengue inactivated vaccine development
�� Why developing a purified inactivated vaccine?Why developing a purified inactivated vaccine?
�� No viral interference with inactivated antigens No viral interference with inactivated antigens
�� Shorter immunization schedule/ rapid onset of protectionShorter immunization schedule/ rapid onset of protection
�� Development considered less complex than for a liveDevelopment considered less complex than for a live--attenuated vaccineattenuated vaccine
�� No environmental risk No environmental risk
�� Purified inactivated vaccine is considered highly feasible: Purified inactivated vaccine is considered highly feasible:
�� Technical & preclinical proof of principle demonstrated by the WTechnical & preclinical proof of principle demonstrated by the WRAIR RAIR
�� Two examples of highly effective inactivated Two examples of highly effective inactivated flavivirusflavivirus vaccines: JE and TBE vaccines: JE and TBE vaccines vaccines
�� Use of GSK Adjuvant Systems is considered:Use of GSK Adjuvant Systems is considered:
�� Use of adjuvant system to enhance immune response & to provide rUse of adjuvant system to enhance immune response & to provide rapid apid onset of durable protectiononset of durable protection
�� Acceptable risk/benefit profile of GSK AS demonstrated for Acceptable risk/benefit profile of GSK AS demonstrated for GSKGSK’’ss adjuvantedadjuvantedHPV and influenza vaccinesHPV and influenza vaccines
�� ~~10 10 MiosMios (HPV) and (HPV) and ~~70 70 MiosMios (influenza H1N1) doses administered to (influenza H1N1) doses administered to date date
Status of GSK/FIOCRUZ Dengue Status of GSK/FIOCRUZ Dengue inactivated vaccine developmentinactivated vaccine development
�� Preclinical evaluation began in 2009Preclinical evaluation began in 2009
�� Starting Phase I clinical trials in 2011Starting Phase I clinical trials in 2011
�� GSK is committed to develop this vaccine as rapidly as GSK is committed to develop this vaccine as rapidly as possible:possible:
�� GSK aims at starting clinical endpoint studies in 2014 GSK aims at starting clinical endpoint studies in 2014
�� Timing of any file submission must be agreed with Timing of any file submission must be agreed with AuthoritiesAuthorities
�� Epidemiological studies in Brazil:Epidemiological studies in Brazil:
�� GSK & FIOCRUZ development of site of studies 2010GSK & FIOCRUZ development of site of studies 2010
c) c) TechnologyTechnology TransferTransfer: : GovtGovt committmentcommittment
�� LongLong termterm policypolicy andand multimulti--yearyear forecastforecast;;
�� BrazilianBrazilian PublicPublic MarketMarket -- veryvery largelarge -- industrial industrial scalescaleof of productionproduction is is requiredrequired;;
�� GaranteeGarantee of of thethe marketmarket andand competitivecompetitive priceprice;;
�� Financial Financial supportsupport for new for new facilityfacility andand modernizationmodernizationof of facilitiesfacilities;;
�� ExistanceExistance of a of a functionalfunctional NRA;NRA;
�� GovernmentGovernment´́ss policypolicy::
�� Use of Use of buyerbuyer powerpower; ;
�� wheneverwhenever a new a new vaccinevaccine is is introducedintroduced intointo NIP NIP thethe local local productionproduction andand TT is TT is consideredconsidered..
