Single Dose Oral Cholera Vaccine Study in Dhaka, Bangladesh
Single Dose Oral Cholera Vaccine Study in Dhaka, Bangladesh
Bangladesh remains endemic for cholera, which experiences biannual outbreaks with additional
 epidemics seen during times of floods, cyclones or any natural disaster. It affects all age
 groups with the majority of fatal cases occurring in children . Therefore, immunization
 against cholera remains an important public health component in the prevention and control of
 the disease .The current two-dose regimen of the internationally available oral cholera
 vaccines (OCV) create a logistical and programmatic challenge for use in national programs or
 during epidemics ,so it is important to determine if a single dose vaccine will be protective
 in regions where cholera is endemic. If the vaccine is found to be efficacious following a
 single dose, this will have profound implications for the use of the vaccine in areas with
 limited resources particularly in complex emergencies where a multiple dose regimen is
 difficult to deploy. A single-dose regimen of this vaccine will improve its 'field ability'
 and allow the vaccine to be used for outbreak control, especially in difficult settings where
 the risk of cholera is extremely high and provisions for clean water and sanitation are not
 available. With low OCV production rates, larger populations could be immunized against
 cholera if a single dose is found to be efficacious. A single-dose schedule could facilitate
 the inclusion of a global stockpile strategy.

 The study design is a two-arm individually randomized double-blind placebo-controlled trial.
 The primary outcome of the study is the proportion of persons receiving 1 dose of vaccine or
 placebo who are detected with diarrhea with faecal excretion of V. cholera O1 in the study
 treatment centres from 7 days to 6 months after dosage and whose identity is confirmed
 through home visit.
Background:

 Cholera is a serious public health problem worldwide. Recently, unprecedented outbreaks have
 been seen in many countries including Zimbabwe, Haiti, Pakistan, Nepal, Guinea, Cuba, Congo,
 and Sierra Leone. These cholera outbreaks cause undue suffering with high mortality and
 morbidity figures as well as economic and social disruption. Bangladesh remains endemic for
 cholera, which peaks biannually with further increases seen during floods and cyclones .It
 affects all age groups, although the majority of fatal cases occur in children. Therefore,
 immunization against cholera remains an important public health tool for preventing and
 controlling the disease .

 Considerable progress has been made during the last decade in the development of new
 generation oral vaccines against cholera. Dukoral , a killed whole cell V. cholerae O1 with
 recombinant B-subunit (rBS-WC), was the first to be licensed internationally and has been
 available mostly in developed countries as a traveller's vaccine. This vaccine is licensed in
 over 50 countries, including Bangladesh. The WHO now recommends Dukoral for both endemic and
 epidemic cholera. However, two disadvantages limit the broader use of Dukoral. First, its
 current price is high. Second, Dukoral needs to be administered with a buffer, which
 complicates large scale deployment.

 The Shanchol vaccine is licensed in India and the vaccine was prequalified by the WHO in
 2011.The technology for vaccine manufacturing has been transferred to Shantha Biotechnics in
 India (now owned by Sanofi) by IVI. A large double-blind placebo controlled phase III trial
 by NICED and IVI has evaluated the efficacy of the vaccine produced by Shantha in preventing
 diarrhea from cholera in 70,000 people in Kolkata. An analysis of the phase III trial after
 three years concluded that the vaccine was 66% efficacious . Advantages of the Shanchol™
 vaccine include that its cost is lower and does not require administration with buffer, thus
 making it more feasible for use in mass vaccination programs in resource poor settings.

 The current multi-dose schedules for both Dukoral and Shanchol™ have restricted the
 application of the oral cholera vaccine in situations where they are most needed. Getting a
 vaccine to the same people twice poses difficulties in the control of cholera in both endemic
 and epidemic settings. In a study performed in a cholera-endemic area in Kolkata, India it
 was found that Shanchol™ induces significant vibriocidal responses even after a single dose
 .This study is designed to determine the protective efficacy and duration of protection
 offered by a single dose regimen and is not intended to replace the recommended 2 dose
 regimen in endemic areas. This will be useful for epidemics and outbreaks situation.

 Study population:

 Mirpur has been selected for this study. Mirpur is a part of the Dhaka metropolitan area with
 an estimated population of over 2.5 million people. Different socio-economic groups of
 communities live in the area. The icddr,b hospitals treat more patients from Mirpur than from
 any other part of Dhaka. We have selected 9 wards in Mirpur (7-13, 15 and 41) for the study
 out of 16 wards. The selection has been based on the high number of cholera patients from
 these wards visiting the icddr,b hospitals over the last few years. Before starting the study
 we will commission a census of these high cholera incidence wards in Mirpur. The census team
 will create geographic information system (GIS) database by digitizing buildings and other
 structures in the target wards using satellite derived images. The digitized buildings and
 structures will be verified for ground verification. The census team will visit each building
 and ascertain whether or not people are living in the building. Based on this survey, the
 team will assess whether the people living in each building/structure are a high risk group
 or not. The census team then will collect verbal consent from the respondent and other
 information about the household . We will conduct a de jure census and will enumerate 324,178
 high risk residents from the target wards.

