UMIN-CTR Clinical Trial

Basic information
Official scientific title of the study	Evaluation of the effect of hepatitis B vaccines derived from different genotypes of hepatitis B viruses
Title of the study (Brief title)	Evaluation of HB vaccines from different HBV genotypes
Region	Japan

Condition
Condition	Infection of hepatitis B virus
Classification by specialty	Hepato-biliary-pancreatic medicine
Classification by malignancy	Others
Genomic information	NO

Objectives
Narrative objectives1	To examine whether HBs antibodies produced by hepatitis B vaccination bind to HBs antigens from different genotypes.
Basic objectives2	Bio-equivalence
Basic objectives -Others
Trial characteristics_1	Confirmatory
Trial characteristics_2	Pragmatic
Developmental phase	Not applicable

Assessment
Primary outcomes	To detect cross-reaction of HBs antibodies in HB vaccine-immunized sera to HBs antigens from different HBV genotypes by ELISA.
Key secondary outcomes	To examine whether anti-HBs antibodies generated by HB vaccination protect the infection of HBV whose genotype is different from that of the immunized vaccine.

Base
Study type	Observational

Study design
Basic design
Randomization
Randomization unit
Blinding
Control
Stratification
Dynamic allocation
Institution consideration
Blocking
Concealment

Intervention
No. of arms
Purpose of intervention
Type of intervention
Interventions/Control_1
Interventions/Control_2
Interventions/Control_3
Interventions/Control_4
Interventions/Control_5
Interventions/Control_6
Interventions/Control_7
Interventions/Control_8
Interventions/Control_9
Interventions/Control_10

Eligibility
Age-lower limit	18 years-old <=
Age-upper limit	Not applicable
Gender	Male and Female
Key inclusion criteria	People whose informed consents were obtained. Sufficient amount of serum was obtained after their medical examinations.
Key exclusion criteria	Informed consents were not obtained. Sufficient amount of serum was not obtained after their medical examinations.
Target sample size	150

Research contact person
Name of lead principal investigator	Manae S. Kurokawa
Organization	St. Marianna University, Graduate School of Medicine
Division name	Disease Biomarker Analysis and Molecular Regulation
Address	2-16-1, Sugao, Miyamae-ku, Kawasaki
TEL	81-44-977-8111
Email	manae@marianna-u.ac.jp

Public contact
Name of contact person	Manae S. Kurokawa
Organization	St. Marianna University, Graduate School of Medicine
Division name	Disease Biomarker Analysis and Molecular Regulation
Address	2-16-1, Sugao, Miyamae-ku, Kawasaki
TEL	81-44-977-8111
Homepage URL
Email	manae@marianna-u.ac.jp

Sponsor
Institute	St. Marianna University, School of Medicine
Institute
Department

Funding Source
Organization	Study Group of MHLW
Organization
Division
Category of Funding Organization	Japanese Governmental office
Nationality of Funding Organization	Japan

Other related organizations
Co-sponsor
Name of secondary funｄer(s)

Secondary IDs
Secondary IDs	NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions
Institutions

Other administrative information
Date of disclosure of the study information	2014 Year 06 Month 24 Day

Progress
Recruitment status	Completed
Date of protocol fixation	2014 Year 02 Month 07 Day
Anticipated trial start date	2014 Year 04 Month 01 Day
Last follow-up date	2018 Year 11 Month 22 Day
Date of closure to data entry	2018 Year 11 Month 22 Day
Date trial data considered complete	2018 Year 11 Month 22 Day
Date analysis concluded	2018 Year 11 Month 22 Day

Related information
URL releasing protocol
Publication of results	Published
URL releasing results
Results	Background: In universal hepatitis B (HB) vaccination, single vaccine-derived polyclonal anti-HBs antibodies (anti-HBs) need to inhibit infection of HB viruses (HBV) of non-vaccine genotypes. We experimentally addressed this issue. Methods: Anti-HBs-positive sera were obtained by vaccination with genotype A- or C-derived HBs antigen (HBsAg, gtA-sera or gtC-sera). Their reactivity to genotype A- and C-derived HBsAg (gtA-Ag and gtC-Ag) was measured by ELISA. The capacity of sera to neutralize HBV was evaluated using an in vitro infection model. Results: Of 135 anti-gtA-Ag-reactive gtA-sera, 134 (99.3%) were anti-gtC-Ag-reactive. All (100%) 120 anti-gtC-Ag-reactive gtC-sera were anti-gtA-Ag-reactive. The reactivity to gtA-Ag was strongly correlated with that to gtC-Ag (gtA-sera, rho=0.989; gtC-sera, rho=0.953; p<0.01). In gtA-sera (n=10), anti-HBs to gtA-Ag were less completely absorbed with gtC-Ag (96.4%) than with gtA-Ag (100%, p<0.05). Similarly, in gtC-sera (n=10), anti-HBs to gtC-Ag were less completely absorbed with gtA-Ag (96.0%) than with gtC-Ag (100%, p<0.01). Thus, 3.6% and 4.0% of anti-HBs in gtA-sera and gtC-sera were vaccine genotype HBsAg-specific, respectively. In the neutralization test, gtA-sera (n=4) and gtC-sera (n=3) with anti-HBs titers adjusted to 100 mIU/mL equally inhibited genotype C HBV infection (92.8% vs. 95.4%, p=0.44). However, at 30 mIU/mL, the gtA-sera less effectively inhibited infection than the gtC-sera (60.2% vs. 90.2%, p<0.05). Conclusions: Vaccination with genotype A- or C-derived HBsAg provided polyclonal anti-HBs that sufficiently bound to non-vaccine genotype HBsAg. However, a small portion of anti-HBs were specific to the vaccine genotype HBsAg. High anti-HBs titers would be required to prevent HBV infection of non-vaccine genotypes.
Other related information	The subjects were medical students and health care providers 18 years or more of age who needed to be immunized with HB vaccines for their future work. Subjects with a fever and acute diseases were excluded from the vaccination. In total, 474 subjects were enrolled in this study at St. Marianna University School of Medicine (including its branch, Kawasaki Municipal Tama Hospital) and University of Tsukuba. Of these, 196 subjects were vaccinated with Heptavax-II (MSD, Kenilworth, NJ, USA) (genotype A-derived vaccine). The anti-HBs titers were evaluated by Stacia (LSI Medience, Tokyo, Japan) or Architect (Abbott, Abbott Park, IL, USA). Anti-HBs-positive sera (10 or more mIU/mL) were selected as genotype A-derived vaccine-immunized sera (gtA-sera). A total of 150 gtA-sera with low-to-high anti-HBs titers, obtained 3-57 months after the last vaccination, were subjected to our analyses. Another gtA-serum, the anti-HBs titer of which was 842.7 mIU/mL measured by Stacia, was used as an internal control serum sample. Similarly, 148 subjects were vaccinated with Bimmugen (Kaketsuken, Kumamoto, Japan). Their anti-HBs titers were evaluated by Stacia or Architect. Anti-HBs-positive sera (10 or more mIU/mL) were selected as genotype C-derived vaccine-immunized sera (gtC-sera). A total of 124 gtC-sera with low-to-high anti-HBs titers, obtained 1-2 months after the last vaccination, were subjected to our analyses. The anti-HBs titers were evaluated by Stacia in 130 university freshmen, 101 of whom were anti-HBs-negative and had no experience of HB vaccination. Sera from these 101 students were subjected to our analyses as HB vaccine-non-immunized sera (NI-sera).

Management information
Registered date	2014 Year 06 Month 24 Day
Last modified on	2019 Year 01 Month 03 Day

Link to view the page
URL(English)	https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000016711