1937
1982
2003
20041976
1980 1999
2008
2007
2002
Meningitispolysaccharidesg A and C:MérieuxInstitute
Measles:BikenInstitute
Attenuatedpoliomielitis, Oral:JPRI
Haemophilusinfluenzae, type b:GSK
Triple viral (MMR):GSK
DTP + Hib:ButantanInstitute
Rapid Test HIV diagnostic:Chembio
Interferon Alpha 2bhumanrecombinant:Heber Biotec
ErythropoietinhumanRecombinant:Cimab
YellowFeverVaccine:RockefellerFoundation
Rotavirus:GSK
Interferon Alpha 2b PeguilatedHeber Biotec
DPP Leishmaniasis, Leptospirosis, HIV 1/2 ScreenHIV 1 ImunoblotChembio
MeningitispolysaccharideA and C:FinlayInstitute
BM - Technological Transfers / Partnerships
PneumococcusDengue:GSK
NAT: Qiagen
DPP ImunoblotRapid HIV-2:Chembio
2009
1900 – Federal Serotherapeutic Intitute
- 1976 – creation of Bio-Manguinhos
BM PortfolioVaccines
DTP+Hib (5 doses)DTP/HBV + Hib (5 doses)Hib (1 and 5 doses)Yellow Fever (5, 10 and 50 doses)Meningitis Polysaccharides A+C (10 and 50 doses)OPV (25 doses)Measles (05 doses)Triple Viral MMR (10 doses)Rotavirus (1 dose)Pneumococcal conjugate 10 valent (1 dose)
IVD ReagentsHIV-1 IFA (100 and 500 tests)HIV-1 and 2 Rapid Test (20 tests)Chagas Disease ELISA (384 tests), and IFA (600 tests)Canine Leishmaniasis ELISA (384 tests) and IFA (2,000 tests)Human Leishmaniasis IFA (600 tests)Human Leptospirosis ELISA (96 tests and 192 tests)Schistosomiasis Helm Test (100 test and 500 tests)
BiopharmaceuticalsInterferon Alpha 2b Human Recombinant (3, 5 and 10 MUI)Erythropoietin Human Recombinant (2,000 and 4,000 UI)
�Yellow Fever 05, 10, 50 doses � Meningitis A and C 10 dosesPRE-QUALIFYED BY WHO
�Yellow Fever 05, 10, 50 doses � Meningitis A and C 10 dosesPRE-QUALIFYED BY WHO
c) c) TheThe HibHib vaccinevaccine TechnologyTechnology TransferTransfer
�� BioBio-- ManguinhosManguinhos featuresfeatures::
�� TechnologicalTechnological capabilitycapability –– productionproduction of of MengMeng A/CA/C
polissacharidespolissacharides vaccinevaccine; ; conjugationconjugation groupgroup; ; clinicalclinical studiesstudies; ;
�� AdequateAdequate facilitiesfacilities andand equipmentsequipments –– largelarge freezefreeze--dryingdrying
facilityfacility;;
�� StrutuctureStrutucture, , organizationorganization andand budget for budget for longlong termterm
implementationimplementation -- teamteam organizedorganized to to receivereceive technologytechnology; ;
�� selectionselection of of thethe mostmost adequateadequate technologytechnology andand proposalproposal;;
�� MustMust bebe a WINa WIN--WIN WIN modelmodel
c) c) HibHib vaccinevaccine TechnologyTechnology TransferTransfer: : GSK GSK featuresfeatures
�� ModernModern andand updateupdate technologytechnology
�� ScientificScientific andand technolgytechnolgy knowledgeknowledge; ;
�� OperationalOperational andand functionalfunctional productionproductionoperationoperation;;
�� CompromiseCompromise to to makemake fullfull technologytechnology transfertransfer;;
�� entireentire organizationorganization mustmust agreeagree andand cooperatecooperate;;
�� OrganizationOrganization of a of a specificspecific groupgroup dedicateddedicated to to TT.TT.
�� MustMust bebe a a winwin--winwin modelmodel
�� GSK/BM GSK/BM ------ The WinThe Win--win modelwin model
�� The TT provider (according to BM view)The TT provider (according to BM view)�� Expansion of market;Expansion of market;
�� Guarantee of market while the technology transfer is in process;Guarantee of market while the technology transfer is in process;
�� Economic benefit and revenue assurance for long term;Economic benefit and revenue assurance for long term;
�� Long term planning for production operation;Long term planning for production operation;
�� Production facility Production facility –– use of full production capacity;use of full production capacity;
�� Perception on social awareness and international recognition;Perception on social awareness and international recognition;
�� Brand Marketing;Brand Marketing;
�� Royalty up to 5% with a full local production of Royalty up to 5% with a full local production of HibHib vaccine.vaccine.
