Research Projects : Export

Main objective

To better characterize cholera transmission in cholera hotspot in DRC and assess the impact of a large vaccination campaign reaching high coverage on sustained control of cholera transmission for at least two years.

Methods

Clinical surveillance (Goma and Bukama)
Observational surveillance study at CTC/CTU level, including all patients in all active structures of the zones (ZS Goma, Karisimbi, Nyiragong, Kirotshe and ZS Bukama). Systematic RDT testing, questionnaire, collection of dry and humid filter papers

Seroprevalence surveys (Goma and Bukama) – collecting venous blood samples
Goma: 6 serosurveys at different time of the year (all post-vaccination). Bukama: 3 serosurveys once a year (1 before vacci, then 1 and 2 years after), + mortality survey

Home follow-up (Goma only)
Repeated home visits for RDT positive cases (D1, D4, D7, D14, D28, D90 and D180). Stool testing from the family, questionnaire, collecting environmental samples.

Evaluate the impact of OCV preventive campaigns at different levels:

• Impact on number of cholera cases: symptomatic cases in CTC/CTUs
• Impact on transmission in the community: monitoring level of immunity in the population including asymptomatic cases
• Impact on transmission at household level

This study will help us better understand the impact of mass cholera vaccination programs to set expectations for decision makers and help understand when revaccination may be needed.

Cholera remains a public health concern in Ethiopia. We aim to contribute to reducing the burden of cholera and generate scientifically strong data on the effectiveness and impact of OCV (Euvichol-Plus) vaccination in target areas in Ethiopia, as well as various aspects of cholera epidemiology. This includes the disease burden, disease severity and fatality, transmission and carriage/shedding, site-specific risk factors and healthcare seeking behaviour associated with cholera, etiologies of non-cholera diarrheal diseases and antimicrobial resistance, and etc. This project will contribute to the country’s efforts towards the national cholera plan (NCP), with evidence-based data to be generated and stakeholder engagements in alignment with the WHO Global Task Force for Cholera Control (GTFCC) ‘Ending Cholera – Global Roadmap to 2030’.

Cholera remains a persistent global health problem that can be controlled by appropriate water and sanitation and oral cholera vaccination. Our project aims to support the geographic targeting of cholera control interventions with four key objectives:

• maintenance of a global database of cholera surveillance data which can be used by countries and GTFCC stakeholders to access centralized data sources and understand the country and regional cholera epidemiology;
• development of a statistical mapping pipeline, which produces high resolution global maps of cholera burden;
• provision of technical epidemiological and modeling support to countries and NGOs in cholera control;
• participation in GTFCC working groups to develop evidence-driven guidance related to cholera surveillance and elimination, targeting OCV campaigns, and identifying cholera burden hotspots.

This project supports efforts to map the global burden of cholera through the maintenance of a global database of cholera incidence and mortality and the development of statistical modeling methods to produce high resolution maps of cholera burden. The study team is working to develop a user-friendly web interface to the cholera database to support country and GTFCC stakeholder access to centralized data sources, and the global burden maps serve as the foundation for many planning and intervention targeting activities such as strategic demand forecasts for OCV and hotspot identification.

Effective targeting of OCV campaigns and WASH interventions for cholera control requires knowledge of the highest burden areas worldwide. The global cholera database and mapping efforts resulting from this project support countries and GTFCC stakeholders in characterizing cholera epidemiology and targeting their cholera control efforts.

Oral cholera vaccination (OCV) has typically been used in responsive, outbreak response settings, but growing vaccine supply and efforts to promote cholera control planning at national scales have led to more frequent use of preventive vaccination campaigns. The Vaccine Impact Modelling Consortium coordinates a multi-modeling effort to estimate the global impact of vaccines for several vaccine-preventable diseases. This work will expand on an existing OCV modeling framework to project the impact of multiple scenarios of global cholera vaccination campaigns, inform strategic planning for vaccine supply and vaccine demand and underscores the importance of the effective targeting of OCV campaigns. An R package will be developed to make the model more accessible and flexible for other users and policy questions.

This research aims to develop a flexible vaccine impact model that can project the global impact of oral cholera vaccination campaigns under different sets of planning scenarios.

