DEVELOPMENT AND PRODUCTION OF INFLUENZA VACCINES INSTITUTO BUTANTAN PROF. ISAIAS RAW JANUARY 2013

Transcription

1 DEVELOPMENT AND PRODUCTION OF INFLUENZA VACCINES INSTITUTO BUTANTAN PROF. ISAIAS RAW JANUARY 2013

2 BUTANTAN: GOALS AS A PUBLIC INSTITUTE, THE GOAL OF BUTANTAN IS TO PRODUCE EFFICACIOUS AND SAFE VACCINES AND OTHER IMMUNOBIOLOGICALS FOR FREE DISTRIBUTION BY THE MINISTRY OF HEALTH TO SOCIETY, AT COSTS AFFORDABLE TO THE GOVERNMENT. TO ACCOMPLISH THIS GOAL, IB INVESTS IN INNOVATION, DEVELOPMENT, PRODUCTION TECHNOLOGY, CLINICAL ASSAY, DESIGN AND PRODUCTION PLANTS TO GUARANTEE SELF SUFFICIENCY. IB ASSOCIATE WITH PUBLIC RESEARCH INSTITUTES AND UNIVERSITIES, BRINGING THE DEVELOPMENT FROM THE LAB BENCH TO SOCIETY. EXCEPTIONALLY IT MIGHT OBTAIN TRANSFERS OF TECHNOLOGY, THAT ONCE IMPLEMENTED IS THE BASIS FOR FURTHER INNOVATIONS. BUTANTAN MAY OFFER PARTNERSHISP IN R@D, AND IF CONVENIENT SUPPLY BULK FOR LOCAL FINISHING AS A STEP IN TECH TRANSFER. 2

3 H5N1 GRANTS FROM WHO (HHS), THE BRAZILIAN MINISTRY OF HEALTH, THE PUBLIC DEVELOPMENT BANK AND PUBLIC RESEARCH AGENCIES, ALLOWED US TO BUILD A PILOT LABORATORY TO PREPARE VIRUS BANKS, DOMINATE THE PRODUCTION OF MONOVALENT VACINES AND TRAIN IN SERVICE A CORE STAFF. THIS PILOT REMAINS AS A SPECIAL LAB TO PREPARE PRODUCTION BANKS. A PRODUCTION BANK WAS CONSTRUCTED FOR H5N1 AND A SMALL STOCK OF VACCINES PREPARED FOR EVENTUAL EMERGENCIES, WHICH DID NOT OCCUR. SINCE 2000 IB HAS FORMULATED ABOUT 180 MILLION SEASONAL INFLUENZA AND 50 MILLION AH1 DOSES. IN 2012 THE BANK FOR AH1, H3N2 AND B SEROTYPES WAS TRANSFERRED TO THE PLANT AND 15 MILLION DOSES OF SEASONAL VACCINE WERE PRODUCED. THE DEMAND TO VACCINATE > 60 YEARS, PERSONS WITH HEALTH PROBLEMS AND HEALTH CARE STAFF REQUIRES 20 MILLION DOSES, BUT THE AH1 THREAT REQUIRES THE VACCINATION OF YOUNG CHILDREN, ADULTS AND PREGNANT WOMEN INCREASING THE DEMAND TO > 100 MILLION /YEAR. 3

4 INFLUENZA : A UNIQUE CASE OF TECHNOLOGY TRANSFER BUTANTAN SIGNED AN AGREEMENT WITH C. MERIEUX (AVENTIS/SANOFI) FOR THE TRANSFER OF TECHNOLOGY FOR A PLANT TO PRODUCE 20 MILLION DOSES OF INFLUENZA SEASONAL VACCINE, PROCESSING ABOUT 20 MILLION EGGS, TO BE OFFERED FREE TO THE POPULATION 60+. MERIEUX S ROLE INCLUDED THE VALIDATION OF THE PLANT, FOLLOW-UP AND TESTING THE PRODUCTION OF 3 SUCCESSIVE LOTS, THUS PROVIDING CERTIFICATION THAT OUR PLANT, THE FIRST IN LATIN AMERICA, COMPLIED WITH THE EUROPEAN REQUIREMENTS. THE CONSTRUCTION AND ASSEMBLY OF THE PLANT TOOK SEVERAL YEARS, DUE TO LOCAL PROBLEMS. TOTAL INVESTMENT WAS ABOUT 40 MILLION DOLLARS. UNTIL WE ACHIEVED FULL PRODUCTION SANOFI SOLD MONOVALENTS IN BULK FOR LOCAL FORMULATION. THE AGREEMENT WAS CARRIED OUT AND IS NOW FINISHED. 4

