Field Application of Shanchol in Adults in Bangladesh
Condition: Other Specified Effects of Reduced Temperature
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

      Cholera is a public health problem globally and in Bangladesh and its prevention is
      important. Despite recent availability of an effective and affordable oral cholera vaccine
      (OCV), its field application remains a challenge and needs to be addressed in carefully
      conducted research studies.There is lack of information on temperature sensitivity and
      resulting immunogenicity of Shanchol OCV and it is not known if administration of two doses
      of OCVs, one month apart, instead of currently recommended 14 days, to improve success of
      vaccination programme will be effective;also if one dose of the vaccine, instead of currently
      recommended two doses, would result in adequate immune response in population exposed to V.
      cholerae in an endemic country like Bangladesh.

      Objectives:

      To determine immunogenicity of Shanchol in adults. when:

        1. the vaccine is stored at three defined temperatures(25 oC ,37 oC and 42oC) for 14 days,
           before putting back in cold box for administration in the field and compare them with
           the response when the vaccine is stored under currently recommended temperatures.

        2. two doses of the vaccine administered one month apart and compared vaccines administered
           at currently recommended interval of 14 days.

        3. a single dose is administered and compare them with responses after recommended two
           doses.

      Methods: The study will be conducted among adults living in the Mirpur community in urban
      Dhaka, the capital of Bangladesh.Studying safety and acute and long-term immune responses
      over a period of one year.

      Outcome measures/variables:

        1. Objective 1: safety and immunogenicity of vaccine in adults after its storage at three
           defined temperatures (25oC ,37oC and 42oC) by measuring vibriocidal antibody responses
           and compare them with the findings when the vaccine is stored at currently recommended
           temperature of 2-8oC (recommended by manufacturer, Shantha Biotechnic).

        2. Objective 2: compare vibriocidal responses following administration of two doses of the
           vaccine one month apart and compare them with vaccination 14 days apart over a period of
           one year, with study of the memory responses over a one year period as a secondary
           outcome.

        3. Objective 3: compare acute immune responses (vibriocidal antibody) following one and two
           doses of vaccine, and compare memory response as a secondary outcome measure, over a one
           year period.

      The above information is needed urgently for developing effective vaccination strategies for
      prevention and control of cholera in endemic countries.
    

Detailed description: 
      Cholera remains a major cause of morbidity and mortality in Bangladesh and many other endemic
      countries in the world.The WHO recommends using the cholera vaccine in both epidemic and
      endemic areas to control outbreaks.An affordable oral vaccine is now available for use in
      endemic settings; however, successful vaccination remains challenging and expensive due to
      the need for temperature-controlled distribution systems, which is difficult in most
      developing countries.Therefore, it would be important to test heat stability of the current
      vaccines without significantly compromising its safety and efficacy.

      In cholera endemic populations their baseline immune responses and memory to the pathogen
      already exists. Therfore, a single dose of cholera vaccine could act as booster dose
      eliminating the need for the second dose, saving costs but more importantly significantly
      improving its delivery to large number of people within a very short time. However, that
      needs study in endemic countries, such as Bangladesh, to examine both acute and memory
      responses following a single dose and to determine how long they persist.

      In the developing countries such as in Bangladesh, vaccination with two doses can be
      problematic, with logistic and cost issues. It is also difficult to administer two doses of
      the vaccine after an interval of 14 days - increasing the interval to one month would be more
      practical and that would improve coverage of large number of populations. It would,
      therefore, be important to examine if immunogenicity could be increased when the second dose
      is administered 30 days following the first dose.

      Adult males and females living in the Mirpur community in urban Dhaka will be recruited in
      the study.The community will be informed by the field staff and interested persons will be
      recruited according to the inclusion/exclusion criteria.

      Eligible participants will receive Shanchol vaccine according to study design. The vaccine
      comes in single-dose vials and is 1.5 mL in volume.

      Group 1: Immunogenicity studies on temperature stability of Shanchol The vaccines will be
      stored at different temperatures

      1a. 25°C for 14 days

      1b. 37°C for 14 days and

      1c. 42°C for 14 days.

      After that vaccine will be stored at the recommended tempature in cold chain until their
      administration to the participants. The second dose will be administered 14 days after the
      first dose, as currently recommended. These three groups will be compared to those receiving
      the same vaccine maintained at standard conditions of 2-8oC.We will enroll 145 participants
      in each of the four groups (three interventions and a control) i.e. a total of 580 eligible
      participants. We will measure acute responses to the vaccine by measuring vibriocidal
      antibodies up to a period of 28 days.

