Long-term Persistence of Immunity to Hepatitis B in Adults Vaccinated With GlaxoSmithKline (GSK) Biologicals' Hepatitis B Vaccine (HBV), Engerix-B

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02901951
• Collaborator: (none)
• Enrollment: 106
• Locations: 4
• Arm: 1
• Actual Duration (Months): 6.6
• Patients Per Site: 26.5
• Patients Per Site Per Month: 4

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the long-term protection against HBV infection in adult subjects, aged 18-40 years vaccinated with three or four doses of Engerix-B 20 to 30 years ago

Condition or Disease	Intervention/Treatment	Phase
Hepatitis B Vaccine	Biological: Engerix-B	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 106 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Long-term Persistence of Immunity to Hepatitis B in Adults Vaccinated 20 to 30 Years Ago With Engerix-B
• Actual Study Start Date: Oct 11, 2016
• Actual Primary Completion Date: May 1, 2017
• Actual Study Completion Date: May 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: HBV Group Subjects aged 40 to 60 years old who received 3 or 4 doses of Engerix-B (HBV vaccine) 20 to 30 years ago and were administered with a single challenge dose of HBV vaccine in this study at Day 0 (Visit 1).	Biological: Engerix-B; Intramuscular administration of single challenge dose of Engerix-B vaccine in the deltoid region of the non-dominant arm.

Outcome Measures

Primary Outcome Measures

1. Percentage of Subjects With an Anamnestic Response to the HBV Challenge Dose, Based on the Last Available Time Point Before the Challenge Dose [7 days after the challenge dose (Day 7)]

   Anamnestic response to the challenge dose was defined as: At least (i.e. greater than or equal to [≥]) 4-fold rise in one month post-vaccination anti-hepatitis B surface antigen (anti-HBs) antibody concentrations in previously seropositive subjects (Subjects with anti-HBs antibody concentration ≥ 6.2 milli International Unit/Milliliter (mIU/mL) at the pre-challenge dose time point); In previously seronegative subjects (Subjects with anti-HBs antibody concentration < 6.2 mIU/mL at the pre-challenge dose time point), anti-HBs antibody concentrations ≥10 mIU/mL at one month post-challenge dose time-point.

2. Percentage of Subjects With an Anamnestic Response to the HBV Challenge Dose, Based on the Last Available Time Point Before the Challenge Dose [30 days after the challenge dose (Day 30)]

   Anamnestic response to the challenge dose was defined as: At least (i.e. ≥ 4-fold rise in one month post-vaccination anti-HBs antibody concentrations in previously seropositive subjects (Subjects with anti-HBs antibody concentration ≥ 6.2 mIU/mL at the pre-challenge dose time point); In previously seronegative subjects (Subjects with anti-HBs antibody concentration < 6.2 mIU/mL at the pre-challenge dose time point), anti-HBs antibody concentrations ≥10 mIU/mL at one month post-challenge dose time-point.

Secondary Outcome Measures

1. Percentage of Subjects With Anti-HBs Antibody Concentrations Equal to or Above Cut-off Values [At the pre-challenge dose time-point (Day 0), at 7 days post-challenge time-point (Day 7) and at 30 days post-challenge time-point (Day 30)]

   Percentage of subjects with anti-HBs antibody concentrations ≥ 6.2 mIU/mL, ≥ 10 mIU/mL and ≥ 100 mIU/mL.

2. Anti-HBs Antibody Concentrations [At the pre-challenge dose time-point (Day 0), at 7 days post-challenge dose time-point (Day 7) and at 30 days post-challenge dose time-point (Day 30)]

   Anti-HBs antibody concentrations were expressed as Geometric Mean Concentrations (GMCs) in mIU/mL.

3. Number of Subjects With Any Solicited Local Adverse Events (AEs) [During the 4-day (Days 0-3) follow-up period after the challenge dose]

   Assessed solicited local symptoms were injection site pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination.

4. Number of Subjects With Any Solicited General AEs [During the 4-day (Days 0-3) follow-up period after the challenge dose]

   Assessed solicited general symptoms were fatigue, fever (defined as axillary temperature ≥ 37.5 degrees Celsius [°C]) , gastrointestinal symptoms (nausea, vomiting, diarrhoea and/or abdominal pain) and headache. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination.

5. Number of Subjects With Any Unsolicited AEs [During the 31-day (Days 0-30) follow-up period after the challenge dose]

   An unsolicited AE covers any AE reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination.