 Census of study population:

 A paperless data collection system will be used in the census survey and subsequent census
 updates will also be performed biannually using handheld devices, a Samsung tab ("TAB"). The
 demographic surveillance will be conducted by community health workers to update the
 population through vital demographic events including births, deaths, internal and external
 migrations.

 Name and description of study agents:

 1. Bivalent oral killed cholera vaccine: each dose of this vaccine contains V. cholerae O1
 Inaba El Tor strain Phil 6973 formalin killed 600 ELISA units (EU) of Lipopolysaccharide
 (LPS) V. cholerae O1 Ogawa classical strain Cairo 50 heat killed 300 EU of LPS V.
 cholerae O1 Ogawa classical strain Cairo 50 formalin killed 300 EU of LPS V. cholerae O1
 Inaba classical strain Cairo 48 heat killed 300 EU of LPS V. cholerae O139 strain 4260B
 formalin killed 600 EU of LPS

 2. Non Biological placebo: The composition of the placebo is as follows :

 Ingredients Per 1.5 ml dose Starch: 60mg Ponceau 4R dye : 0.019 mg Brilliant blue : 0.003mg
 Tetrazine dye : 0.02 mg Xanthum gum : 3 mg Preservative: 0.002%(w/v)of Thiomersal (equivalent
 to .03 mg per 1.5 ml) Water : Up to 1.5 ml

 Administration of vaccine or placebo:

 The agent to be received by the participants will be determined by the randomization number
 on the vial. Vials will be consecutively numbered, but individually randomized into the
 vaccine or placebo arm. After shaking the vial properly, it will be opened and given to the
 participant. The contents will be poured into the mouth by the recipient, followed by intake
 of a small volume of water.

 Census update:

 The census in the study population will be updated every six months after intervention with
 the study agents.

 Disease Surveillance:

 All patients from the study area presenting for care at the hospital with diarrhea will be
 included in routine hospital surveillance.The diarrheal disease surveillance for the project
 will be conducted at icddr,b hospitals at Mohakhali and Mirpur and other health facilities
 for patients coming from the Mirpur study area (wards 7-13 , 15 and 41). Clinical staff at
 each of the two hospitals and other facilities will evaluate each patient at the hospital
 triage area and provide treatment as per the routine procedure.

 Immunological assays using blood specimens from study participants:

 Blood: Immunological analyses will be conducted in a small subgroup (334 participants) of
 participants .To account for unblocked unique number coding, we plan on enrolling 500
 participants (less than 5 years, 5 to less than 15 years and 15 years of age or older; so as
 to obtain at least 108 in each age group) from the vaccination sites. Venous blood (2-5 ml)
 will be collected from these participants prior to immunization and 14 days after intake of
 the study agent.

 Active follow up for safety:

 We will select 6,000 participants purposively from the study participants after verbal
 consent is obtained. These 6,000 participants will be actively followed once every two weeks
 for safety outcomes for a 28 day period after study agent administration.

 Primary Analysis at 6 months of follow-up:

 Primary analysis will be planned at 6 months following dosing.

 Analysis at 6, 12, 18 and 24 months of follow-up:

 Primary analysis is to be performed at 6 months. The following available time points (12, 18
 and/or 24 months will be for secondary analysis points.

 Surveillance for 24 months Surveillance will be continued to complete 2 years of follow-up.
 Blinding will be maintained until the end of the follow-up period. The analysis at the 2
 years of follow-up point will still be performed in a blinded manner.

 Verbal Autopsy:

 We will carry out 'Verbal Autopsy' in our study area where deaths will be identified through
 a household search by home visits which will be conducted by study staff. We will use two
 questionnaires for verbal autopsy, one for children aged 1 year to 14 years and the other for
 person aged 15 years and above. After identification, trained medical professional will visit
 homes of the deceased to perform verbal autopsy.

 Pregnancy Outcome Study:

 Pregnancy status in married women will be ascertained at least two months after vaccination
 by home visits of trained field staff. Those who will be confirmed for pregnancy at this time
 point will be followed up at 6 months as well as with further visits monthly to ascertain
 pregnancy outcome after delivery. A pregnancy follow up questionnaire will be used after
 consent taking for these visits
Inclusion Criteria:

 Healthy subjects > 1 year of age and above Living in high risk area for cholera Provision
 of Informed consent for participating in the study by participant /parent or guardian as
 well as verbal assent for children 11-17 years.

 Exclusion Criteria:

 Pregnant women Aged less than 1 year History of taking cholera vaccine