Trial Outcomes & Findings for Evaluation of Antibody Persistence & Immune Memory in Subjects Vaccinated During Adolescence With Twinrix™ (NCT NCT00875485)

NCT ID: NCT00875485

Last Updated: 2018-08-20

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 210 participants
• Primary outcome timeframe: 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
• Results posted on: 2018-08-20

Participant Flow

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.

Participant milestones

Measure	Twinrix Adult Group Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	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
Year 11 STARTED	99	111
Year 11 COMPLETED	99	111
Year 11 NOT COMPLETED	0	0
Year 12 STARTED	101	109
Year 12 COMPLETED	101	109
Year 12 NOT COMPLETED	0	0
Year 13 STARTED	102	113
Year 13 COMPLETED	102	113
Year 13 NOT COMPLETED	0	0
Year 14 STARTED	100	113
Year 14 COMPLETED	100	113
Year 14 NOT COMPLETED	0	0
Year 15 STARTED	98	111
Year 15 COMPLETED	98	111
Year 15 NOT COMPLETED	0	0
Challenge Dose Epoch STARTED	8	11
Challenge Dose Epoch COMPLETED	7	11
Challenge Dose Epoch NOT COMPLETED	1	0

Reasons for withdrawal

Measure	Twinrix Adult Group Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	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
Challenge Dose Epoch Pregnancy	1	0

Baseline Characteristics

The analysis Population includes all subjects that returned for the Year 11 follow up time point.

Baseline characteristics by cohort

Measure	Twinrix Adult Group n=102 Participants Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=113 Participants 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 n=215 Participants Total of all reporting groups
Age, Continuous	29.4 Years STANDARD_DEVIATION 1.2 • n=8 Participants • The analysis Population includes all subjects that were administrated a challenge dose.	29.4 Years STANDARD_DEVIATION 1.3 • n=11 Participants • The analysis Population includes all subjects that were administrated a challenge dose.	29.4 Years STANDARD_DEVIATION 1.22 • n=19 Participants • The analysis Population includes all subjects that were administrated a challenge dose.
Sex: Female, Male Female	4 Participants n=8 Participants • The analysis Population includes all subjects that were administrated a challenge dose.	7 Participants n=11 Participants • The analysis Population includes all subjects that were administrated a challenge dose.	11 Participants n=19 Participants • The analysis Population includes all subjects that were administrated a challenge dose.
Sex: Female, Male Male	4 Participants n=8 Participants • The analysis Population includes all subjects that were administrated a challenge dose.	4 Participants n=11 Participants • The analysis Population includes all subjects that were administrated a challenge dose.	8 Participants n=19 Participants • The analysis Population includes all subjects that were administrated a challenge dose.

PRIMARY outcome

Timeframe: 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

Population: 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.

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.

Outcome measures

Measure	Twinrix Adult Group n=78 Participants Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=92 Participants Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Anti-HAV Antibody Concentrations Year 11 (N= 78; 92)	360.5 mIU/mL Interval 292.0 to 445.1	257.2 mIU/mL Interval 215.1 to 307.5
Anti-HAV Antibody Concentrations Year 12 (N= 75; 90)	450.8 mIU/mL Interval 359.6 to 565.1	335.6 mIU/mL Interval 279.0 to 403.6
Anti-HAV Antibody Concentrations Year 13 (N= 77; 92)	401.5 mIU/mL Interval 328.2 to 491.1	293.6 mIU/mL Interval 244.2 to 352.9
Anti-HAV Antibody Concentrations Year 14 (N= 75; 91)	388.0 mIU/mL Interval 309.2 to 487.0	291.4 mIU/mL Interval 240.6 to 352.9
Anti-HAV Antibody Concentrations Year 15 (N= 74; 88)	387.5 mIU/mL Interval 306.6 to 489.8	299.4 mIU/mL Interval 247.6 to 362.0

PRIMARY outcome

Timeframe: 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

Population: 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

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).

