Field Application of Shanchol in Adults in Bangladesh

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).