UMIN-CTR Clinical Trial

Public title

Evaluation of the effect of hepatitis B vaccines derived from different genotypes of hepatitis B viruses

Acronym

Evaluation of HB vaccines from different HBV genotypes

Scientific Title

Evaluation of the effect of hepatitis B vaccines derived from different genotypes of hepatitis B viruses

Scientific Title:Acronym

Evaluation of HB vaccines from different HBV genotypes

Region

Japan

Condition

Infection of hepatitis B virus

Classification by specialty

Hepato-biliary-pancreatic medicine

Classification by malignancy

Others

Genomic information

NO

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

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.

Study type

Observational

Basic design

Randomization

Randomization unit

Blinding

Control

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

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

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

Name of lead principal investigator

1st name
Middle name
Last name	Manae S. Kurokawa

Organization

St. Marianna University, Graduate School of Medicine

Division name

Disease Biomarker Analysis and Molecular Regulation

Zip code

Address

2-16-1, Sugao, Miyamae-ku, Kawasaki

TEL

81-44-977-8111

Email

manae@marianna-u.ac.jp

Name of contact person

1st name
Middle name
Last name	Manae S. Kurokawa

Organization

St. Marianna University, Graduate School of Medicine

Division name

Disease Biomarker Analysis and Molecular Regulation

Zip code

Address

2-16-1, Sugao, Miyamae-ku, Kawasaki

TEL

81-44-977-8111

Homepage URL

Email

manae@marianna-u.ac.jp

Institute

St. Marianna University, School of Medicine

Institute

Department

Personal name

Organization

Study Group of MHLW

Organization

Division

Category of Funding Organization

Japanese Governmental office

Nationality of Funding Organization

Japan

Co-sponsor

Name of secondary funder(s)

Organization

Address

Tel

Email

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

Date of disclosure of the study information

2014

Year

06

Month

24

Day

URL releasing protocol

Publication of results

Published

URL related to results and publications

Number of participants that the trial has enrolled

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.

Results date posted

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Participant flow

Adverse events

Outcome measures

Plan to share IPD

IPD sharing Plan description

Recruitment status

Completed

Date of protocol fixation

2014

Year

02

Month

07

Day

Date of IRB

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

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).

Registered date

2014

Year

06

Month

24

Day

Last modified on

2019

Year

01

Month

03

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000016711