Evaluation of Antibody Persistence & Immune Memory in Subjects Vaccinated During Adolescence With Twinrix™

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00875485
• Collaborator: (none)
• Enrollment: 210
• Locations: 2
• Arms: 2
• Duration (Months): 62
• Patients Per Site: 105
• Patients Per Site Per Month: 1.7

Study Details

Study Description

Brief Summary

This study will evaluate the immune response against Hepatitis-A (HAV) and Hepatitis B surface (HBs) antigen in healthy subjects aged 12 to 15 years (at the time of primary vaccination), who received vaccination course with GSK Biologicals' Twinrix Adult and Twinrix Junior vaccine, approximately 10 years ago in the primary study. The subjects will be invited for blood sampling at 11, 12, 13, 14 and 15 years after primary vaccination to evaluate the persistence of immune response. For subjects detected with decreased immunity, the presence of immune memory against hepatitis A & B antigens will be investigated by the administration of a challenge dose of the appropriate vaccine 6 to 12 months after the Year 15 follow-up time-point.

No new subjects will be recruited during this booster phase of the study.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis B; Hepatitis A	Procedure: Blood sampling; Biological: Additional challenge dose	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 210 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: An Open Multicentre, Multicountry Study to Evaluate Long-term Antibody Persistence and Immune Memory Between Years 11 and 15 After the Primary Study HAB-084 in Which Healthy Adolescents Were Vaccinated With Twinrix™ Adult Following a Two-dose Schedule or Twinrix™ Junior Following a Three-dose Schedule.
• Study Start Date: May 1, 2009
• Actual Primary Completion Date: Jul 1, 2014
• Actual Study Completion Date: Jul 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Twinrix Adult Group Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Procedure: Blood sampling; Blood sampling at Years 11, 12, 13, 14, 15 and at the time of challenge dose administration and one month after challenge dose administration.; Biological: Additional challenge dose; If a subject became seronegative for anti-HAV antibodies (< 15 mIU/mL) or if anti-HBs antibody concentrations decreased below 10 mIU/mL during the long-term follow-up, immune memory against the antigen was evaluated by administering a challenge dose of the appropriate antigen (vaccine) 6 to 12 months after the Year 15 follow-up time-point.
Experimental: Twinrix Junior Group Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study	Procedure: Blood sampling; Blood sampling at Years 11, 12, 13, 14, 15 and at the time of challenge dose administration and one month after challenge dose administration.; Biological: Additional challenge dose; If a subject became seronegative for anti-HAV antibodies (< 15 mIU/mL) or if anti-HBs antibody concentrations decreased below 10 mIU/mL during the long-term follow-up, immune memory against the antigen was evaluated by administering a challenge dose of the appropriate antigen (vaccine) 6 to 12 months after the Year 15 follow-up time-point.

Outcome Measures

Primary Outcome Measures

1. Anti-HAV Antibody Concentrations [At Year 11, 12, 13, 14 and 15 after the first vaccine dose of two-dose or three-dose primary vaccination in study HAB-084]

   Antibody concentrations are expressed as Geometric Mean Concentrations (GMCs) in mIU/mL. The analysis was performed on anti-HAV seropositive subjects. Seropositive subjects are subjects with anti-HAV antibody concentrations >= 15 mIU/mL.

2. Number of Subjects With Anti-Hepatitis B Surface Antigen (HBs) Antibody Concentrations Equal to or Above the Cut-Off Values [At Year 11, 12, 13, 14 and 15 after the first vaccine dose of the two-dose or three-dose primary vaccination in study HAB-084]

   Anti-HBs antibody cut-off values assessed were >= 6.2 mIU/mL and >= 10 mIU/mL. Note: A decrease in the specificity of the anti-HB ELISA assay had been observed in some studies for low levels of antibody (10-100 mIU/mL). The table shows updated results following complete retesting and reanalysis for years 11 to 13. Results of year 14 and year 15 were only analysed by ChemiLuminescence ImmunoAssay (CLIA).

3. Anti-HBs Antibody Concentrations [At Year 11, 12, 13, 14 and 15 after the first vaccine dose of a two-dose or a three-dose primary vaccination in study HAB-084.]