Outcome measures

Measure	Twinrix Adult Group n=78 Participants Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=92 Participants Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Number of Subjects With Anti-Hepatitis B Surface Antigen (HBs) Antibody Concentrations Equal to or Above the Cut-Off Values Year 11 [6.2 mIU/mL] (N = 78;91)	68 Subjects	79 Subjects
Number of Subjects With Anti-Hepatitis B Surface Antigen (HBs) Antibody Concentrations Equal to or Above the Cut-Off Values Year 12 [6.2 mIU/mL] (N = 75;90)	64 Subjects	80 Subjects
Number of Subjects With Anti-Hepatitis B Surface Antigen (HBs) Antibody Concentrations Equal to or Above the Cut-Off Values Year 13 [6.2 mIU/mL] (N = 77;92)	65 Subjects	83 Subjects
Number of Subjects With Anti-Hepatitis B Surface Antigen (HBs) Antibody Concentrations Equal to or Above the Cut-Off Values Year 14 [6.2 mIU/mL] (N= 75;91)	66 Subjects	80 Subjects
Number of Subjects With Anti-Hepatitis B Surface Antigen (HBs) Antibody Concentrations Equal to or Above the Cut-Off Values Year 15 [6.2 mIU/mL] (N= 74;88)	62 Subjects	79 Subjects
Number of Subjects With Anti-Hepatitis B Surface Antigen (HBs) Antibody Concentrations Equal to or Above the Cut-Off Values Year 11 [10 mIU/mL] (N = 78;91)	64 Subjects	75 Subjects
Number of Subjects With Anti-Hepatitis B Surface Antigen (HBs) Antibody Concentrations Equal to or Above the Cut-Off Values Year 12 [10 mIU/mL] (N = 75;90)	62 Subjects	76 Subjects
Number of Subjects With Anti-Hepatitis B Surface Antigen (HBs) Antibody Concentrations Equal to or Above the Cut-Off Values Year 13 [10 mIU/mL] (N = 77;92)	62 Subjects	77 Subjects
Number of Subjects With Anti-Hepatitis B Surface Antigen (HBs) Antibody Concentrations Equal to or Above the Cut-Off Values Year 14 [10 mIU/mL] (N= 75;91)	62 Subjects	73 Subjects
Number of Subjects With Anti-Hepatitis B Surface Antigen (HBs) Antibody Concentrations Equal to or Above the Cut-Off Values Year 15 [10 mIU/mL] (N= 74;88)	60 Subjects	72 Subjects

PRIMARY outcome

Timeframe: 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.

Population: 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.

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.

Outcome measures

Measure	Twinrix Adult Group n=78 Participants Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=92 Participants Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Anti-HBs Antibody Concentrations Year 12 (N = 75;90)	93.3 mIU/mL Interval 66.2 to 131.6	77.0 mIU/mL Interval 56.1 to 105.7
Anti-HBs Antibody Concentrations Year 13 (N = 77;92)	92.4 mIU/mL Interval 65.9 to 129.5	70.1 mIU/mL Interval 51.2 to 96.0
Anti-HBs Antibody Concentrations Year 14 (N= 75;91)	81.8 mIU/mL Interval 57.5 to 116.4	70.2 mIU/mL Interval 51.0 to 96.8
Anti-HBs Antibody Concentrations Year 15 (N= 74;88)	87.2 mIU/mL Interval 61.0 to 124.5	69.6 mIU/mL Interval 50.0 to 96.9
Anti-HBs Antibody Concentrations Year 11 (N = 78;91)	88.0 mIU/mL Interval 63.2 to 122.5	75.2 mIU/mL Interval 55.6 to 101.8

PRIMARY outcome

Timeframe: One month after the challenge dose.

Population: 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.

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.

Outcome measures

Measure	Twinrix Adult Group n=8 Participants Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=11 Participants Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Anti-HBs Anamnestic Response.	8 Subjects	10 Subjects

PRIMARY outcome

Timeframe: 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.

Population: 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.

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

Outcome measures

Measure	Twinrix Adult Group n=78 Participants Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=92 Participants Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Number of Subjects With Anti-Hepatitis A (HAV) Antibody Concentrations Equal to or Above the Cut-Off Value. Year 11 (N= 78; 92)	78 subjects	92 subjects
Number of Subjects With Anti-Hepatitis A (HAV) Antibody Concentrations Equal to or Above the Cut-Off Value. Year 12 (N= 75; 90)	75 subjects	90 subjects
Number of Subjects With Anti-Hepatitis A (HAV) Antibody Concentrations Equal to or Above the Cut-Off Value. Year 13 (N= 77; 92)	76 subjects	92 subjects
Number of Subjects With Anti-Hepatitis A (HAV) Antibody Concentrations Equal to or Above the Cut-Off Value. Year 14 (N= 75; 91)	75 subjects	91 subjects
Number of Subjects With Anti-Hepatitis A (HAV) Antibody Concentrations Equal to or Above the Cut-Off Value. Year 15 (N= 74; 88)	74 subjects	88 subjects

SECONDARY outcome

Timeframe: Since the last long-term follow-up visit up to Year 11.