The modeling framework that results from this project can be used to estimate the impact of cholera vaccination campaigns and advocate for increases to OCV campaign funding and supply.

Bangladesh remains endemic for cholera, which experiences biannual outbreaks with additional epidemics seen during times of floods, cyclones or any natural disaster [1, 2]. It affects all age groups with the majority of fatal cases occurring in children [3-6]. Therefore, immunization against cholera remains an important public health component in the prevention and control of the disease [6]. A problem that may be a stumbling block in the path is that the oral cholera vaccine (OCV) is in short supply globally and only about 2-3 million doses are produced each year. In Bangladesh alone we anticipate that 170 million doses will be needed in a 5 year time frame if only high risk populations are targeted. Globally for the rest of Asia and Africa as well as for Haiti, millions of doses of vaccine is needed for control of endemic and epidemic cholera. The global demand for the vaccine is therefore high and the good news is that, there is now provision for local production of over 50 million doses in Bangladesh. With this prospect in view, planning for prevention of cholera by use of OCV, it may be possible to decrease the burden of the disease in Bangladesh.

Knowledge gap

More evidence is needed to address uncertainties around the cholera disease burden, as well as the impact, feasibility, and cost-effectiveness of various vaccination strategies against cholera, to add to the existing knowledge base. A special need for acquiring field evidence of these vaccine attributes in settings with endemic cholera, which account for a very large fraction of the global cholera disease burden, is also recognized [7].

There is a great need for identify financing mechanisms for introduction of vaccination against cholera. All these efforts will hopefully decrease the burden due to cholera which has both health and financial burden on the country. Studies have shown that the cost of hospitalization and illness to the patient and the family is around ten times higher than the cost of vaccine [8, 9].

A countrywide surveillance is needed which will help to identify the disease burden in the country, so as to plan appropriate treatment and preventive measures.

Relevance

Bangladesh needs to plan strategies for introduction of a locally produced oral cholera vaccine in Bangladesh. Thus clear information from national stakeholders on the cholera investment strategy for Bangladesh is needed based on which future plans can be made. In addition, information i s needed on the strategies for vaccination and areas which need to come under coverage. With the availability of a locally produced vaccine in Bangladesh, financing plans and funders will be needed to materialize the immunization plans for people with OCV.

Objectives

The objectives of the proposal are as follows:

• Build a plan (including surveillance of high risk areas) and identify strategies for the introduction of OCV in Bangladesh by developing the cholera investment case based on the present scenario.
• Identify a financing plan for the introduction of the locally produced vaccine in Bangladesh in the short term.

Methods

We will update the current cholera investment case study on cholera vaccination for Bangladesh which was previously prepared by International Vaccine Institute (IVI) in 2009. This will provide a useful evidence based guide to policy makers in Bangladesh in making decisions about the use of OCV as well as to the global health community in considering technical and financial support for cholera vaccine introduction. The information on where and whom to vaccinate will also be obtained to accumulate information by working on nationwide cholera surveillance from all over Bangladesh. Surveillance will be conducted in different government and non government hospitals and medical colleges in sites already known to have diarrheal disease burden.

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. In Bangladesh alone we anticipate that 170 million doses will be needed in a 5 year time frame if only high risk populations are targeted. The global demand for the vaccine is high and the good news is that, there is now provision for local production of over 50 million doses in Bangladesh. With this prospect in view, planning for prevention of cholera by use of OCV, it may be possible to decrease the burden of the disease in Bangladesh.

Bangladesh needs to plan strategies for introduction of a locally produced oral cholera vaccine in Bangladesh. Thus clear information from national stakeholders on the cholera investment strategy for Bangladesh is needed based on which future plans can be made. In addition, information is needed on the strategies for vaccination and areas which need to come under coverage. With the availability of a locally produced vaccine in Bangladesh, financing plans and funders will be needed to materialize the immunization plans for people with OCV.

Therefore, the objectives of the current study are as follows:

• Build a plan (including surveillance of high risk areas) and identify strategies for the introduction of OCV in Bangladesh by developing the cholera investment case based on the present scenario.
• Identify a financing plan for the introduction of the locally produced vaccine in Bangladesh in the short term.