   Antibodys concentrations are expressed as Geometric Mean concentrations (GMCs) in mIU/mL. The analysis was performed on anti-HBs seropositive subjects. Seropositive subjects are subjects with anti-HBs antibody concentrations >= 6.2 mIU/mL. Note: A decrease in the specificity of the anti-HB ELISA assay had been observed in some studies for low levels of antibody (10-100 mIU/mL). The table shows updated results following complete retesting and reanalysis for years 11 to 13. Results of year 14 and year 15 were only analysed by CLIA.

4. Anti-HBs Anamnestic Response. [One month after the challenge dose.]

   Anamnestic response was defined as: Anti-HBs antibody concentrations ≥ 10 mIU/mL at one month post-challenge dose in subjects seronegative at the pre-challenge time-points. At least a 4-fold increase in anti-HBs antibody concentrations, at one month post-challenge dose in subjects seropositive at the pre-challenge time-points.

5. Number of Subjects With Anti-Hepatitis A (HAV) Antibody Concentrations Equal to or Above the Cut-Off Value. [At Year 11, 12, 13, 14 and 15 after the first vaccine dose of the two-dose or three-dose primary vaccination in study HAB-084.]

   Anti-HAV antibody cut-off value assessed was >= 15 milli-International Units per milliliter (mIU/mL).

Secondary Outcome Measures

1. Number of Subjects Reporting Serious Adverse Events (SAEs) or Hepatitis A or B Infection. [Since the last long-term follow-up visit up to Year 11.]

   SAE is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above.

2. Number of Subjects Reporting Serious Adverse Events (SAEs) or Hepatitis A or B Infection. [Since the last long-term follow-up visit up to Year 12.]

   SAE is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above.

3. Number of Subjects Reporting Serious Adverse Events (SAEs) or Hepatitis A or B Infection. [Since the last long-term follow-up visit up to Year 13.]

   SAE is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above.

4. Number of Subjects Reporting Serious Adverse Events (SAEs) or Hepatitis A or B Infection. [Since the last long-term follow-up visit up to Year 14.]

   SAE is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above.

5. Number of Subjects Reporting Serious Adverse Events (SAEs) or Hepatitis A or B Infection. [Since the last long-term follow-up visit up to Year 15.]

   SAE is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above.

6. Number of Subjects With Anti-hepatitis A (HAV) Antibody Concentrations Equal to or Above the Cut-off Value. [Before (PRE) the challenge dose]

   Anti-HAV antibody cut-off value assessed was >= 15 milli-International Units per milliliter (mIU/mL). Note: Since none of the subjects were seronegative for anti-HAV antibody concentration at the pre-challenge time point, subjects received only the HBV vaccine as the challenge dose.

7. Anti-HAV Antibody Concentrations [Before (PRE) the challenge dose]

   Antibody concentrations are expressed as Geometric Mean Concentrations (GMCs) in mIU/mL. The analysis was performed on anti-HAV seropositive subjects. Seropositive subjects are subjects with anti-HAV antibody concentrations >= 15 mIU/mL.

8. Number of Subjects Reporting Any and Grade 3 Solicited Local Adverse Events. [During the 4-day (Day 0 to Day 3) follow-up period after the challenge dose]

   Solicited local symptoms assessed were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 50 millimeters (mm) of injection site.

9. Number of Subjects With Anti-hepatitis B Surface Antigen (HBs) Antibody Concentrations Equal to or Above the Cut-off Values [Before (PRE) and one month after (POST) the challenge dose]

   Anti-HBs antibody cut-off values assessed were >= 6.2 mIU/mL and >= 10 mIU/mL

10. Anti-HBs Antibody Concentrations [Before (PRE) and one month after (POST) the challenge dose]

    Antibody concentrations are expressed as Geometric Mean concentrations (GMCs) in mIU/mL. The analysis was performed on anti-HBs seropositive subjects. Seropositive subjects are subjects with anti-HBs antibody concentrations >= 6.2 mIU/mL.

11. Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms. [During the 4-day (Day 0 to Day 3) follow-up period after the challenge dose.]

    Solicited general symptoms assessed were fatigue, gastrointestinal symptoms, headache and fever (axillary temperature). Gastrointestinal symptoms included nausea, vomiting, diarrhoea and/or abdominal pain. Any = occurrence of any general symptom regardless of intensity grade or relationship to vaccination. Grade 3 symptoms = symptoms that prevented normal activity. Grade 3 fever = axillary temperature > 39.5°C. Related = general symptoms which were assessed by the investigator as causally related to vaccination.

12. Number of Subjects Reporting Any, Grade 3 and Related Unsolicited Symptoms. [During the 31-day (Day 0 to 30) follow-up period after the challenge dose.]

    An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any was defined as an adverse event (AE) reported in addition to those solicited during the clinical study. Any solicited symptom with onset outside the specified period of follow-up for solicited symptoms was reported as an unsolicited adverse event. Grade 3 = AE that prevented normal activity. Related = AE assessed by the investigator as causally related to the study vaccination.

13. Number of Subjects With Serious Adverse Events (SAEs). [One month after the administration of the challenge dose (Month 0 to Month 1)]

    Serious adverse events (SAEs) assessed included medical occurrences that resulted in death, were life threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity or was a congenital anomaly/birth defect in the offspring of a study subject.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 15 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Subjects who the investigator believes that they can and will comply with the requirements of the protocol should be enrolled in the study.

• A male or female who received the complete primary vaccination course according to his/her group allocation in the primary study

• Written informed consent obtained from the subject.

All subjects must satisfy the following criteria at entry into the challenge dose phase:

• A male or female who received the complete primary vaccination course according to his/her group allocation in the primary study.

• Subjects who participated in the long-term follow-up phase of the primary study and for whom the antibody concentrations were below specified value for anti-HAV antibodies and/ or for anti-HBs antibodies at the last available follow-up time-points.

• Subjects who the investigator believes that they can and will comply with the requirements of the protocol should be enrolled in the study.

• Written informed consent obtained from the subject.

• Healthy subjects as established by medical history and clinical examination before entering into the challenge dose phase of this study.

• If the subject is female, she must be of non-childbearing potential, i.e. either surgically sterilized; or, if of childbearing potential, she must be abstinent or have used adequate contraceptive precautions for 30 days prior to vaccination, have a negative pregnancy test and must agree to continue such precautions for two months after the vaccination.

Exclusion Criteria:

The following criteria should be checked at each follow-up visit. If any apply at study entry, the subject must not be included at that long-term follow-up visit.

• Use of any investigational or non-registered product (drug or vaccine) since the last blood sampling visit.

• Administration of a hepatitis A, hepatitis B or hepatitis combination vaccine since the primary vaccination course of the primary study.

• History of hepatitis A or hepatitis B infection.

• Administration of hepatitis A or hepatitis B immunoglobulins and/or any blood products within 3 months prior to blood sampling.

The following criteria should be checked before the challenge dose phase. If any apply, the subject must not be included in the challenge dose phase:

• Use of any investigational or non-registered product (drug or vaccine) within 30 days before the administration of the challenge dose or planned use during the study period outside the context of the study.

• Administration of a hepatitis A, hepatitis B or hepatitis combination vaccine between the primary vaccination course of the primary study and the challenge dose visit.

• History of hepatitis A or hepatitis B infection.

• Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within six months prior to the challenge dose.

• Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required).

• History of allergic disease or reactions likely to be exacerbated by any component of the vaccines.

• Acute disease at the time of.

• Administration of immunoglobulins and/or any blood products within the three months preceding the administration of the challenge dose or planned administration before the final blood sampling point (one month after the challenge dose).

