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

3. Worldwide HBV Infection
Epidemiology
Worldwide HBV Infection
More than 2 billion people infected during lifetime
Up to 2 million die each year from HBV infection
Worldwide there are ~ 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
Virology
Vaccine
Production
Clinical
Summary

4. Hepatitis B Virus Virology M H B s (Pre-S2) L S (Pre-S1) S S (S) c3 . 2 k b D N A 4 n m
Pre-S2
Epidemiology
Virology
Vaccine
Production
Clinical
Summary

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

6. Non-Response to Immunization
Vaccines
Factors Which Affect
Non-Response to Immunization
Epidemiology
Virology
Vaccine
Production
Clinical
Summary
enhancing
Genetically determined resistance
Advanced age
Overweight
Gender
Smoking
Chronic liver diseases
Systemic diseases
Immune suppression
Pre-S
attenuating
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

7. Populations of Non-Responders to Conventional Vaccination
Vaccines
Populations of Non-Responders to Conventional Vaccination
Epidemiology
Virology
Vaccine
Production
Clinical
Summary
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

8. Why Do We Need Better HBV Vaccines?
Epidemiology
Virology
Vaccine
Production
Clinical
Summary
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)

9. History of Hepatitis B Vaccines
Epidemiology
Virology
Vaccine
Production
Clinical
Summary
1st Generation:
Plasma-derived -HBsAg, Pre-S
2nd Generation:
Yeast-derived, (recombinant)
-HBsAg, (S Antigen only)
3rd Generation:
Mammalian cell derived (recombinant)
-HBsAg, Pre-S2
-HBsAg, Pre-S2, Pre-S1

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

11. Third Generation Hepatitis B vaccine
Production
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
Epidemiology
Virology
Vaccine
Production
Clinical
Summary
*Previously manufactured under the trade names of Bio-Hep-B® and HepimmuneTM

12. Expression of the r-HBsAg in Sci-B-Vac™
Production
Structure of HBV DNA
Expression of the r-HBsAg in Sci-B-Vac™
Epidemiology
Virology
Vaccine
Production
Clinical
Summary
* Glycosylation sites (PreS2 Asn 4; S Asn 146)

13. Development of Recombinant HB Vaccine HBs Proteins (PreS1, PreS2, S)
Production
Development of Recombinant HB Vaccine +
Epidemiology
Virology
Vaccine
Production
Clinical
Summary
Expression Vector
(recombinant plasmid)
HBs gene fragment
rDNA
Transfection
Host (CHO cells)
Expression
HBs Proteins (PreS1, PreS2, S)

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

15. Formalin Inactivation Release Criteria (Bulk)
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
Production
Production of Sci-B-Vac ™ (Flow Chart 1)
Epidemiology
Virology
Vaccine
Production
Clinical
Summary

16. Release Criteria (Final)
Production
(Flow Chart 2)
Epidemiology
Virology
Vaccine
Production
Clinical
Summary
Formulation
Adsorption to Alum
20 µg/ml
10 µg/ml
5 µg/ml
Final Filling
Quality 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

17. Surface Antigen Composition of Sci-B-Vac™ (SDS-PAGE & immunoblot)
Production
Surface Antigen Composition of Sci-B-Vac™ (SDS-PAGE & immunoblot)
Epidemiology
Virology
Vaccine
Production
Clinical
Summary ]S
]pre-S1
] pre-S2

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

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

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

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

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

23. Efficacy of Sci-B-Vac™ in Children
Results of clinical trials
Efficacy of Sci-B-Vac™ in Children
Epidemiology
Virology
Vaccine
Production
Clinical
Summary
Injections
Age: 2m - 11y
Anti-HBs, mIU/ml 1 10
100
1000
10000
100000 2 6 7
12 Months
2.5µg, n=33
5µg, n=36
Data on file

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

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

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

27. Immunogenicity of Sci-B-Vac™
Results of clinical trials
Immunogenicity of Sci-B-Vac™
in Dialysis Patients
Epidemiology
Virology
Vaccine
Production
Clinical
Summary
Anti-HBs, mIU/ml
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.

28. Results of clinical trials
Efficacy of Sci-B-Vac™ in Non-and Low Responders to Standard Vaccine (N=719, Comparative Study)
Epidemiology
Virology
Vaccine
Production
Clinical
Summary
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

29. Study Parameters Age: ≥18 years Randomized: 719
Results of clinical trials
Study Parameters
Epidemiology
Virology
Vaccine
Production
Clinical
Summary
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
Rendi-Wagner P. et al. Vaccine 2006

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

31. Analyses of 10,815 Individual Anti-HBs Measurements for 1,923 Vaccinees
Epidemiology
Virology
Vaccine
Production
Clinical
Summary
The 3rd 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
*Wilson J. et.al. 2002

32. Performance of Sci- B-Vac™ in > 20 Clinical Trials
Epidemiology
Virology
Vaccine
Production
Clinical
Summary
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

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

34. THANK YOU