6. Number of Subjects With Any Serious Adverse Events (SAEs) [During the entire study period (Day 0 to Day 30)]

   SAEs assessed included any untoward medical occurrences that resulted in death, was life threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity or congenital anomaly/birth defect in the offspring of a study subject. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol.

• A male or female between and including 40 and 60 years of age (from and including the 40th birthday up to, but excluding, the 61st birthday) at the time of the vaccination.

• Written informed consent obtained from the subject.

• Documented evidence of previous vaccination with three or four consecutive doses of Engerix-B administered in adulthood (i.e. at least 18 years of age) with

• the last dose received 4 to 12 months after the previous one,

• no subsequent booster dose ever received later, and

• the last dose received 20 to 30 years before enrolment.

• Female subjects of non-childbearing potential may be enrolled in the study.

• Non-childbearing potential is defined as pre-menarche, hysterectomy, ovariectomy or post-menopause.

• Female subjects of childbearing potential may be enrolled in the study, if the subject:

• has practiced adequate contraception for 30 days prior to vaccination, and

• has a negative pregnancy test on the day of vaccination, and

• has agreed to continue adequate contraception during the entire treatment period and for one month after vaccination.

Exclusion Criteria:

• Use of any investigational or non-registered product other than the study vaccine during the period starting 30 days before the dose of study vaccine, or planned use during the study period.

• Chronic administration of immunosuppressants or other immune-modifying drugs within six months prior to the vaccine dose. For corticosteroids, this will mean prednisone ≥ 20 mg/day, or equivalent. Inhaled and topical steroids are allowed.

• Administration of long-acting immune-modifying drugs at any time during the study period.

• Previous hepatitis B booster vaccination since completion of the primary vaccination series with three or four doses of Engerix-B.

• Planned administration of a vaccine not foreseen by the study protocol within 30 days preceding the dose of study vaccine, or planned administration during the study period, with the exception of seasonal influenza vaccine.

• Any medical condition that in the judgment of the investigator places the subject at undue risk by participating in the study.

• Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational vaccine/product.

• History of hepatitis B disease or episode of jaundice with unknown etiology.

• History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine.

• Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination.

• Major congenital defects or serious chronic illness (including insulin-dependent diabetes).

• Acute disease and/or fever at the time of enrolment.

• Fever is defined as temperature ≥37.5°C for oral, axillary or tympanic route, or 38.0°C on rectal route.

• Subjects with a minor illness without fever may be enrolled at the discretion of the investigator.

• Administration of immunoglobulins and/or any blood products during the period starting 3 months before the dose of study vaccine, or planned administration during the study period.

• Drug and/ or alcohol abuse within the last 5 years.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Ghent		Belgium	9000
2	GSK Investigational Site	Wilrijk		Belgium	2610
3	GSK Investigational Site	Québec City	Quebec	Canada	G1E 7G9
4	GSK Investigational Site	Sherbrooke	Quebec	Canada	J1H 2G2

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

• Study Protocol - Feb 2, 2016
• Statistical Analysis Plan - Oct 12, 2017

More Information

Publications

• Van Damme P, Dionne M, Leroux-Roels G, Van Der Meeren O, Di Paolo E, Salaun B, Surya Kiran P, Folschweiller N. Persistence of HBsAg-specific antibodies and immune memory two to three decades after hepatitis B vaccination in adults. J Viral Hepat. 2019 Sep;26(9):1066-1075. doi: 10.1111/jvh.13125. Epub 2019 Jun 2.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT02901951
• Other Study ID Numbers: 116811; 2015-004099-31
• First Posted: Sep 15, 2016
• Last Update Posted: Jan 2, 2020
• Last Verified: Dec 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by GlaxoSmithKline: Hepatitis B surface antigen antibody; adult subjects; Hepatitis B; HBV
• Additional relevant MeSH terms: Hepatitis A; Hepatitis B; Hepatitis

Study Results

Participant Flow

Recruitment Details	Subjects aged between and including 40 to 60 years were enrolled in this study, in compliance with the inclusion criteria, which required the documented evidence of previous vaccination with three or four consecutive doses of Engerix-B administered in adulthood (i.e. at least 18 years of age).
Pre-assignment Detail	106 subjects were enrolled in the study but 3 subjects were withdrawn before vaccine administration. Therefore, the number of subjects started is 103.

