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1. Prevalence of HBV* by Region Epidemiology Virology Vaccine Production Clinical Summary Epidemiology * Hepatitis B Virus 2.

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Presentation on theme: "1. Prevalence of HBV* by Region Epidemiology Virology Vaccine Production Clinical Summary Epidemiology * Hepatitis B Virus 2."— Presentation transcript:

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2 Prevalence of HBV* by Region Epidemiology Virology Vaccine Production Clinical Summary Epidemiology * Hepatitis B Virus 2

3 Worldwide HBV Worldwide HBV Infection More than 2 billion people infected during lifetime Up to 2 million die each year from HBV infection Worldwide there are ~350-400 million HBsAg carriers In the WHO European Region, 14 million people are estimated to live with chronic hepatitis B; Up to 36,000 deaths are attributable to HBV every year in Europe Annual infection in US ~320,000, ~32,000 HBsAg carriers Persistent HBV is considered a significant risk factor for development of primary liver cancer Epidemiology Epidemiology Virology Vaccine Production Clinical Summary 3

4 Hepatitis B Virus Virology Epidemiology Virology Vaccine Production Clinical Summary 4

5 HBsAg – Protein Composition Virology *Wild type rHBsAg (CHO-derived) WHBV* Epidemiology Virology Vaccine Production Clinical Summary 5

6 Factors Which Affect Non-Response to Immunization Genetically determined resistance Advanced age Overweight Gender Smoking Chronic liver diseases Systemic diseases Immune suppression Pre-S enhancing attenuating Vaccines Craven DE, et al. Ann Int Med1986; Alper CA, et al. N Eng J Med 1989, Milich DR Immunol Today 1988, Hohler T, et al. Hum Immunol 1998 Epidemiology Virology Vaccine Production Clinical Summary 6

7 Populations of Non-Responders to Conventional Vaccination Cancer patients (children) ~57% (31% on Rx 88% off Rx) Acute lymphocytic leukemia ~ 10% Bone marrow transplant patients 15-68% Chronic renal failure & dialysis 34-81% Patients with chronic liver disease ~50% Pre-transplantation candidates 28-36% Post-transplantation patients ~10% HIV (children & adolescents) ~30% Miscellaneous Vaccines Epidemiology Virology Vaccine Production Clinical Summary 7

8 Why Do We Need Better HBV Vaccines? Non–response to conventional HBV vaccines in special populations Fast induction of immunity to HBV in defined populations Low compliance with the 3 dose regimen of conventional HBV vaccines Possible protection against HBV envelope mutant(s) Vaccines Epidemiology Virology Vaccine Production Clinical Summary 8

9 History of Hepatitis B Vaccines 1 st Generation: Plasma-derived -HBsAg, Pre-S 3 rd Generation: Mammalian cell derived (recombinant) -HBsAg, Pre-S 2 -HBsAg, Pre-S 2, Pre-S 1 2 nd Generation: Yeast-derived, (recombinant) -HBsAg, (S Antigen only) Vaccines Epidemiology Virology Vaccine Production Clinical Summary 9

10 Three Generations of HB Vaccines Plasma derived vaccines rDNA Yeast derived rDNA Mammalian cell derived vaccines Sci-B-Vac TM with the 3 epitopes Vaccines Epidemiology Virology Vaccine Production Clinical Summary 10

11 Sci- B-Vac ™ * Third Generation Hepatitis B vaccine Biosynthesized via recombinant DNA technology in engineered Chinese Hamster Ovary [CHO] cells harboring the entire HBs gene Manufactured under full GMP Produced in Chinese Hamster Ovary Cells and contains all three epitopes of the native virus surface antigen Production *Previously manufactured under the trade names of Bio-Hep-B ® and Hepimmune TM Epidemiology Virology Vaccine Production Clinical Summary 11

12 Structure of HBV DNA Expression of the r-HBsAg in Sci-B-Vac™ * Glycosylation sites (PreS 2 Asn 4; S Asn 146) Production Epidemiology Virology Vaccine Production Clinical Summary 12

13 Development of Recombinant HB Vaccine HBs gene fragment + Expression Vector (recombinant plasmid) rDNA Transfection Host (CHO cells) HBs Proteins (PreS 1, PreS 2, S) Expression Production Epidemiology Virology Vaccine Production Clinical Summary 13

14 Development of Recombinant HB Vaccine Production Epidemiology Virology Vaccine Production Clinical Summary 14

15 Production of Sci-B-Vac ™ (Flow Chart 1) Production Tissue Culture Cell Propagation 1 Vial / WCB 3 – 9X10” cells Bioreactors Production Cell Inoculation Growth phase Production Phase Post Production Phase Protein purification Purification Clarification Concentration Dialysis I DNasa treatment Dialysis II DEAE-I Anion Exchange Formalin Inactivation 0.2µ filtration bulk API Quality Control Release Criteria (Bulk) Identification Composition Sterility Impurities Endotoxin Protein Content DEAE-II Anion Exchange Epidemiology Virology Vaccine Production Clinical Summary 15

16 (Flow Chart 2) Formulation Adsorption to Alum 20 µg/ml 10 µg/ml 5 µg/ml Final FillingQuality Control Release Criteria (Final) pH Alum content General Safety Potency Endotoxin Sterility Physical Inspection Volume in Container Visual Inspection 20µg/1ml 10µg/1ml 5µg/0.5ml 2.5µg/0.5ml Production Epidemiology Virology Vaccine Production Clinical Summary 16

17 Surface Antigen Composition of Sci-B-Vac™ (SDS-PAGE & immunoblot) ]S]S ] pre-S 1 ] pre-S 2 Production Epidemiology Virology Vaccine Production Clinical Summary 17