• Pregnant or lactating female.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Bruxelles		Belgium	1200
2	GSK Investigational Site	Hradec Kralove		Czechia	500 03

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00875485
• Other Study ID Numbers: 110699; 110700; 110701; 110702; 110703; 110704
• First Posted: Apr 3, 2009
• Last Update Posted: Aug 20, 2018
• Last Verified: Jul 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by GlaxoSmithKline: Monovalent Hepatitis A; hepatitis B vaccine; Belgium and Czech Republic
• Additional relevant MeSH terms: Hepatitis A; Hepatitis B; Hepatitis

Study Results

Participant Flow

Pre-assignment Detail	In this study, a total of 210 subjects were enrolled who participated at Year 11 (Y11) and Y12. There were a total of 8 additional subjects at Y13 and Y14 who came back from the primary study but did not participate in Y11 and Y12 as allowed by the protocol. One subject from the 210 subjects who participated in Y11 and Y12 did not return at Y15.

Arm/Group Title	Twinrix Adult Group	Twinrix Junior Group
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Period Title: Year 11
STARTED	99	111
COMPLETED	99	111
NOT COMPLETED	0	0
Period Title: Year 11
STARTED	101	109
COMPLETED	101	109
NOT COMPLETED	0	0
Period Title: Year 11
STARTED	102	113
COMPLETED	102	113
NOT COMPLETED	0	0
Period Title: Year 11
STARTED	100	113
COMPLETED	100	113
NOT COMPLETED	0	0
Period Title: Year 11
STARTED	98	111
COMPLETED	98	111
NOT COMPLETED	0	0
Period Title: Year 11
STARTED	8	11
COMPLETED	7	11
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Twinrix Adult Group	Twinrix Junior Group	Total
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study	Total of all reporting groups
Overall Participants	102	113	215
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	24.5 (1.06)	24.5 (1.05)	24.5 (1.05)
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	25.4 (1.06)	25.4 (1.04)	25.40 (1.05)
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	26.40 (1.07)	26.4 (1.06)	26.40 (1.06)
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	27.40 (1.11)	27.40 (1.05)	27.40 (1.08)
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	28.4 (1.15)	28.3 (1.09)	28.3 (1.12)
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	29.4 (1.2)	29.4 (1.3)	29.4 (1.22)
Sex: Female, Male (Count of Participants)
Female	49 48%	52 46%	101 47%
Male	50 49%	59 52.2%	109 50.7%
Sex: Female, Male (Count of Participants)
Female	50 49%	50 44.2%	100 46.5%
Male	51 50%	59 52.2%	110 51.2%
Sex: Female, Male (Count of Participants)
Female	50 49%	53 46.9%	103 47.9%
Male	52 51%	60 53.1%	112 52.1%
Sex: Female, Male (Count of Participants)
Female	49 48%	53 46.9%	102 47.4%
Male	51 50%	60 53.1%	111 51.6%
Sex: Female, Male (Count of Participants)
Female	47 46.1%	52 46%	99 46%
Male	51 50%	59 52.2%	110 51.2%
Sex: Female, Male (Count of Participants)
Female	4 3.9%	7 6.2%	11 5.1%
Male	4 3.9%	4 3.5%	8 3.7%

Outcome Measures

1. Primary Outcome

Title	Anti-HAV Antibody Concentrations
Description	Antibody concentrations are expressed as Geometric Mean Concentrations (GMCs) in mIU/mL. The analysis was performed on anti-HAV seropositive subjects. Seropositive subjects are subjects with anti-HAV antibody concentrations >= 15 mIU/mL.
Time Frame	At Year 11, 12, 13, 14 and 15 after the first vaccine dose of two-dose or three-dose primary vaccination in study HAB-084

Outcome Measure Data

Analysis Population Description

Analysis was performed on subjects from the Long Term According-to-Protocol (LT ATP) cohort for immunogenicity on anti-HAV seropositive subjects with available data at the specified time-points.

