A Study to Qualify an In-house Reference Standard Batch of Sci-B-Vac™

Each Sci-B-Vac™ lot to be released to the market is tested in comparison to a reference batch,which has to be tested in a human clinical trial. This study was conducted by SciVac Ltd. to to evaluate the immunogenicity and explore the immune kinetics of Sci-B-Vac™ in support of its qualification as new reference standard which according to the European Pharmacopeia (Ph.Eur. 1056) should elicit ≥ 95% seroprotection rate (SPR) of Hepatitis B surface (HBs) antibody concentrations ≥ 10 milli-International Units (mIU) per ml in young, healthy adult subjects.

This study was a post-marketing, open-label, single arm study in healthy volunteers who had never been vaccinated with any hepatitis B vaccine and were seronegative to HBsAg, Hepatitis B core (HBc) and HBs antibodies. This study consisted of three periods: screening period (up to 1 month prior to first vaccination), treatment (Day 1 to month 6), and post-vaccination follow-up period (months 6 -12). Immunogenicity endpoints were examined one month after the first injection and at every month until month 6, then at months 7, 9 and 12. The primary safety endpoint was the frequency, severity, and duration of adverse events, including clinically-significant laboratory abnormalities after administration of Sci-B-Vac™.

Statistical Methods: A total of 92 subjects were recruited into the study. Subjects who fully complied with the study protocol, had no inclusion/exclusion criteria violation and who early terminated the study but reached the primary endpoint prior to withdrawal (modified intention-to-treat (mITT) population) were included in the final population for statistical analysis. mITT population was defined as the subset of the ITT set, which consisted of all enrolled subjects who were vaccinated at least once with Sci-B-Vac™ and had at least one post-vaccination follow-up visit, fully complied with the protocol and had no violation of the inclusion/exclusion criteria. Eligible subjects were followed for a total duration of 12 months.

Significance Level: The overall significance level for this study was 5% using two-tailed tests. Sample size determination was performed under the following assumptions:

The primary endpoint for the study was the SPR, defined as the proportion of subjects with HBs antibody titer ≥10 mIU/ml by month 7 (i.e. one month after the third immunization with Sci-B-Vac™). Subjects terminated early from the study for any reason at any time and who met the primary endpoint were included.

In compliance with the European Pharmacopeia, the SPR threshold was set at ≥ 95%. Based on a 9% margin of non-inferiority, the study was considered successful if the lower bound of the 95.0% exact confidence interval (CI) was 86.0% or more (lower non-inferiority limit) by month 7.

The secondary objective of the study was to explore kinetics of immune response induced by Sci-B-Vac™ based on serial immunogenicity measurements.

Demographic and baseline data as well as disease prognostic factors, medical history and prior medications were summarized for the mITT population,For continuous variables, descriptive statistics (number \[n\], mean, standard deviation (SD), standard error, median, minimum, and maximum) were provided. For categorical variables, subject counts and percentages were provided.

Eligibility Criteria:
Inclusion Criteria:

1. Healthy males and females 20 - 40 years of age.
2. Subjects who provided written informed consent to participate in the study.
3. Subjects in general good health in the opinion of the investigator as determined by medical history, vital signs and a physical examination.
4. No clinically-significant abnormalities in hematology, blood chemistry, or urinalysis lab tests at Screening.
5. Women of child-bearing potential had to practice an acceptable method of birth control or practice abstinence during the study period or be surgically sterilized, from Screening visit throughout the vaccination phase and for 28 days after the last injection and agree to undergo repeated pregnancy tests.
6. Subjects had to be able to understand the requirements of the study and willing to comply with the requirements of the study.

Exclusion Criteria:

1. Known history of significant medical disorder, which in the investigator's judgment contraindicates administration of the vaccine or may interfere with the subject's compliance or the interpretation of study assessment parameters.
2. Any clinically-significant abnormality upon physical examination or in the clinical laboratory tests at Screening visit.
3. Treatment with immune suppressive agents.
4. Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose.
5. History of Hepatitis B virus (HBV) infection or confirmed exposure to HBV
6. Previous vaccination against Hepatitis B.
7. Positive for HBsAg, anti-HBs antibodies, anti-HBc antibodies, anti-HCV (hepatitis C virus) antibodies or anti- HIV antibodies.
8. Drug abuse
9. Known hypersensitivity or allergy to any component of the study vaccine.
10. Body mass index (BMI) \< 18.5 or ≥ 30 kg/m2.
11. Known concomitant disease or any other medical condition that is considered by the investigator likely to interfere with the subject's compliance or the interpretation of study assessments.
12. Any acute illness (e.g. acute infection) within 48 hours prior to the first study drug administration that is considered of significance by the Principal Investigator.
13. Female subjects: pregnant, lactating or planning a pregnancy.
14. Any confirmed or suspected immunosuppressive or immunodeficient condition.
15. Receipt of blood or immunoglobulin transfusion six months prior to the first vaccine dose and during the course of the trial.
16. Unwilling or unable (in the judgment of the investigator) to comply with all the requirements of the protocol.
17. Participate in another clinical trial within 3 months prior to first vaccination (calculated from the previous study's last dosing date).