5 Partial view of the pertussis plant: fully automated production. More than 300 million doses used for Brazilian children since 1985 Present installed capacity: 100 million doses per year 5

6 Instituto Butantan: one process and two products B.pertussis culture cells Tangential filtration Recombinant BCG-Pertussis Neonatal immunization Molecular Ultrafiltration Whole cell pertussis vaccine Organic extraction Acellular pertussis vaccine (adolescents) WC P low LPS (infants) MPLA (adjuvant) Dias WO et al /Commun Curr Res Ed Topics and Trends in Appl Microb (2007) 6

7 Plow a safe, eficacious, inexpensive pertussis vaccine doses = 150 kg MPL/year 1 billion 10 ug doses of MPLA 7

8 MPLA ACTIVATES IMMUNO RESPONSE WITHOUT INFLAMMATORY REACTION LPS MPLA Cell membrane Nuclear membrane Transcripts INF- INF- TNF- IL-1 IL-6 IL-12 Effect Inflammatory reaction T-cell activation Immune respponse 8

9 Phase I clinical trial A/H1N1 pandemic influenza vaccine with reduced dose using different adjuvants in human volunteers Effect of different combinations of Adjuvants on the immunization against A/H1N1 Seroprotection* in Participants with Hemagglutination-inhibition Antibody Titers <1:40 Prior to the First Vaccination (N=219). After 1 st vaccination After 2 nd vaccination % (95% CI) % (95% CI) 15 µg + AL (N=25) 76 ( ) 87.5 ( ) 7.5 µg+al (N=21) 57.1 ( ) 70 ( ) 7.5 µg+al+mpla (N=26) 34.6 (17-56) 50 ( ) 7.5 µg+al+squa (N=21) 66.7 ( ) 84.2 ( ) 7.5 µg+al +MPLA+Squa (N=18) 88.9 ( ) 88.2 ( ) 3.75 µg+al (N=26) 38.5 ( ) 52 ( ) 3.75 µg+al+mpla (N=25) 84 ( ) 87.5 ( ) 3.75 µg+al+squa (N=26) 73.1 ( ) 95.8 ( ) 3.75 µg+al+mpl+squa (N=26) 30.8 ( ) 36.3 ( ) SPLIT VS WHOLE VIRUS VACCINE 3.75μg doses/egg split whole H5N adjv AH adjv results after optimization μg doses/egg H1N1 2.4 H3N2 3.0 B 3.3 Placebo (N=5) 0 (0-52.2) 0 (0-52.2) *HI antibody titer postvaccination 1:40. Abbreviations: HI=Hemagglutination-inhibition; CI=confidence interval; Al=aluminum hydroxide; MPL=monophosphoryl lipid A derived from Bordetella pertussis; Squa=squalene. 9

10 YEAR EXPECTED PRODUCTION CAPACITY, COST OF BULK Seasonal split 15ug Seasonal split 3.7 ug with adjuvant Seasonal whole vaccine 3,.7 ug with adjuvant Dose/eggs Eggs (20 m) US$ 15 m US$ 15 m US$ 15 m Labor, supplies etc Production 1 semester US$ 20 m 7 m US$ 7m 80 m US$ 7 m 160 m Bullk cost/dose US$ 1.10 US$ US$ Production 2 semesters Bulk cost/dose 40 m U$ m US$ 0, m US$ 0,07 10