Arm/Group Title	Twinrix Adult Group	Twinrix Junior Group
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Measure Participants	78	92
Year 11 (N= 78; 92)	360.5	257.2
Year 12 (N= 75; 90)	450.8	335.6
Year 13 (N= 77; 92)	401.5	293.6
Year 14 (N= 75; 91)	388.0	291.4
Year 15 (N= 74; 88)	387.5	299.4

2. Primary Outcome

Title	Number of Subjects With Anti-Hepatitis B Surface Antigen (HBs) Antibody Concentrations Equal to or Above the Cut-Off Values
Description	Anti-HBs antibody cut-off values assessed were >= 6.2 mIU/mL and >= 10 mIU/mL. Note: A decrease in the specificity of the anti-HB ELISA assay had been observed in some studies for low levels of antibody (10-100 mIU/mL). The table shows updated results following complete retesting and reanalysis for years 11 to 13. Results of year 14 and year 15 were only analysed by ChemiLuminescence ImmunoAssay (CLIA).
Time Frame	At Year 11, 12, 13, 14 and 15 after the first vaccine dose of the two-dose or three-dose primary vaccination in study HAB-084

Outcome Measure Data

Analysis Population Description

Analysis was performed on subjects from the Long Term According-to-Protocol (LT ATP) cohort for immunogenicity on subjects with available data at the specified time-points

Arm/Group Title	Twinrix Adult Group	Twinrix Junior Group
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Measure Participants	78	92
Year 11 [6.2 mIU/mL] (N = 78;91)	68	79
Year 12 [6.2 mIU/mL] (N = 75;90)	64	80
Year 13 [6.2 mIU/mL] (N = 77;92)	65	83
Year 14 [6.2 mIU/mL] (N= 75;91)	66	80
Year 15 [6.2 mIU/mL] (N= 74;88)	62	79
Year 11 [10 mIU/mL] (N = 78;91)	64	75
Year 12 [10 mIU/mL] (N = 75;90)	62	76
Year 13 [10 mIU/mL] (N = 77;92)	62	77
Year 14 [10 mIU/mL] (N= 75;91)	62	73
Year 15 [10 mIU/mL] (N= 74;88)	60	72

3. Primary Outcome

Title	Anti-HBs Antibody Concentrations
Description	Antibodys concentrations are expressed as Geometric Mean concentrations (GMCs) in mIU/mL. The analysis was performed on anti-HBs seropositive subjects. Seropositive subjects are subjects with anti-HBs antibody concentrations >= 6.2 mIU/mL. Note: A decrease in the specificity of the anti-HB ELISA assay had been observed in some studies for low levels of antibody (10-100 mIU/mL). The table shows updated results following complete retesting and reanalysis for years 11 to 13. Results of year 14 and year 15 were only analysed by CLIA.
Time Frame	At Year 11, 12, 13, 14 and 15 after the first vaccine dose of a two-dose or a three-dose primary vaccination in study HAB-084.

Outcome Measure Data

Analysis Population Description

Analysis was performes on subjects from the Long Term According-to-Protocol (LT ATP) cohort forimmunogenicity on anti-HBs seropositive subjects with available data at the specified time-points.

Arm/Group Title	Twinrix Adult Group	Twinrix Junior Group
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Measure Participants	78	92
Year 11 (N = 78;91)	88.0	75.2
Year 12 (N = 75;90)	93.3	77.0
Year 13 (N = 77;92)	92.4	70.1
Year 14 (N= 75;91)	81.8	70.2
Year 15 (N= 74;88)	87.2	69.6

4. Primary Outcome

Title	Anti-HBs Anamnestic Response.
Description	Anamnestic response was defined as: Anti-HBs antibody concentrations ≥ 10 mIU/mL at one month post-challenge dose in subjects seronegative at the pre-challenge time-points. At least a 4-fold increase in anti-HBs antibody concentrations, at one month post-challenge dose in subjects seropositive at the pre-challenge time-points.
Time Frame	One month after the challenge dose.

Outcome Measure Data

Analysis Population Description

Analysis was performed on Total Vaccinated cohort for challenge dose that included all subjects who received the challenge dose and for whom the immunogenicity data were available.

Arm/Group Title	Twinrix Adult Group	Twinrix Junior Group
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Measure Participants	8	11
Number [Subjects]	8	10

5. Primary Outcome

Title	Number of Subjects With Anti-Hepatitis A (HAV) Antibody Concentrations Equal to or Above the Cut-Off Value.
Description	Anti-HAV antibody cut-off value assessed was >= 15 milli-International Units per milliliter (mIU/mL).
Time Frame	At Year 11, 12, 13, 14 and 15 after the first vaccine dose of the two-dose or three-dose primary vaccination in study HAB-084.