18 CHO Cells in Production Phase Production Epidemiology Virology Vaccine Production Clinical Summary 18

19 HBsAg Particles ( Electron Microscopy ) Production Epidemiology Virology Vaccine Production Clinical Summary 19

20 Efficacy of Sci-B-Vac ™ in Neonates ( n=1206, Four Dose-Ranging Studies ) Study was conducted in endemic populations / Data on file Results of clinical trials Seroprotection (%) Months P < 0.05 98 94 95 94 87 56 35 Injections: Epidemiology Virology Vaccine Production Clinical Summary 20

21 Efficacy of Sci-B-Vac TM in Neonates (n=205, Comparative Study) *p<0.01 Yerushalmi et al. – Ped. Inf. Dis. J 1997 GMT significantly* higher at all points in the Sci-B-Vac group 11 2 13055 6074 3211 722 Months GMT mIU/ml Epidemiology Virology Vaccine Production Clinical Summary Results of clinical trials 21

22 Efficacy of Sci-B-Vac™ in Neonates (Born to HBsAg+ Mothers) Data on file Results of clinical trials Epidemiology Virology Vaccine Production Clinical Summary Seroprotection (%) Sci-B-Vac = 5  g 20 50 Months 85 94 98 94 22

23 Efficacy of Sci-B-Vac ™ in Children Data on file Results of clinical trials Age: 2m - 11y Anti-HBs, mIU/ml 1 10 100 1000 10000 100000 1267 12 Months 2.5µg, n=33 5µg, n=36 Epidemiology Virology Vaccine Production Clinical Summary Injections 23

24 Immunogenicity of 2 Doses* Sci-B-Vac TM in Adults (n=36, Comparative Study ) *OFF LABEL Shapira et al. J. of Hepatology 2001 Results of clinical trials Sci-B-Vac 10µg Engerix B 20µg Epidemiology Virology Vaccine Production Clinical Summary 12 Injection 28,800 923 81 18.1 4.7 Anti-HBs, mIU/ml 24

25 GMT Levels (mIU/ml) in Adults ( n=476, Comparative Study) GMT values about 5 times higher at months 7 and 12 (P<0.0001) Raz R. et al. IMAJ 2001 Months Anti-HBs mIU/ml Epidemiology Virology Vaccine Production Clinical Summary Results of clinical trials 25

26 Immunogenicity of a Sci-B-Vac™ According to Weight Data on file Results of clinical trials 10µg/ml Sci-B-Vac n=260 5µg/ml Sci-B-Vac n=253 20µg/ml Engerix B n=315 GMT mIU/ml (log) Epidemiology Virology Vaccine Production Clinical Summary 26

27 Immunogenicity of Sci-B-Vac™ in Dialysis Patients Anti-HBs, mIU/ml 0 30 60 90 180 210 days 10000 1000 100 10 1 Sci-B-Vac – 20  g (n=9) HB-Vax- II – 40  g (n=12) Shouval D. et al. In: Viral Hepatitis and Liver Disease. Eds., K Nishioka, H Suzuki, S Mishiro, Toda, Springer Verlag, pp. 543,1994. Results of clinical trials Epidemiology Virology Vaccine Production Clinical Summary 27

28 Efficacy of Sci-B-Vac™ in Non-and Low Responders to Standard Vaccine (N=719, Comparative Study) Open, randomized, comparative, controlled, multi- center international parallel group study. To demonstrate superiority of Sci-B-Vac over standard vaccine after one or two additional doses in non-responders ≥4 prior injections of standard vaccine. To evaluate efficacy of the two vaccines in low responders after ≥4 and non responders after 3 prior injections of the standard vaccine. Rendi-Wagner P. et al. Vaccine 2006 Results of clinical trials Epidemiology Virology Vaccine Production Clinical Summary 28

29 Study Parameters Rendi-Wagner P. et al. Vaccine 2006 Age: ≥18 years Randomized: 719 Injected with Sci-B-Vac: 479 Injected with Engerix B: 237 Injections: on days 1 and 85 Adverse Events: 3% Sci-B-Vac vs 0.8% Engerix B Results of clinical trials Epidemiology Virology Vaccine Production Clinical Summary 29

30 Seroprotection After 1 st or 2 nd Additional Injection (n=719, Comparative Study) Rendi-Wagner P. et al. Vaccine 2006 Seroprotection % Results of clinical trials Epidemiology Virology Vaccine Production Clinical Summary 30

31 Analyses of 10,815 Individual Anti-HBs Measurements for 1,923 Vaccinees *Wilson J. et.al. 2002 The 3 rd generation HBV vaccine Sci-B-Vac and HBV/MF59 appear the more immunogenic vaccines Hevac B and HB Vax vaccines appear less immunogenic Priming of immune memory is successful after a single dose Immune memory is maintained after anti-HBs antibody decay Antibody boosts following completion of conventional immunization are unnecessary Vaccines tested: Engerix B, SL*, Bio-Hep- B, China HBV MF/59, Recombivax, Herbiovac, Hevac B, HB Vax Epidemiology Virology Vaccine Production Clinical Summary 31

32 Performance of Sci- B-Vac™ in > 20 Clinical Trials Sci-B-Vac is safe and highly immunogenic Rapid (earlier/higher) immune responses High seroprotection rates Tested in adults and children in over 5,000 subjects Protects neonates of HBeAg positive and negative mothers Induces seroconversion in high-risk patients and in non-responders Epidemiology Virology Vaccine Production Clinical Summary 32

33 Possible Future Applications For Sci-B-Vac™ Non / hypo responders to standard vaccines Vaccination of health care workers Immune suppressed patients Organ donors Universal vaccination for neonates in endemic countries using less than three doses Epidemiology Virology Vaccine Production Clinical Summary 33

34 THANK YOU 34


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