Arm/Group Title	HBV Group
Arm/Group Description	Subjects aged 40 to 60 years old who received 3 or 4 doses of Engerix-B (HBV vaccine) 20 to 30 years ago and were administered with a single challenge dose of HBV vaccine in this study at Day 0 (Visit 1).
Period Title: Overall Study
STARTED	103
COMPLETED	103
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	HBV Group
Arm/Group Description	Subjects aged 40 to 60 years old who received 3 or 4 doses of HBV vaccine 20 to 30 years ago and were administered with a single challenge dose of HBV vaccine in this study at Day 0 (Visit 1).
Overall Participants	103
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	48.6 (5.9)
Sex: Female, Male (Count of Participants)
Female	87 84.5%
Male	16 15.5%
Race/Ethnicity, Customized (Count of Participants)
White - Caucasian / European Heritage	103 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Subjects With an Anamnestic Response to the HBV Challenge Dose, Based on the Last Available Time Point Before the Challenge Dose
Description	Anamnestic response to the challenge dose was defined as: At least (i.e. greater than or equal to [≥]) 4-fold rise in one month post-vaccination anti-hepatitis B surface antigen (anti-HBs) antibody concentrations in previously seropositive subjects (Subjects with anti-HBs antibody concentration ≥ 6.2 milli International Unit/Milliliter (mIU/mL) at the pre-challenge dose time point); In previously seronegative subjects (Subjects with anti-HBs antibody concentration < 6.2 mIU/mL at the pre-challenge dose time point), anti-HBs antibody concentrations ≥10 mIU/mL at one month post-challenge dose time-point.
Time Frame	7 days after the challenge dose (Day 7)

Outcome Measure Data

Analysis Population Description

Analysis was performed on the According-to-protocol (ATP) cohort for analysis of immunogenicity which included all evaluable subjects who had received the challenge dose of HRV vaccine and for whom data concerning immunogenicity outcome measures at pre-challenge (Day 0) and one month post-challenge (Day 30) were available.

Arm/Group Title	HBV Group
Arm/Group Description	Subjects aged 40 to 60 years old who received 3 or 4 doses of HBV vaccine 20 to 30 years ago and were administered with a single challenge dose of HBV vaccine in this study at Day 0 (Visit 1).
Measure Participants	101
< 6.2 mIU/mL	66.7
≥ 6.2 mIU/mL	85.3

2. Primary Outcome

Title	Percentage of Subjects With an Anamnestic Response to the HBV Challenge Dose, Based on the Last Available Time Point Before the Challenge Dose
Description	Anamnestic response to the challenge dose was defined as: At least (i.e. ≥ 4-fold rise in one month post-vaccination anti-HBs antibody concentrations in previously seropositive subjects (Subjects with anti-HBs antibody concentration ≥ 6.2 mIU/mL at the pre-challenge dose time point); In previously seronegative subjects (Subjects with anti-HBs antibody concentration < 6.2 mIU/mL at the pre-challenge dose time point), anti-HBs antibody concentrations ≥10 mIU/mL at one month post-challenge dose time-point.
Time Frame	30 days after the challenge dose (Day 30)

Outcome Measure Data

Analysis Population Description

Analysis was performed on the ATP cohort for analysis of immunogenicity which included all evaluable subjects who had received the challenge dose of HRV vaccine and for whom data concerning immunogenicity outcome measures at pre-challenge (Day 0) and one month post-challenge (Day 30) were available.

Arm/Group Title	HBV Group
Arm/Group Description	Subjects aged 40 to 60 years old who received 3 or 4 doses of HBV vaccine 20 to 30 years ago and were administered with a single challenge dose of HBV vaccine in this study at Day 0 (Visit 1).
Measure Participants	101
< 6.2 mIU/mL	100
≥ 6.2 mIU/mL	100

3. Secondary Outcome

Title	Percentage of Subjects With Anti-HBs Antibody Concentrations Equal to or Above Cut-off Values
Description	Percentage of subjects with anti-HBs antibody concentrations ≥ 6.2 mIU/mL, ≥ 10 mIU/mL and ≥ 100 mIU/mL.
Time Frame	At the pre-challenge dose time-point (Day 0), at 7 days post-challenge time-point (Day 7) and at 30 days post-challenge time-point (Day 30)

Outcome Measure Data

Analysis Population Description

Analysis was performed on the ATP cohort for analysis of immunogenicity which included all evaluable subjects who had received the challenge dose of HRV vaccine and for whom data concerning immunogenicity outcome measures at pre-challenge (Day 0) and one month post-challenge (Day 30) were available.