Different data will be used to develop and recommend up to 3 optimal strategies for introduction of Oral Cholera vaccine (OCV) with associated vaccine demand, budget and health impact. For this recommendation we will communicate with different level of Government of Bangladesh (GoB) and other internal and external stakeholders with our preferred feasible strategy for introduction of vaccine.

Cholera, an acute watery diarrheal disease, caused by toxigenic strains of the bacterium Vibrio cholerae O1 and O139, causes an estimated over 2.9 million cases and over 95,000 deaths annually in cholera endemic countries alone and frequent epidemics in other settings with poor water and sanitation infrastructure. Global estimates range from 1.4-4.8 million cases and 28,000 – 142,000 deaths every year 1. The disease is characterized by acute onset watery diarrhea leading to rapid dehydration and death, if not promptly treated.

Recently a conflict has been conducted in the Rakhine province of Myanmar. During this conflict over 500,000 Rohingya refugees (URMN) have recently been displaced and entered into Cox’s Bazar district in Bangladesh. Among newly arrived displaced people, 60% are women and children living in conditions where public health facilities are lacking. These people are probably not primed and exposed to cholera and the prevailing conditions are high risk for cholera. In the recent past, e.g in Yemen, South Sudan, Haiti and other countries, lack of WaSH and public health facilities have led to large epidemics with high numbers of cholera cases and death. Considering this risk assessment international co-ordination group (ICG) of WHO allocate 900,000 oral cholera vaccines from WHO stockpile to deploy among the refugees.

The prevention of cholera has become a high priority in the global community. Immunization with OCV is the most effective means of preventing cholera infection and its consequence. The World Health Organization (WHO) has warned of a growing risk of a cholera epidemic at makeshift refugee camps in Bangladesh where hundreds of thousands of Myanmarese Rohingya Muslim refugees are sheltered in dire conditions. The camps did not have safe drinking water and lacked sufficient hygiene; filthy water and feces flowed openly through the camps. Risk of waterborne diseases is high, especially there is very high risk of cholera in these camp. Interventions like vaccination are being scaled-up as the situation remains critical and challenging.

The study of ShanChol OCV on Unregistered Myanmar Nationals (URMN) in children and adults will be able to give information regarding the safety and immunogenicity of the vaccine in URMN subjects. This information will be important for proceeding with the cholera vaccination in the refugee population of same socioeconomic structure in future.

Hypothesis

Oral Cholera vaccine (OCV) is immunogenic in different age groups of Unregistered Myanmar Nationals (URMN).

Objectives

The objective of this study is to evaluate the immunogenicity of OCV among healthy Unregistered Myanmar Nationals (URMN) in Bangladesh.

Methods

This will be cross sectional study on a total of 226 healthy Unregistered Myanmar Nationals (URMN). There will be three age cohort which will consist of 80 participants for age 1-5 yrs, 63 participants for age 6-17 yrs and 83 for age 18 yrs and above, with a total of 226 participants. Blood will be taken before and after OCV administration.

Outcome measures/variables

To evaluate the immunogenicity of OCV among Unregisterd Myanmar Nationals (URMN).
The immunogenicity component will be measured by assessing the sero-conversion rate of vibriocidal antibodies after vaccination with OCV to Vibrio cholerae O1.

Cholera, an acute watery diarrheal disease, caused by toxigenic strains of the bacterium Vibrio cholerae O1 and O139, causes an estimated over 2.9 million cases and over 95,000 deaths annually in cholera endemic countries alone and frequent epidemics in other settings with poor water and sanitation infrastructure. The disease is characterized by acute onset watery diarrhea leading to rapid dehydration and death, if not promptly treated.

Among newly arrived displaced people, 60% are women and children living in conditions where public health facilities are lacking. These people are probably not primed and exposed to cholera and the prevailing conditions are high risk for cholera. In the recent past, e.g in Yemen, South Sudan, Haiti and other countries, lack of WaSH and public health facilities have led to large epidemics with high numbers of cholera cases and death.

The study of ShanChol OCV on FDMN in children and adults will be able to give information regarding the safety and immunogenicity of the vaccine in URMN subjects. This information will be important for proceeding with the cholera vaccination in the refugee population of same socioeconomic structure in future.