�� BioBio--ManguinhosManguinhos/Fiocruz/Fiocruz�� Accelerate incorporation of technology of production;Accelerate incorporation of technology of production;
�� Guarantee of vaccine supply Guarantee of vaccine supply ––avoid shortage;avoid shortage;
�� Incorporation of modern technology platforms;Incorporation of modern technology platforms;
�� The cost per dose drops as the steps of TT is performed and The cost per dose drops as the steps of TT is performed and further price drops whenever the TT is fully accomplishedfurther price drops whenever the TT is fully accomplished
Hib Technology Transfer - Step wise transfer -
� Agreement/Oct 1998 - GSK just got license for Hib in Brazil
� 1st step – importantion of bulk material and formulation, filling freeze-drying and quality control 1999-2003;
• training in quality control and assurance trainning;
• modernization of facilities and new equipments;
• training in production: conjugation step at GSK
� 2nd step – Conjugation of polyssacharides and tetanustoxoid using imported materials 2003-2006;
• local conjugated vaccine production;
• training in polyssacharides production: up stream and downstream;
• validation of new facilities
Hib Technology Transfer - Step wise transfer
� 3rd step – Production of polyssachrarides and conjugationusing locally produced tetanus toxoid 2004-2006;
� Local produced tetanus toxoid: validation of facilities, methodologiesand production;
� Production of three consecutive lots for clinical uses;
� Development of protocol for non-inferiority clinical study
� 4th step – Noninferioty study using the 2nd step vaccine as control 2005-2007;
� Protocol approval by Ethical Committee;
� Preparation of the site of study – 1000 volunteers;
� Organization and implementation of the clinical study;
� 5th step – License at ANVISA in 2007� Preparation of the documentation for licensing by ANVISA;
� 6th step – pharmacovigilance� Organization and implementation of pharmacovigilance
BioBio--ManguinhosManguinhos & TT & TT -- TangibleTangible andand intangibleintangiblebenefitsbenefits
�� InstitutionalInstitutional strengtheningstrengthening�� AdministrationAdministration andand managerialmanagerial capacitycapacity;;
�� FocusFocus onon resultsresults;;
�� BetterBetter visibilityvisibility; ;
�� AccelerateAccelerate thethe incorporationincorporation of new of new technologytechnology of of productionproduction;;
�� increaseincrease of of specilizedspecilized professionalsprofessionals;;
�� new new laboratorieslaboratories, new , new equipmentsequipments; ;
�� StrengthenStrengthen thethe technologicaltechnological capacitycapacity;;
�� StrengthenStrengthen thethe infrastructureinfrastructure; ;
�� New New productsproducts & & developmentsdevelopments: : �� tetravalenttetravalent (DTP + (DTP + HibHib); );
�� pentavalentpentavalent ((DTP/HB+HibDTP/HB+Hib); );
�� developmentdevelopment of of heptavalentheptavalent ((DTP/HB/IPV/MenCDTP/HB/IPV/MenC + + HibHib))
Kmetzsch CI, et al. J Pediatr (Rio J). 2003;79(6):530-6:
�� In Latin America, In Latin America, HibHib vaccination was first introduced in Uruguay in 1994, vaccination was first introduced in Uruguay in 1994,
followed by Costa Rica and Chile.followed by Costa Rica and Chile.
�� The The HibHib vaccine was incorporated into the national immunization programvaccine was incorporated into the national immunization program of of
Brazil in mid 1999.Brazil in mid 1999.
�� HibHib vaccine was incorporated universally in mid 1999 to children <2vaccine was incorporated universally in mid 1999 to children <2 years old, years old, with gradual expansion to the target age of 4 years old, in 2002with gradual expansion to the target age of 4 years old, in 2002
�� In 2002, the tetravalent vaccine protecting against In 2002, the tetravalent vaccine protecting against diphteriadiphteria--tetanustetanus--whole cell whole cell pertussispertussis (DTP) and (DTP) and HibHib infections infections waswas establishedestablished to to childrenchildren <1 <1 yearyear oldold
�� Current vaccination schedule:Current vaccination schedule:
�� three doses of three doses of DTP+HibDTP+Hib administered at 2, 4 and 6 months of ageadministered at 2, 4 and 6 months of age
�� In Brazil, there are currently three vaccines:In Brazil, there are currently three vaccines:
�� Vaccine against Vaccine against HibHib
�� Tetravalent (Tetravalent (DTP+HibDTP+Hib))
�� PentavalentPentavalent ((DTP+HB+HibDTP+HB+Hib))
Simoes LLP, et al. Rev Saude Pub. 2004;38:664-670; Ribeiro GS, et al. Vaccine. 2007;25:4420–4428
VaccineVaccineAdministered Administered Doses in 2009Doses in 2009
Against Against HibHib 85,89485,894
DTP+HibDTP+Hib 8,784,2428,784,242
DTP+HB+HiDTP+HB+Hibb
17,04317,043
�� A comparison of incidence rates in the A comparison of incidence rates in the prevaccineprevaccine (10.8x10(10.8x1055) and ) and
postpost--vaccine (2.3x10vaccine (2.3x1055) periods shows a) periods shows a 78% reductio78% reduction in the risk of n in the risk of
HibHib meningitis in meningitis in GoiGoiááss..