Arm/Group Title	HBV Group
Arm/Group Description	Subjects aged 40 to 60 years old who received 3 or 4 doses of HBV vaccine 20 to 30 years ago and were administered with a single challenge dose of HBV vaccine in this study at Day 0 (Visit 1).
Measure Participants	101
≥ 6.2 mIU/mL [Day 0]	94.1
≥ 10 mIU/mL [Day 0]	90.1
≥ 100 mIU/mL [Day 0]	61.4
≥ 6.2 mIU/mL [Day 7]	98.0
≥ 10 mIU/mL [Day 7]	97.0
≥ 100 mIU/mL [Day 7]	92.1
≥ 6.2 mIU/mL [Day 30]	100
≥ 10 mIU/mL [Day 30]	100
≥ 100 mIU/mL [Day 30]	98.0

4. Secondary Outcome

Title	Anti-HBs Antibody Concentrations
Description	Anti-HBs antibody concentrations were expressed as Geometric Mean Concentrations (GMCs) in mIU/mL.
Time Frame	At the pre-challenge dose time-point (Day 0), at 7 days post-challenge dose time-point (Day 7) and at 30 days post-challenge dose time-point (Day 30)

Outcome Measure Data

Analysis Population Description

Analysis was performed on the ATP cohort for analysis of immunogenicity which included all evaluable subjects who had received the challenge dose of HRV vaccine and for whom data concerning immunogenicity outcome measures at pre-challenge (Day 0) and one month post-challenge (Day 30) were available.

Arm/Group Title	HBV Group
Arm/Group Description	Subjects aged 40 to 60 years old who received 3 or 4 doses of HBV vaccine 20 to 30 years ago and were administered with a single challenge dose of HBV vaccine in this study at Day 0 (Visit 1).
Measure Participants	101
At Day 0	184.6
At Day 7	3840.0
At Day 30	48999.1

5. Secondary Outcome

Title	Number of Subjects With Any Solicited Local Adverse Events (AEs)
Description	Assessed solicited local symptoms were injection site pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination.
Time Frame	During the 4-day (Days 0-3) follow-up period after the challenge dose

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Total Vaccinated cohort (TVC) which included all subjects who received the challenge dose.

Arm/Group Title	HBV Group
Arm/Group Description	Subjects aged 40 to 60 years old who received 3 or 4 doses of HBV vaccine 20 to 30 years ago and were administered with a single challenge dose of HBV vaccine in this study at Day 0 (Visit 1).
Measure Participants	103
Any Pain	40 38.8%
Any Redness (mm)	4 3.9%
Any Swelling (mm)	3 2.9%

6. Secondary Outcome

Title	Number of Subjects With Any Solicited General AEs
Description	Assessed solicited general symptoms were fatigue, fever (defined as axillary temperature ≥ 37.5 degrees Celsius [°C]) , gastrointestinal symptoms (nausea, vomiting, diarrhoea and/or abdominal pain) and headache. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination.
Time Frame	During the 4-day (Days 0-3) follow-up period after the challenge dose

Outcome Measure Data

Analysis Population Description

Analysis was performed on the TVC which included all subjects who received the challenge dose.

Arm/Group Title	HBV Group
Arm/Group Description	Subjects aged 40 to 60 years old who received 3 or 4 doses of HBV vaccine 20 to 30 years ago and were administered with a single challenge dose of HBV vaccine in this study at Day 0 (Visit 1).
Measure Participants	103
Any Fatigue	27 26.2%
Any Gastrointestinal symptoms	10 9.7%
Any Headache	20 19.4%
Any Fever	0 0%

7. Secondary Outcome

Title	Number of Subjects With Any Unsolicited AEs
Description	An unsolicited AE covers any AE reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination.
Time Frame	During the 31-day (Days 0-30) follow-up period after the challenge dose

Outcome Measure Data

Analysis Population Description

Analysis was performed on the TVC which included all subjects who received the challenge dose.

Arm/Group Title	HBV Group
Arm/Group Description	Subjects aged 40 to 60 years old who received 3 or 4 doses of HBV vaccine 20 to 30 years ago and were administered with a single challenge dose of HBV vaccine in this study at Day 0 (Visit 1).
Measure Participants	103
Count of Participants [Participants]	41 39.8%

8. Secondary Outcome

Title	Number of Subjects With Any Serious Adverse Events (SAEs)
Description	SAEs assessed included any untoward medical occurrences that resulted in death, was life threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity or congenital anomaly/birth defect in the offspring of a study subject. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination.
Time Frame	During the entire study period (Day 0 to Day 30)

Outcome Measure Data

Analysis Population Description

Analysis was performed on the TVC which included all subjects who received the challenge dose.