Outcome Measure Data

Analysis Population Description

Analysis was performed on subjects from the Long Term According-to-Protocol (LT ATP) cohort for immunogenicity on subjects with available data at the specified time-points.

Arm/Group Title	Twinrix Adult Group	Twinrix Junior Group
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Measure Participants	78	92
Year 11 (N= 78; 92)	78	92
Year 12 (N= 75; 90)	75	90
Year 13 (N= 77; 92)	76	92
Year 14 (N= 75; 91)	75	91
Year 15 (N= 74; 88)	74	88

6. Secondary Outcome

Title	Number of Subjects Reporting Serious Adverse Events (SAEs) or Hepatitis A or B Infection.
Description	SAE is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above.
Time Frame	Since the last long-term follow-up visit up to Year 11.

Outcome Measure Data

Analysis Population Description

Analysis was performed on Long Term (LT) Total Cohort which included all subjects who returned at the current follow-up study and who belonged to the Total cohort in the primary study.

Arm/Group Title	Twinrix Adult Group	Twinrix Junior Group
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Measure Participants	99	111
Number [subjects]	0	0

7. Secondary Outcome

Title	Number of Subjects Reporting Serious Adverse Events (SAEs) or Hepatitis A or B Infection.
Description	SAE is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above.
Time Frame	Since the last long-term follow-up visit up to Year 12.

Outcome Measure Data

Analysis Population Description

Analysis was performed on Long Term (LT) Total Cohort which included all subjects who returned at the current follow-up study and who belonged to the Total cohort in the primary study.

Arm/Group Title	Twinrix Adult Group	Twinrix Junior Group
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Measure Participants	101	109
Number [subjects]	0	0

8. Secondary Outcome

Title	Number of Subjects Reporting Serious Adverse Events (SAEs) or Hepatitis A or B Infection.
Description	SAE is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above.
Time Frame	Since the last long-term follow-up visit up to Year 13.

Outcome Measure Data

Analysis Population Description

Analysis was performed on Long Term (LT) Total Cohort which included all subjects who returned at the current follow-up study and who belonged to the Total cohort in the primary study.

Arm/Group Title	Twinrix Adult Group	Twinrix Junior Group
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Measure Participants	102	113
Number [subjects]	0	0

9. Secondary Outcome

Title	Number of Subjects Reporting Serious Adverse Events (SAEs) or Hepatitis A or B Infection.
Description	SAE is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above.
Time Frame	Since the last long-term follow-up visit up to Year 14.

Outcome Measure Data

Analysis Population Description

Analysis was performed on Long Term (LT) Total Cohort which included all subjects who returned at the current follow-up study and who belonged to the Total cohort in the primary study.

Arm/Group Title	Twinrix Adult Group	Twinrix Junior Group
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Measure Participants	100	113
Number [Subjects]	0	0

10. Secondary Outcome

Title	Number of Subjects Reporting Serious Adverse Events (SAEs) or Hepatitis A or B Infection.
Description	SAE is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above.
Time Frame	Since the last long-term follow-up visit up to Year 15.

Outcome Measure Data

Analysis Population Description

Analysis was performed on Long Term (LT) Total Cohort which included all subjects who returned at the current follow-up study and who belonged to the Total cohort in the primary study.

Arm/Group Title	Twinrix Adult Group	Twinrix Junior Group
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Measure Participants	98	111
Number [Subjects]	0	0

11. Secondary Outcome

Title	Number of Subjects With Anti-hepatitis A (HAV) Antibody Concentrations Equal to or Above the Cut-off Value.
Description	Anti-HAV antibody cut-off value assessed was >= 15 milli-International Units per milliliter (mIU/mL). Note: Since none of the subjects were seronegative for anti-HAV antibody concentration at the pre-challenge time point, subjects received only the HBV vaccine as the challenge dose.
Time Frame	Before (PRE) the challenge dose

Outcome Measure Data

Analysis Population Description

Analysis was performed on Total Vaccinated cohort for challenge dose that included all subjects who received the challenge dose and for whom the immunogenicity data were available.