�� In In CuritibaCuritiba, southern Brazil, the incidence of meningitis dropped , southern Brazil, the incidence of meningitis dropped
from 35.5 to 9.7x10from 35.5 to 9.7x105 5 (72% reduction)(72% reduction), one year after the introduction , one year after the introduction
of the vaccine. of the vaccine.
�� In Salvador, northeastern Brazil, In Salvador, northeastern Brazil, 69% reduction 69% reduction was observed after was observed after
the first year of vaccination.the first year of vaccination.
�� Five years Five years after the introduction of after the introduction of HibHib conjugate vaccine, conjugate vaccine, HibHib
meningitis incidence decreased from 2.39 to 0.06 cases per 100,0meningitis incidence decreased from 2.39 to 0.06 cases per 100,000 00
population population (98%)(98%) overall, and from 60.9 to 3.1 cases per 100,000 overall, and from 60.9 to 3.1 cases per 100,000
population population (95%) in children <1 year of age.(95%) in children <1 year of age.
Simoes LLP, et al. Rev Saude Pub. 2004;38:664-670; Ribeiro GS, et al. Vaccine. 2007;25:4420–4428
Incidence per 100,000Incidence per 100,000
StudyStudyYears postYears post--vaccinevaccine
introductionintroductionPrePre--vaccine vaccine PostPost--vaccinevaccine
Reduction Reduction (%)(%)
TakemuraTakemura & Andrade, 2001& Andrade, 2001J J PediatrPediatr 77, 38777, 387--9292
1 year1 year 35.435.4 9.7 9.7 72.6%72.6%
RibeiroRibeiro et al., 2003et al., 2003J Infect J Infect DisDis 187, 109187, 109--1616 1 year1 year 2.62.6 0.80.8 69.0%69.0%
KmetzschKmetzsch et al., 2003et al., 2003J J PediatrPediatr 79, 53079, 530--66
2 years2 years 36.536.5 3.4*3.4* 90.7%90.7%
SimõesSimões et al., 2004et al., 2004Rev Rev SaudeSaude PublicaPublica 38, 66438, 664--
70702 years2 years 10.8 10.8 2.32.3 78.7%78.7%
RibeiroRibeiro et al., 2007et al., 2007Vaccine 25, 4420Vaccine 25, 4420--2828 5 years5 years 25.425.4 0.630.63
97.5%97.5%
Impact of vaccination against Impact of vaccination against Impact of vaccination against Impact of vaccination against HibHibHibHib on meningitis in children <5 years on meningitis in children <5 years on meningitis in children <5 years on meningitis in children <5 years
old in Brazilold in Brazilold in Brazilold in Brazil
*<1 year of age
Nascimento-Carvalho & Andrade, Haemophilus influenzae type b vaccination: long-term protection. J Pediatr. 2006, 82 (3) S109-14
Ribeiro et al., Haemophilus influenzae meningitis 5 years after introduction of the Haemophilus influenzae type b conjugate vaccine in Brazil. Vaccine, 2007, 25, 4420-28
Data: SINAN/SVS/MS www.saude.gov.br/svs
IAL-São Paulo with permission of Dr Ma. Cristina Brandileone
Vaccine introductionVaccine introductionVaccine introductionVaccine introduction
H. H. H. H. InfluenzaeInfluenzaeInfluenzaeInfluenzae serotypeserotypeserotypeserotype distributiondistributiondistributiondistribution andandandand incidenceincidenceincidenceincidence ofofofof meningitis meningitis meningitis meningitis
duedueduedue totototo H. H. H. H. influenzaeinfluenzaeinfluenzaeinfluenzae
BrazilBrazil andand NIPNIP´́ss figuresfigures�� TerritoryTerritory –– 8,51 8,51 millionmillion km2km2 ( 47% ( 47% LatinLatin AmericaAmerica););
�� PopulationPopulation -- > 190 > 190 millionmillion;;
�� NewbornNewborn –– 3,200 3,200 million/yearmillion/year;;
�� 26 provincial states + Federal 26 provincial states + Federal DistrictDistrict ((BrasiliaBrasilia););
�� 5.565 5.565 municipalitiesmunicipalities;;
