Simplifying the Rabies Pre-exposure Vaccination
Condition: Rabies
MeSH terms: Rabies
Study type: Interventional
Phase: Phase 3

Summary: 
      Rabies is a viral zoonosis that causes an encephalitis, almost invariably fatal. It is widely
      distributed across the globe: the World Health Organization (WHO) estimates that about 2,4
      billion people live in endemic areas for canine rabies. Vaccination of domestic animals is
      limited to industrialized and middle-income countries.

      The development of clinical rabies can be prevented through timely immunization after
      exposure: however, preventive vaccination simplifies the post-exposure procedure
      considerably, as immunoglobulins are no longer needed and less vaccine administrations are
      scheduled. Pre-exposure prophylaxis consists of an intramuscular (IM)of intradermal (ID) dose
      given on days 0, 7 and 21 or 28. The development of immunological memory after this
      vaccination is critical for the establishment of long lasting immunity. Subjects receiving a
      booster dose 1 year after pre-exposure prophylaxis segregate themselves into 'good' and
      'poor' responders; the former may not need further boosters for 10 years, whereas the latter
      may need more frequent boosters.

      Until recently, guidelines in travel medicine recommended pre-exposure vaccination only for
      some risk groups. Since recent studies have shown the effectiveness of the ID vaccination,
      the policies are changing towards pre-exposure vaccination for a larger population, including
      travelers to endemic regions, where immunoglobulins and vaccine are often not readily
      available.

      Based on the above, the investigators must stress the concept of "boostability" after a risk
      exposure. However, the current pre-exposure vaccination scheme could be improved: a schedule
      of 1 week would be less time consuming, would improve compliance and give less interference
      with other prophylaxis measures, e.g. mefloquine. Two small studies suggest that a schedule
      of 1 week interval is as effective and immunogenic as the standard one.

      The investigators will investigate whether the accelerated schedule is as effective as the
      classical schedule, by carrying out a randomized, non-inferiority study.
    

Detailed description: 
      Rabies is a viral infection that affects the central nervous system and causes an
      encephalitis which is almost invariably fatal. Being a zoonosis, the infection usually occurs
      following a transdermal bite or scratch by an infected animal, but contamination may also
      occur when infectious material, usually saliva, comes into direct contact with the victim's
      mucosa or with fresh skin wounds. Human-to-human transmission is extremely uncommon.

      Rabies is widely distributed across the globe: the World Health Organization (WHO) estimates
      that 87 countries with a total population of about 2,4 billion people are afflicted with
      endemic canine rabies, and the inclusion of all species poses a potential threat to >3.3
      billion people. The number of rabid wild animals that die without being detected is however
      estimated to be more than 90% of the total, so identified infections represent only a small
      fraction of wild animal rabies cases. Vaccination of domestic animals is limited to
      industrialized nations, the most urbanized areas of Latin America and some Asian countries
      such as Thailand.

      The development of clinical rabies can be prevented through timely immunization after
      exposure to the infecting agent: preventive vaccination alone implies no complete protection,
      but it simplifies the post-exposure procedure considerably, as immunoglobulins are no longer
      needed and less vaccine administrations are scheduled. Pre-exposure prophylaxis consists of
      an intramuscular (IM)of intradermal (ID) dose given on days 0, 7 and 21 or 28. The
      development of immunological memory after this vaccination is therefore critical for the
      establishment of long lasting immunity against rabies in humans. If a booster dose is given 1
      year after pre-exposure prophylaxis, subjects segregate themselves into 'good' and 'poor'
      responders; the former group, who represent 75% of subjects, may not need further booster
      vaccination for 10 years, whereas the latter may need more frequent boosters.

      Until recently, guidelines in travel medicine recommended the pre-exposure vaccination only
      to the classic risk groups. Since recent studies have shown the effectiveness of the ID
      vaccination, the policies are changing towards the recommendation of pre-exposure vaccination
      for a larger population, including all travelers to endemic regions, where rabies
      immunoglobulins and vaccine are often not readily available. The ID pre-exposure vaccination,
      which is more cost-effective, could also become an affordable alternative to protect the
      local population in high endemic regions.

      Based on all the above, the investigators must stress the concept of "boostability" after a
      risk exposure: the main target of travel medicine today is to get a sufficient serological
      response on day 7 after a risk in prevaccinated persons (accelerated immune response through
      memory cells) and after two post-exposure vaccinations (day 0 and 3). It should also be noted
      that a schedule of 1 week would be preferable to the current schedule, because it would be
      less time consuming, would improve compliance and gives less interference with the intake of
      other prophylaxis measures, e.g. mefloquine. Two recent but small studies from Thailand
      suggest that an accelerated schedule of three intradermal injections within 1 week interval
      is as effective and immunogenic as administered within 4 weeks.

      Therefore, this randomized, non-inferiority study will investigate whether the accelerated
      schedule is as effective as the classical schedule. The investigators will also increase the
      number of sites of injection, from one to two, to stimulate several different groups of lymph
      nodes on the same time to initiate more antibody production.
    

Intervention name(s): Human Diploid Cell Vaccine (HDCV) rabies vaccine
Intervention type(s): Biological
Intervention description(s): Human Diploid Cell Vaccine (HDCV) rabies Merieux 1 ml vaccine for rabies, provided by Sanofi-Pasteur, administered zvia ID route at two sites
Intervention MeSH terms: Vaccines
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Rabies; Vaccination; Boostability