Arm/Group Title	HBV Group
Arm/Group Description	Subjects aged 40 to 60 years old who received 3 or 4 doses of HBV vaccine 20 to 30 years ago and were administered with a single challenge dose of HBV vaccine in this study at Day 0 (Visit 1).
Measure Participants	103
Count of Participants [Participants]	0 0%

Adverse Events

Time Frame	Solicited local & general AEs: during 4-day (Days 0-3) follow-up period after challenge dose; Unsolicited AEs: during 31-day (Days 0-30) follow-up period after challenge dose; SAEs: during the entire study period (Day 0 to Day 30).
Arm/Group Title	HBV Group
Arm/Group Description	Subjects aged 40 to 60 years old who received 3 or 4 doses of HBV vaccine 20 to 30 years ago and were administered with a single challenge dose of HBV vaccine in this study at Day 0 (Visit 1).
All Cause Mortality
	HBV Group
	Affected / at Risk (%)	# Events
Total	0/103 (0%)
Serious Adverse Events
	HBV Group
	Affected / at Risk (%)	# Events
Total	0/103 (0%)
Other (Not Including Serious) Adverse Events
	HBV Group
	Affected / at Risk (%)	# Events
Total	75/103 (72.8%)
Ear and labyrinth disorders
Tinnitus	1/103 (1%)	1
Eye disorders
Eye pruritus	2/103 (1.9%)	2
Lacrimation increased	1/103 (1%)	1
Gastrointestinal disorders
Abdominal distension	1/103 (1%)	1
Frequent bowel movements	1/103 (1%)	1
Gastrointestinal disorder	10/103 (9.7%)	10
Lip swelling	1/103 (1%)	2
Nausea	1/103 (1%)	1
Toothache	1/103 (1%)	1
Vomiting	1/103 (1%)	1
General disorders
Fatigue	29/103 (28.2%)	30
Injection site erythema	4/103 (3.9%)	4
Injection site pain	40/103 (38.8%)	40
Injection site pruritus	1/103 (1%)	1
Injection site swelling	3/103 (2.9%)	3
Pain	1/103 (1%)	1
Pyrexia	1/103 (1%)	1
Infections and infestations
Bronchitis	1/103 (1%)	1
Gastroenteritis	1/103 (1%)	1
Sinusitis	1/103 (1%)	1
Upper respiratory tract infection	3/103 (2.9%)	3
Upper respiratory tract infection bacterial	1/103 (1%)	1
Nasopharyngitis	6/103 (5.8%)	6
Injury, poisoning and procedural complications
Contusion	1/103 (1%)	1
Meniscus injury	1/103 (1%)	1
Procedural pain	3/103 (2.9%)	3
Musculoskeletal and connective tissue disorders
Arthralgia	1/103 (1%)	1
Back pain	4/103 (3.9%)	4
Joint warmth	1/103 (1%)	1
Musculoskeletal pain	1/103 (1%)	1
Musculoskeletal stiffness	1/103 (1%)	1
Myalgia	2/103 (1.9%)	2
Neck pain	2/103 (1.9%)	2
Pain in extremity	3/103 (2.9%)	4
Nervous system disorders
Headache	25/103 (24.3%)	26
Psychiatric disorders
Insomnia	2/103 (1.9%)	2
Reproductive system and breast disorders
Menopausal symptoms	1/103 (1%)	1
Respiratory, thoracic and mediastinal disorders
Cough	3/103 (2.9%)	3
Dyspnoea	1/103 (1%)	1
Nasal congestion	2/103 (1.9%)	3
Oropharyngeal pain	1/103 (1%)	1
Pharyngeal erythema	1/103 (1%)	1
Rhinorrhoea	2/103 (1.9%)	3
Sinus pain	1/103 (1%)	1
Sneezing	1/103 (1%)	1
Throat irritation	1/103 (1%)	1
Skin and subcutaneous tissue disorders
Erythema	1/103 (1%)	1
Hyperhidrosis	1/103 (1%)	1
Vascular disorders
Hypertension	1/103 (1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.