Hepatitis B Booster Study in Adolescence
Condition: Hepatitis B
MeSH terms: Hepatitis A; Hepatitis B; Hepatitis
Study type: Interventional
Phase: Phase 4

Summary: 
      This study looks at protection in 10-11 and 15-16 year olds, immunized as infants with
      Hepatitis B (HB) vaccine to see if they still have residual protection against Hepatitis B
      disease. Adolescents will be invited to have a blood test and those without a minimal level
      of protection (antibody titer) will be offered a "test" vaccination to see if they still have
      capacity to recall an immune response. About one month later they will get another blood test
      to see if a booster response occurred. A few participants will have lost protection (no
      booster response) and will be offered a second HB vaccination to restore protection. Results
      of this study could influence the way in which children in British Columbia (BC) are
      immunized against HB disease.
    

Detailed description: 
      Purpose:

      The purpose of the study is to assess whether or not individuals immunized as infants with
      Hepatitis B vaccine have residual immunity in their pre-adolescent and adolescent years. Two
      age groups (10, 11 year olds and 15, 16 year olds) will be invited to have blood taken to
      measure their level of protection (antibody titer). Those without a minimum protective titer
      will be offered a Hepatitis B "test" vaccination to determine if they still have the capacity
      to recall an immune response (ie immune memory), as a second line of protection against
      infection. A second blood sample will be obtained to determine if a booster response occurred
      (immune memory persists, protection intact) or not. The study vaccine will be a pediatric
      dose of HB vaccine (EngerixB) made by GlaxoSmithKline Canada (10mcg), a licensed product used
      in the public immunization program in British Columbia (BC) currently.

      Hypothesis:

      The hypothesis being tested is that protection has been lost in a sufficient proportion of
      15-16 year olds to warrant consideration of a pre-adolescent HB booster, modeled by the 10-11
      year olds whose protection is expected to be uniformly reinforceable.

      Justification:

      This will be the first Canadian study of the duration of the HB immune memory after infant
      immunization. According to a systematic review of 46 studies, evidence of progressive loss of
      immune memory and protection decades after infant HB vaccination is clear. Provinces in
      Canada recently took a leap of faith in dropping their adolescent HB immunization programs,
      assuming that HB protection from infancy will be life-long. This project investigates
      residual HB immunity 10 and 15 years after infant vaccination and evaluates a prototype
      booster program to provide health officials with timely, strategic information for
      maintaining optimal, informed HB disease control.

      Research Methods:

      The study will be conducted in BC which has used a consistent infant HB dosing schedule
      throughout. Eligible participants will be healthy 10-11 or 15-16 year olds. After obtaining
      informed consent/assent, a blood sample (8 ml) will be obtained to measure serum anti-HBs
      (anti-HB surface antigen) titer. Participants with a titer ≥10 IU/L will be informed of their
      ongoing protection and will exit the study. Those with a titer of ≤10 IU/L will be invited to
      return for a second visit for an HB challenge immunization. Participants will be asked to
      return 28 days post-vaccination for another blood test. Those who developed a booster
      response will be informed that they are immune and will exit the study. Those who do not
      boost will be invited to return for an additional (remedial) HB vaccination with a final
      titer check available to confirm restoration of protection. Tests will be carried out at BC
      Center for Disease Control's Hepatitis Laboratory. Booster responses are expected to be
      strong (titers >100 IU/L). Samples with post-booster titers 10-99 IU/L may be retested to
      assess antibody avidity to distinguish between primary and secondary type responses.

      Data will be assembled by the study center team. Electronic case report forms will capture
      case and laboratory information, using a commercial platform.

      Statistical Analysis Plan The baseline blood test will identify participants with residual
      anti-HBs titers above or below the minimum protective threshold of 10 IU/L. Based on the
      meta-analysis of studies involving 10 or 15 years of follow-up after infant immunization, the
      investigators project that about 30% of younger and 60% of older participants will have
      titers <10 IU/L. The booster challenge will identify those who are able to mount an
      anamnestic/recall response (titer ≥100 IU/L), a possible primary response (titer 10-99 IU/L,
      low avidity) or no response (titers <10 IU/L). The investigators project that 25-30% of older
      booster recipients will not have an anamnestic response, representing 15-20% overall of that
      study population. To detect a susceptibility rate of 15% with a precision of ± 0.05 and 95%
      confidence intervals, it will be necessary to screen 220 individuals, allowing for a 10%
      drop-out rate. Among younger booster recipients, the investigators project that 10% will not
      have an anamnestic response, representing an overall susceptibility rate of ~3%. For a
      precision ± 0.03 and 95% confidence intervals, the number of younger subjects to be screened
      will be 140, allowing for a 10% drop-out rate.

      Multivariable analysis will be undertaken to identify factors associated with loss of
      detectable protection, such as age at final dose, interval since vaccination, gender etc. The
      apparent rate of decline in titers between 10 and 16 years of age will be calculated.

      Mathematical modelling and economic analysis of immunization program options will be included
      to aid subsequent decision-making by health authorities. Among the options to be modelled are
      no intervention (relying on herd immunity of adjacent age groups) and a single booster dose
      at age 10-11years (grade 6 in BC, the locus of the cancelled adolescent HB vaccination
      program).
    

Intervention name(s): EngerixB, GlaxoSmithKline Vaccines
Intervention type(s): Biological
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: A prospective, single-center, parallel group study of residual HBV seroprotection rates and the capacity of seronegative individuals to respond to a challenge dose of HBV vaccine.
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Hepatitis B; Vaccine; Immunogenicity