Arm/Group Title	Twinrix Adult Group	Twinrix Junior Group
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Measure Participants	8	11
Number [Subjects]	8	11

12. Secondary Outcome

Title	Anti-HAV Antibody Concentrations
Description	Antibody concentrations are expressed as Geometric Mean Concentrations (GMCs) in mIU/mL. The analysis was performed on anti-HAV seropositive subjects. Seropositive subjects are subjects with anti-HAV antibody concentrations >= 15 mIU/mL.
Time Frame	Before (PRE) the challenge dose

Outcome Measure Data

Analysis Population Description

Analysis was performed on Total Vaccinated cohort for challenge dose that included all subjects who received the challenge dose and for whom the immunogenicity data were available.

Arm/Group Title	Twinrix Adult Group	Twinrix Junior Group
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Measure Participants	8	11
Geometric Mean (95% Confidence Interval) [mIU/mL]	270.9	201.3

13. Secondary Outcome

Title	Number of Subjects Reporting Any and Grade 3 Solicited Local Adverse Events.
Description	Solicited local symptoms assessed were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 50 millimeters (mm) of injection site.
Time Frame	During the 4-day (Day 0 to Day 3) follow-up period after the challenge dose

Outcome Measure Data

Analysis Population Description

Analysis was performed on Total Vaccinated cohort for challenge dose that included all subjects who received the challenge dose and for whom the immunogenicity data were available.

Arm/Group Title	Twinrix Adult Group	Twinrix Junior Group
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Measure Participants	8	11
Any Pain	5	4
Grade 3 Pain	0	0
Any Redness	1	2
Grade 3 Redness	0	0
Any Swelling	0	0
Grade 3 Swelling	0	0

14. Secondary Outcome

Title	Number of Subjects With Anti-hepatitis B Surface Antigen (HBs) Antibody Concentrations Equal to or Above the Cut-off Values
Description	Anti-HBs antibody cut-off values assessed were >= 6.2 mIU/mL and >= 10 mIU/mL
Time Frame	Before (PRE) and one month after (POST) the challenge dose

Outcome Measure Data

Analysis Population Description

Analysis was performed on Total Vaccinated cohort for challenge dose that included all subjects who received the challenge dose and for whom the immunogenicity data were available.

Arm/Group Title	Twinrix Adult Group	Twinrix Junior Group
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Measure Participants	8	11
PRE [6.2 mIU/mL] (N = 8;11)	0	2
POST [6.2 mIU/mL] (N = 8;11)	8	11
PRE [10 mIU/mL] (N = 8;11)	0	1
POST [10 mIU/mL] (N = 8;11)	8	10

15. Secondary Outcome

Title	Anti-HBs Antibody Concentrations
Description	Antibody concentrations are expressed as Geometric Mean concentrations (GMCs) in mIU/mL. The analysis was performed on anti-HBs seropositive subjects. Seropositive subjects are subjects with anti-HBs antibody concentrations >= 6.2 mIU/mL.
Time Frame	Before (PRE) and one month after (POST) the challenge dose

Outcome Measure Data

Analysis Population Description

Analysis was performed on Total Vaccinated cohort for challenge dose that included all subjects who received the challenge dose and for whom the immunogenicity data were available.

Arm/Group Title	Twinrix Adult Group	Twinrix Junior Group
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Measure Participants	8	11
PRE (N= 8;11)	3.1	4.1
POST (N= 8;11)	3022.8	1433.1

16. Secondary Outcome

Title	Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms.
Description	Solicited general symptoms assessed were fatigue, gastrointestinal symptoms, headache and fever (axillary temperature). Gastrointestinal symptoms included nausea, vomiting, diarrhoea and/or abdominal pain. Any = occurrence of any general symptom regardless of intensity grade or relationship to vaccination. Grade 3 symptoms = symptoms that prevented normal activity. Grade 3 fever = axillary temperature > 39.5°C. Related = general symptoms which were assessed by the investigator as causally related to vaccination.
Time Frame	During the 4-day (Day 0 to Day 3) follow-up period after the challenge dose.