      Group 2a: Immunogenicity of two doses of Shanchol given 14 days apart and immunogenicity
      measured over a one year period Two doses of vaccines, maintained at standard storage
      condition (2-8oC), will be administered 14 days apart to evaluate the acute and long term
      immune responses.A total of 145 eligible participants will be studied in this group. We will
      compare acute and long term immune response among participants in this group with those in
      Group 2b and Group 3.

      Group 2b: Immunogenicity of two doses of Shanchol given 30 days apart and immunogenicity
      measured over a one year period Two doses of vaccines, maintained at standard storage
      condition (2-8oC), will be administered 30 days apart to evaluate the acute and long term
      immune responses. A total of 145 eligible participants will be studied in this group. We will
      compare acute and long term immune responses in this group with those in Group 2a and Group
      3.

      Group 3: Immunogenicity of a single dose of Shanchol over a one year period A single dose of
      the vaccine, maintained at standard temperature (2-8oC), will be administered. The acute and
      long term immune response would be measured for a one-year period. A total of 145
      participants will be enrolled in this group. We will compare immune response among
      particiupants in this group with those in Groups 2a and 2b.

      Duration of the study period for individual participants

      The participants in Group 1 will be followed upto 28 days, and remaining groups will be
      followed up to 1 year.

      Surveillance for adverse effects:

      The study participants will be monitored after the intervention to assess the safety of the
      study agent. After each dose of vaccine, the recipients will be followed up for 30 minutes in
      the clinic and then sent home if they do not have problem. Under the supervision of a clinic
      physician, trained Research Assistants will visit the participants in their respective homes
      for the next 3 cosecutive days to record adverse events such as diarrhea, vomiting, nausea
      and other local and systemic reactions constituting active surveillance. For the next 11
      days, passive surveillance will be carried out and participants will be instructed to visit
      the field clinic if they have any problems. All adverse events during the study period will
      be recorded and the conditions managed either at the clinic or at the Dhaka Hospital of
      icddr, b or at other clinics/hospitals depending on the nature and severity of the condition
      at no costs to the participants. A clinical record form will be used to record all clinical
      signs and symptoms. For serious adverse events data will be entered onto a separate form.

      Study intervention: Oral cholera vaccine, Shanchol Each dose of the vaccine contains
      inactivated whole cell, heat killed and formalin killed bacteria measured as ELISA Units (EU)
      of lipopolysaccharide (LPS). It contains formalin-killed V. cholerae Inaba, El Tor biotype
      (strain Phil 6973; 600 EU); heat-killed V. cholerae Ogawa classical biotype (Cairo 50; 300
      EU); formalin killed V. cholerae Ogawa classical biotype (Cairo 50; 300 EU); LPS of
      heat-killed V. cholerae Inaba, classical biotype (Cairo 48; 300 EU); and formalin killed V.
      cholerae O139 (4260B; 600 EU).

      Storage conditions The vaccine will be stored at 2-8°C under standard conditions
      (recommended) and in incubators at 25°C, 37 °C and 42°C for 14 days for the study purpose.

      Vaccine allocation: The study is an open study although the investigators in the laboratory
      carrying out the tests will be blinded as the batch of vaccine allocation they are testing.
      The vaccines will be allocated based on the temperature at which they have been incubated and
      starting from the lowest 25 oC and then going up finally to 42oC in the different sets of
      study participants. Each set of vaccines stored at the different temperatures will be given a
      code (25oC, 37oC and 42oC stored batches).
    

Intervention name(s): Shanchol
Intervention type(s): Drug
Intervention description(s): Each dose of the vaccine contains inactivated whole cell, heat killed and formalin killed bacteria measured as ELISA Units (EU) of lipopolysaccharide (LPS). It contains formalin-killed V. cholerae Inaba, El Tor biotype (strain Phil 6973; 600 EU); heat-killed V. cholerae Ogawa classical biotype (Cairo 50; 300 EU); formalin killed V. cholerae Ogawa classical biotype (Cairo 50; 300 EU); LPS of heat-killed V. cholerae Inaba, classical biotype (Cairo 48; 300 EU); and formalin killed V. cholerae O139 (4260B; 600 EU).
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Health Services Research