Population: 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.

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.

Outcome measures

Measure	Twinrix Adult Group n=99 Participants Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=111 Participants Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Number of Subjects Reporting Serious Adverse Events (SAEs) or Hepatitis A or B Infection.	0 subjects	0 subjects

SECONDARY outcome

Timeframe: Since the last long-term follow-up visit up to Year 12.

Population: 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.

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.

Outcome measures

Measure	Twinrix Adult Group n=101 Participants Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=109 Participants Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Number of Subjects Reporting Serious Adverse Events (SAEs) or Hepatitis A or B Infection.	0 subjects	0 subjects

SECONDARY outcome

Timeframe: Since the last long-term follow-up visit up to Year 13.

Population: 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.

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.

Outcome measures

Measure	Twinrix Adult Group n=102 Participants Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=113 Participants Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Number of Subjects Reporting Serious Adverse Events (SAEs) or Hepatitis A or B Infection.	0 subjects	0 subjects

SECONDARY outcome

Timeframe: Since the last long-term follow-up visit up to Year 14.

Population: 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.

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.

Outcome measures

Measure	Twinrix Adult Group n=100 Participants Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=113 Participants Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Number of Subjects Reporting Serious Adverse Events (SAEs) or Hepatitis A or B Infection.	0 Subjects	0 Subjects

SECONDARY outcome

Timeframe: Since the last long-term follow-up visit up to Year 15.

Population: 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.

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.

Outcome measures

Measure	Twinrix Adult Group n=98 Participants Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=111 Participants Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Number of Subjects Reporting Serious Adverse Events (SAEs) or Hepatitis A or B Infection.	0 Subjects	0 Subjects

SECONDARY outcome

Timeframe: Before (PRE) the challenge dose

Population: 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.

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.

Outcome measures

Measure	Twinrix Adult Group n=8 Participants Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=11 Participants Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Number of Subjects With Anti-hepatitis A (HAV) Antibody Concentrations Equal to or Above the Cut-off Value.	8 Subjects	11 Subjects

SECONDARY outcome

Timeframe: Before (PRE) the challenge dose

Population: 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.

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.

Outcome measures

Measure	Twinrix Adult Group n=8 Participants Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=11 Participants Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Anti-HAV Antibody Concentrations	270.9 mIU/mL Interval 173.8 to 422.3	201.3 mIU/mL Interval 123.1 to 329.0

SECONDARY outcome

Timeframe: During the 4-day (Day 0 to Day 3) follow-up period after the challenge dose

Population: 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.

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.

Outcome measures

Measure	Twinrix Adult Group n=8 Participants Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=11 Participants Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Number of Subjects Reporting Any and Grade 3 Solicited Local Adverse Events. Grade 3 Pain	0 Subjects	0 Subjects
Number of Subjects Reporting Any and Grade 3 Solicited Local Adverse Events. Any Redness	1 Subjects	2 Subjects
Number of Subjects Reporting Any and Grade 3 Solicited Local Adverse Events. Any Pain	5 Subjects	4 Subjects
Number of Subjects Reporting Any and Grade 3 Solicited Local Adverse Events. Grade 3 Redness	0 Subjects	0 Subjects
Number of Subjects Reporting Any and Grade 3 Solicited Local Adverse Events. Any Swelling	0 Subjects	0 Subjects
Number of Subjects Reporting Any and Grade 3 Solicited Local Adverse Events. Grade 3 Swelling	0 Subjects	0 Subjects

SECONDARY outcome

Timeframe: Before (PRE) and one month after (POST) the challenge dose

Population: 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.

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

Outcome measures

Measure	Twinrix Adult Group n=8 Participants Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=11 Participants Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Number of Subjects With Anti-hepatitis B Surface Antigen (HBs) Antibody Concentrations Equal to or Above the Cut-off Values PRE [6.2 mIU/mL] (N = 8;11)	0 Subjects	2 Subjects
Number of Subjects With Anti-hepatitis B Surface Antigen (HBs) Antibody Concentrations Equal to or Above the Cut-off Values POST [6.2 mIU/mL] (N = 8;11)	8 Subjects	11 Subjects
Number of Subjects With Anti-hepatitis B Surface Antigen (HBs) Antibody Concentrations Equal to or Above the Cut-off Values PRE [10 mIU/mL] (N = 8;11)	0 Subjects	1 Subjects
Number of Subjects With Anti-hepatitis B Surface Antigen (HBs) Antibody Concentrations Equal to or Above the Cut-off Values POST [10 mIU/mL] (N = 8;11)	8 Subjects	10 Subjects

SECONDARY outcome

Timeframe: Before (PRE) and one month after (POST) the challenge dose

Population: 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.

