Evaluation of Immune Memory to Twinrix or Comparator by Challenge Dose Administration 4 Years After Primary Vaccination

• Number of Subjects With Anamnestic Response to the Challenge Dose for Anti-hepatitis A (Anti-HAV) Antibodies [ Time Frame: One month after the challenge dose. ] [ Designated as safety issue: No ]

  Anamnestic response was defined as:

  • for initially seronegative subjects, antibody concentration greater than or equal the cut-off [≥ 15 Milli-International Units per Milliliter (mIU/mL)],
  • for initially seropositive subjects with pre-vaccination antibody, concentration < 100 mIU/mL: antibody concentration at least four times the pre-vaccination antibody concentration,
  • for initially seropositive subjects with pre-vaccination antibody concentration ≥ 100 mIU/mL: antibody concentration at least two times the pre-vaccination antibody concentration.
• Number of Subjects With Anamnestic Response to the Challenge Dose for Anti-hepatitis B Surface Antigen (Anti-HBs) Antibodies [ Time Frame: One month after the challenge dose. ] [ Designated as safety issue: No ]

  Anamnestic response was defined as :

  • for initially seronegative subjects, antibody concentration ≥ 10 Milli-International Units per Milliliter (mIU/mL),
  • for initially seropositive subjects: antibody concentration at ≥ 4 fold the pre-vaccination antibody concentration.

• Anti-HAV antibody response to the challenge dose [ Time Frame: One month after the challenge dose. ]
• Anti-HBs antibody response to the challenge dose [ Time Frame: One month after the challenge dose ]

• Anti-hepatitis A (Anti-HAV) and Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations [ Time Frame: Prior to administration of challenge dose ] [ Designated as safety issue: No ]
  Concentrations are given as geometric mean concentration (GMCs) expressed as mIU/mL.
• Anti-hepatitis A (Anti-HAV) and Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations [ Time Frame: Two weeks and one month after the challenge dose ] [ Designated as safety issue: No ]
  Concentrations are given as geometric mean concentration (GMCs) expressed as mIU/mL.
• Number of Subjects Reporting Solicited Symptoms [ Time Frame: During the 4-day follow-up period after the challenge dose. ] [ Designated as safety issue: No ]
  Solicited local symptoms assessed include pain, redness and swelling. Solicited general symptoms assessed include fatigue, gastrointestinal symptoms, headache and temperature (above 37 degree Celsius).
• Number of Subjects Reporting Unsolicited Symptoms [ Time Frame: During the 31-day follow-up period after the challenge dose. ] [ Designated as safety issue: No ]
  Unsolicited symptoms = any adverse event (AE) reported in addition to those solicited during the clinical study. Also any "solicited" symptom with onset outside the specified period of follow-up for solicited symptoms was reported as an unsolicited adverse event.
• Number of Subjects With Serious Adverse Events (SAEs) Since the Last Study Visit of the HAB-160 (NCT00603252) Long-term Follow-up Study Considered by the Investigator to Have a Causal Relationship to Primary Vaccination [ Time Frame: Since the last study visit of the primary study long-term follow-up study up to challenge dose administration (1 year) ] [ Designated as safety issue: No ]
  A serious adverse event (SAE) is any untoward medical occurrence that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or is a sign of suspected or confirmed hepatitis A or hepatitis B.
• Number of Subjects Reporting Serious Adverse Events (SAEs) [ Time Frame: During one month following the administration of the challenge dose ] [ Designated as safety issue: No ]
  A serious adverse event (SAE) is any untoward medical occurrence that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or is a sign of suspected or confirmed hepatitis A or hepatitis B.

• Anti-HAV and anti-HBs antibody concentrations at Month 48 [ Time Frame: At Month 48 after primary vaccination ]
• Anti-HAV antibody concentrations after the challenge dose [ Time Frame: Two weeks and one month after the challenge dose. ]
• Anti-HBs antibody concentrations after the challenge dose. [ Time Frame: Two weeks and one month after the challenge dose. ]
• Occurrence and intensity of solicited local symptoms. [ Time Frame: 4-day follow-up period after vaccination ]
• Occurrence, intensity and relationship of solicited general symptoms [ Time Frame: 4-day follow-up period after vaccination ]
• Retrospective recording of all serious adverse events (SAEs) with causal relationship to vaccination or referring to hepatitis A or B infection that occurred since the last study visit of the HAB-160 long-term follow-up study. [ Time Frame: since the last study visit of the HAB-160 long-term follow-up study. ]
• Occurrence, intensity and relationship to vaccination of unsolicited symptoms. [ Time Frame: 31-day follow-up period after challenge dose. ]
• Occurrence, intensity and relationship to vaccination of all SAEs following the administration of the challenge dose. [ Time Frame: Following the administration of the challenge dose. ]

Only subjects who participated in the primary study will be invited to participate in the extension phase and the challenge dose phase of this study.

• Viral Hepatitis Vaccines
• Hepatitis B
• Hepatitis A

• Biological: Twinrix
  Intramuscular injection, single dose in left deltoid.
• Biological: Engerix-B
  Intramuscular injection, single dose in left deltoid.
• Biological: Havrix
  Intramuscular injection, single dose in right deltoid.
• Biological: HBVAXPRO
  Intramuscular injection, single dose in the left deltoid.
• Biological: Vaqta
  Intramuscular injection, single dose in right deltoid.

• Experimental: Twinrix Group
  Subjects received a single challenge dose of combined hepatitis A/hepatitis B vaccine (Twinrix).
  Intervention: Biological: Twinrix
• Active Comparator: Engerix + Havrix Group
  Subjects received separate administration of a single challenge dose of hepatitis B vaccine (Engerix) and hepatitis A vaccine (Havrix).
  Interventions:

  • Biological: Engerix-B
  • Biological: Havrix
• Active Comparator: HB VAX PRO + Vaqta Group
  Subjects received separate administration of a single challenge dose of hepatitis B vaccine (HB VAX PRO) and hepatitis A vaccine (Vaqta).
  Interventions:

  • Biological: HBVAXPRO
  • Biological: Vaqta

Inclusion Criteria:

• Subjects who the investigator believes that they can and will comply with the requirements of the protocol.
• A male or female who completed the primary vaccination phase of the HAB-160 study (NCT 00603252).
• Written informed consent obtained from the subject.
• If the subject is female, she must be of non-childbearing potential; 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 the time of study entry. If any apply, the subject must not be included in the study:

• Use of any investigational or non-registered product (drug or vaccine) other than the study vaccines within 30 days preceding the challenge dose, or planned use during the study period.
• History of any hepatitis A or hepatitis B vaccination or infection since the primary vaccination study.
• History of allergic disease or reactions likely to be exacerbated by any component of the vaccine.
• Acute disease at the time of enrolment.
• Pregnant or lactating female.