�� NationalNational ImmunizationImmunization ProgramProgram
�� 17 17 vaccinesvaccines; > 30 in CRIES;; > 30 in CRIES;
�� 36.000 36.000 ImmunizationImmunization officesoffices ((publicpublic + + privateprivate + + indean vaccination center); 30 CRIES officesindean vaccination center); 30 CRIES offices;;
�� RoutineRoutine andand NationalNational DaysDays of of VaccinationVaccination –– NDV;NDV;
�� ColdCold ChainChain: Central; Regional; Local: Central; Regional; Local
NationalNational ImmunizationImmunization ProgramProgram
�� 1973 1973 –– creationcreation withwith 6 6 vaccinesvaccines (DTP; BCG; (DTP; BCG; measlesmeasles; OPV);; OPV);
�� Universal Universal accessaccess of of vaccinationvaccination –– Universal Universal accessaccess-- ChildrenChildren; ; adolescentsadolescents; ; adultsadults andand elderyeldery
�� ContinuousContinuous supportsupport andand continuouscontinuous expansionexpansion::
�� 2008 2008 –– R$ 800 R$ 800 millionmillion (US$ 420 (US$ 420 millionmillion););�� 2009 2009 –– R$ 1,200 R$ 1,200 millionmillion (US$ 720 (US$ 720 millionmillion););�� 2010 2010 –– R$ 3,0 R$ 3,0 billionbillion (US$ 1,750 (US$ 1,750 billionbillion), ), includingincludingH1N1H1N1*;*;
�� * * maymay notnot requiredrequired for 2011for 2011
68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 00 02 04 05
0
1
2
3
4
0
20
40
60
80
100
Taxa de Incidência 1ª Campanha 2ª Campanha
Ta
xa
de
In
cid
ên
cia
po
r 10
0.0
00
hab
.
Co
be
rtu
ra V
ac
ina
l (%
)
Start of NDV
Fonte: Ministério da Saúde SI-PNI.
* VOP: Vacina oral contra poliomielite.
National Immunization Program - Poliomielytes incidence and OPV coverage- National Days of Vaccination (NDV)
N.º.
CASOS
0
10
20
30
40
50
60
70
80
90
100
80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 3 4 5
0
10
20
30
40
50
60
70
80
90
100
Casos/100.000 Cobertura (%)
Fonte: Secretaria de Vigilância em Saúde/MS/Brasil
*1980-2002: <1ano* A partir de 2003: 1 ano
%
National Immunization Program – Measles incidence andvaccinationn coverage
�� NPI, NPI, MoHMoH & TECHNOLOGICAL INNOVATION& TECHNOLOGICAL INNOVATION
STRATEGIC IMPORTANCE OF VACCINES
EPIDEMIOLOGICAL IMPACT –
ELIMINATION OF POLIOMIELYTES, MEASLES, RUBELLA
IMMUNOPREVENTABLE DISEASES AT LOWEST
NOTIFICATION
NEW AND IMPORTANT VACCINES IN PIPELINE –
HPV
DENGUE,MALARIA
RSV, HIV/AIDS,
New combinations
NEW IMPORTANT VACCINES:
EMERG DISEASES,
EPIDEMIC; PANDEMICI;
TECHNOLOGICAL IMPROVEMENTS;
BETTER YIELDS; LOW COST PRODUCTION
�THE EXISTANCE OF NATIONAL TECHNOLOGICAL CAPABILITIES FOR PRODUCTION AND INNOVATION GARANTTEE THE SUPPLY OF THE ESSENTIAL VACCINES
�1982 - THE NATIONAL SELF-SUFFICIENCE PROGRAM WAS CREATED
Bio-Manguinhos’ figures
�� Main Main immunobiologicalimmunobiological producer for producer for the Brazilian MOH programs (only the Brazilian MOH programs (only federal laboratory): vaccines, IVD federal laboratory): vaccines, IVD reagents, biopharmaceuticalsreagents, biopharmaceuticals
�� 1.180 employees 1.180 employees -- 10% of Fiocruz 10% of Fiocruz workforce: 32% workforce: 32% -- Production, 22% Production, 22% Quality Control and Assurance, 11% Quality Control and Assurance, 11% R&D, 3% Maintenance & R&D, 3% Maintenance & Engineering Production, 32% Engineering Production, 32% ManagementManagement
�� 2 post2 post--doctors, 42 doctors, 124 doctors, 42 doctors, 124 masters, 193 postmasters, 193 post--graduatedgraduated
�� 25.000 m2 of lab facilities in 10 25.000 m2 of lab facilities in 10 buildingsbuildings
