The Role of Pre-existing Cross-reactive Antibodies in Determining the Efficacy of Vaccination in Humans
Condition: Yellow Fever; Encephalitis, Japanese
MeSH terms: Encephalitis, Japanese; Yellow Fever; Encephalitis; Fever
Study type: Interventional
Phase: Phase 2

Summary: 
      Epidemic viral diseases have become more prevalent in recent years. Among the various
      strategies to prevent such epidemics, vaccination is the most cost-effective. However,
      populations that are immunized are typically already exposed to multiple previous
      vaccinations or natural infections. Studies from this and other laboratories have revealed
      that pre-existing dengue antibodies can either inhibit or enhance subsequent dengue infection
      depending on the pre-existing antibody levels. While cross-reactive antibody is potentially
      pathogenic in dengue, how it impacts immune response to vaccination is unclear. Indeed,
      aggregated at the site of vaccination and the respective draining lymph nodes are
      antigen-presenting and immune regulatory cells that express Fc receptors and play pivotal
      roles in determining the magnitude and polarity of the immune response. Vaccine uptake by
      these antigen-presenting cells may thus be either inhibited or enhanced when vaccines are
      opsonized with cross-reactive antibodies.

      In view of the limited knowledge on how cross-reactive antibodies affect vaccination outcome,
      investigators propose here a study that exploits the known cross reactivity between Japanese
      encephalitis (JE) virus antibody and yellow fever (YF) vaccine. Investigators hypothesize
      that cross-reactive antibodies impacts antibody response to YF at the point vaccination in a
      concentration-dependent manner by altering both vaccine uptake and the innate immune response
      by antigen presenting cells. Investigators will structure an open label clinical trial on
      sequential vaccination with JE and YF vaccines, with different time intervals between
      vaccinations. This would test immune response to YF vaccination in subjects with different
      titer of cross-reactive JE vaccine-derived antibodies.
    

Detailed description: 
      The primary objective of this clinical study is to examine the role of cross-reactive
      antibodies in modulating immune responses to vaccines.

        1. Hypothesis: Antibody response to YF vaccination is influenced by the heterologous
           antibody titer at the point of YF vaccination.

        2. Hypothesis : Heterologous antibody to YF affect magnitude of vaccine uptake through the
           Fc receptors and alters the quality and magnitude of the innate immune response
           following YF vaccination, which has been previously shown to predictive of immune
           response to YF vaccination.

      Secondary objectives

        1. To determine neutralizing antibody response to YF vaccination in human volunteers at
           different time intervals following a prior JE vaccination.

        2. To characterize the innate immune response to YF vaccination at different time intervals
           after a prior JE vaccination.

      A total of 100 healthy adults, pre-screened to be negative for anti-dengue antibodies will be
      enrolled upon written informed consent. 75 subjects in the test arm will received 2 doses of
      inactivated JE vaccine(Ixiaro), while 25 subjects in the control arm has no JE vaccination.

      Subjects in the test arm will be sub-divided into 3 groups who receive YF17D:

      Group1.YF vaccination 1-month post-JE vaccination Group 2.YF vaccination 4-months post-JE
      vaccination Group 3.YF vaccination 9-months post-JE vaccination Subjects in the control arm
      (group 4) will receive YF vaccination at the same time as group 1.

      Blood sampling in relation to YF17D vaccination:

        1. Pre-dose

        2. 1-day after

        3. 3-days after (+ 1 day)

        4. 1-week after (± 2 days)

        5. 1-month after (± 5 days)

        6. 1-year after (± 14 days)

      Primary end-point: Difference in geometric mean titre of YF17D neutralizing antibody.
    

Intervention name(s): Japanese Encephalitis vaccine; Yellow Fever vaccine
Intervention type(s): Biological; Biological
Intervention description(s): IXIARO, inactivated, adsorbed vaccine. Two doses (0.5 ml each) of IXIARO one month apart; STAMARIL, 1 dose (0.5 ml)
Other intervention name(s): Ixiaro; Stamaril
Intervention MeSH terms: Vaccines
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Keywords: Yellow Fever; vaccination; Japanese encephalitis; antibodies