Outcome Measure Data

Analysis Population Description

Analysis was performed on Total Vaccinated cohort for challenge dose that included all subjects who received the challenge dose and for whom the immunogenicity data were available.

Arm/Group Title	Twinrix Adult Group	Twinrix Junior Group
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Measure Participants	8	11
Any Fatigue	3	3
Grade 3 Fatigue	0	0
Related Fatigue	3	3
Any Gastrointestinal symptoms	1	1
Grade 3 Gastrointestinal symptoms	0	0
Related Gastrointestinal symptoms	1	1
Any Headache	1	2
Grade 3 Headache	0	0
Related Headache	1	2
Any Temperature	0	0
Grade 3 Temperature	0	0
Related Temperature	0	0

17. Secondary Outcome

Title	Number of Subjects Reporting Any, Grade 3 and Related Unsolicited Symptoms.
Description	An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any was defined as an adverse event (AE) reported in addition to those solicited during the clinical study. Any solicited symptom with onset outside the specified period of follow-up for solicited symptoms was reported as an unsolicited adverse event. Grade 3 = AE that prevented normal activity. Related = AE assessed by the investigator as causally related to the study vaccination.
Time Frame	During the 31-day (Day 0 to 30) follow-up period after the challenge dose.

Outcome Measure Data

Analysis Population Description

Analysis was performed on Total Vaccinated cohort for challenge dose that included all subjects who received the challenge dose and for whom the immunogenicity data were available.

Arm/Group Title	Twinrix Adult Group	Twinrix Junior Group
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Measure Participants	8	11
Any AE(s)	4	0
Grade 3 AE(s)	0	0
Related AE(s)	0	0

18. Secondary Outcome

Title	Number of Subjects With Serious Adverse Events (SAEs).
Description	Serious adverse events (SAEs) assessed included medical occurrences that resulted in death, were life threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity or was a congenital anomaly/birth defect in the offspring of a study subject.
Time Frame	One month after the administration of the challenge dose (Month 0 to Month 1)

Outcome Measure Data

Analysis Population Description

Analysis was performed on Total Vaccinated cohort for challenge dose that included all subjects who received the challenge dose and for whom the immunogenicity data were available.

Arm/Group Title	Twinrix Adult Group	Twinrix Junior Group
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Measure Participants	8	11
Number [Subjects]	1	0

Adverse Events

Time Frame	SAEs: one month post challenge dose and up to Year 15 of the long-term follow-up, solicted symptoms: during the 4-day (Days 0-3) post challenge dose and unsolicited AEs: within the 31-day (Days 0-30) post challenge dose.
Adverse Event Reporting Description	No Serious Adverse Events (SAEs) related to primary vaccination or to lack of vaccine efficacy were reported during this long-term follow-up study up to Year 15. Other (non-serious) adverse events were not assessed for the long-term follow-up phase (up to Year 15) as per protocol.
Arm/Group Title	Twinrix Adult Group		Twinrix Junior Group
Arm/Group Description	Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study		Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
All Cause Mortality
	Twinrix Adult Group		Twinrix Junior Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Twinrix Adult Group		Twinrix Junior Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/102 (1%)		0/113 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	1/102 (1%)		0/113 (0%)
Other (Not Including Serious) Adverse Events
	Twinrix Adult Group		Twinrix Junior Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/8 (100%)		7/11 (63.6%)
Gastrointestinal disorders
Gastrointestinal symptoms	1/8 (12.5%)		1/11 (9.1%)
General disorders
Pain	5/8 (62.5%)		4/11 (36.4%)
Redness	1/8 (12.5%)		2/11 (18.2%)
Fatigue	3/8 (37.5%)		3/11 (27.3%)
Nervous system disorders
Headache	1/8 (12.5%)		2/11 (18.2%)
Headache	3/8 (37.5%)		0/11 (0%)

Limitations/Caveats

A decrease in the specificity of the anti-HB ELISA assay had been observed in some studies for low levels of antibody (10-100 mIU/mL).The table shows updated results following complete retesting and reanalysis.

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.