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.

Outcome measures

Measure	Twinrix Adult Group n=8 Participants Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=11 Participants Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Anti-HBs Antibody Concentrations PRE (N= 8;11)	3.1 mIU/mL Interval 3.1 to 3.1	4.1 mIU/mL Interval 2.5 to 6.9
Anti-HBs Antibody Concentrations POST (N= 8;11)	3022.8 mIU/mL Interval 407.8 to 22405.5	1433.1 mIU/mL Interval 324.5 to 6328.9

SECONDARY outcome

Timeframe: During the 4-day (Day 0 to Day 3) follow-up period after the challenge dose.

Population: 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.

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.

Outcome measures

Measure	Twinrix Adult Group n=8 Participants Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=11 Participants Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms. Related Temperature	0 Subjects	0 Subjects
Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms. Any Fatigue	3 Subjects	3 Subjects
Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms. Grade 3 Fatigue	0 Subjects	0 Subjects
Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms. Related Fatigue	3 Subjects	3 Subjects
Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms. Any Gastrointestinal symptoms	1 Subjects	1 Subjects
Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms. Grade 3 Gastrointestinal symptoms	0 Subjects	0 Subjects
Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms. Related Gastrointestinal symptoms	1 Subjects	1 Subjects
Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms. Any Headache	1 Subjects	2 Subjects
Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms. Grade 3 Headache	0 Subjects	0 Subjects
Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms. Related Headache	1 Subjects	2 Subjects
Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms. Any Temperature	0 Subjects	0 Subjects
Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms. Grade 3 Temperature	0 Subjects	0 Subjects

SECONDARY outcome

Timeframe: During the 31-day (Day 0 to 30) follow-up period after the challenge dose.

Population: 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.

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.

Outcome measures

Measure	Twinrix Adult Group n=8 Participants Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=11 Participants Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Number of Subjects Reporting Any, Grade 3 and Related Unsolicited Symptoms. Grade 3 AE(s)	0 Subjects	0 Subjects
Number of Subjects Reporting Any, Grade 3 and Related Unsolicited Symptoms. Any AE(s)	4 Subjects	0 Subjects
Number of Subjects Reporting Any, Grade 3 and Related Unsolicited Symptoms. Related AE(s)	0 Subjects	0 Subjects

SECONDARY outcome

Timeframe: One month after the administration of the challenge dose (Month 0 to Month 1)

Population: 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.

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.

Outcome measures

Measure	Twinrix Adult Group n=8 Participants Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=11 Participants Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Number of Subjects With Serious Adverse Events (SAEs).	1 Subjects	0 Subjects

Adverse Events

Twinrix Adult Group

Serious events: 1 serious events

Other events: 8 other events

Deaths: 0 deaths

Twinrix Junior Group

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Measure	Twinrix Adult Group n=8 participants at risk；n=102 participants at risk Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=11 participants at risk；n=113 participants at risk Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
Pregnancy, puerperium and perinatal conditions Abortion spontaneous	0.98% 1/102 • 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. 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.	0.00% 0/113 • 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. 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.

Other adverse events

Measure	Twinrix Adult Group n=8 participants at risk；n=102 participants at risk Subjects received 2 doses of Twinrix™ Adult intramuscularly according to a 0, 6 month schedule in the primary study	Twinrix Junior Group n=11 participants at risk；n=113 participants at risk Subjects received 3 doses of Twinrix™ Junior (= half dose Twinrix™ Adult) intramuscularly according to a 0, 1, 6 month schedule in the primary study
General disorders Pain	62.5% 5/8 • 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. 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.	36.4% 4/11 • 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. 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.
General disorders Redness	12.5% 1/8 • 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. 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.	18.2% 2/11 • 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. 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.
General disorders Fatigue	37.5% 3/8 • 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. 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.	27.3% 3/11 • 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. 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.
Gastrointestinal disorders Gastrointestinal symptoms	12.5% 1/8 • 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. 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.	9.1% 1/11 • 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. 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.
Nervous system disorders Headache	37.5% 3/8 • 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. 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.	0.00% 0/11 • 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. 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.

Additional Information

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