Therefore, the objective of this study is to evaluate the immunogenicity of OCV among healthy Forcibly Displaced Myanmar Nationals (FDMN) in Bangladesh.

By evaluating the immune responses of OCV among Forcibly Displaced Myanmar Nationals (FDMN), we can compare the immune responses between Bangladeshi population and FDMN. We can also assess the sero-conversion rate of vibriocidal antibodies after vaccination with OCV to Vibrio cholerae O1.

Cholera continues to be a major cause of morbidity and mortality in low-income countries including Bangladesh. It is estimated that over 2.9 million cases and over 95,000 deaths occurs annually in cholera endemic countries alone and frequent epidemics happened in other settings with poor water and sanitation infrastructure. (1) The overall morbidity for cholera remains high. A global stockpile of OCV has been created by WHO in 2013 for epidemic and outbreak settings. (2) The disease is characterized by acute onset of watery diarrhea leading to rapid dehydration and death, if not promptly treated. From August, 2017 Rohingya Myanmar Nationals (RMN) have been influxed to Bangladesh through Cox’s Bazar border of Bangladesh. They are staying at the camps of two different upazilas (Teknaf and Ukhiya) of Cox’s Bazar. According to the latest assessment, more than half (52%) of the total Rakhine state’s population has no access to the improved sanitation facility. Also, around 45% of the population has not access to or is not using improved water supply facility according to the SDG standards.(14) Considering this risk assessment international co-ordination group (ICG) of WHO allocate 900,000 oral cholera vaccines from WHO stockpile to deploy among the RMN.

The prevention of cholera has become a high priority in the global community . Immunization with OCV is the most effective means of preventing cholera infection and its consequence. The World Health Organization (WHO) has warned of a growing risk of a cholera epidemic at the Rohingya camps in Bangladesh where people are sheltered in dire conditions. The camps did not have safe drinking water and lacked sufficient sanitation and hygiene; filthy water and feces flowed openly through the camps. Risk of waterborne diseases is very high, especially there is increasingthe risk of cholera in these camp. Moreover, according to a total number of 782 cases with 11 deaths have been reported in 2016 from Myanmer when the case fatality rate was 1.4%.(9) Interventions like vaccination are being scaled-up as the situation remains critical and challenging. But information related to vaccine effectiveness under this humanitarian condition is lacking

Relevance

The study of Shanchol OCV on Rohingya Myanmar Nationals (RMN) in children and adults will be able to give information regarding the effectiveness of vaccine in RMN subjects. This information will be important for proceeding with the cholera vaccination in the refugee population of same socioeconomic structure in future.

Objectives

The objective of this study is to determine the effectiveness of OCV in a test-negative case control design among Rohingya Myanmar Nationals (RMN) in Bangladesh.

Methods

This study will be conducted in Ukhiya upazila of Cox’s Bazar district. Here we would like to conduct the study through a test-negative case-control design. The participants will be the RMN who will come to the treatment center for seeking management of acute watery diarrhea (AWD). The stool or rectal swab of all participants will be tested. The cholera positive participants will be considered as cases whereas the cholera negative will be considered as control. The vaccine effectiveness will be measured by comparing the ratio of odds of vaccination in the cholera positive patients and odds of vaccination in the cholera negative patients.

Outcome measures/variables

The vaccine effectiveness will be measured by comparing the ratio of odds of vaccination in the cholera positive patients and odds of vaccination in the cholera negative patients.

Cholera continues to be a major cause of morbidity and mortality in low-income countries including Bangladesh. It is estimated that over 2.9 million cases and over 95,000 deaths occurs annually in cholera endemic countries alone and frequent epidemics happened in other settings with poor water and sanitation infrastructure. The overall morbidity for cholera remains high. A global stockpile of OCV has been created by WHO in 2013 for epidemic and outbreak settings. The disease is characterized by acute onset of watery diarrhea leading to rapid dehydration and death, if not promptly treated. From August, 2017 Forcibly Displaced Myanmar Nationals (FDMN) have been influxed to Bangladesh through Cox’s Bazar border of Bangladesh. They are staying at the camps of two different upazilas (Teknaf and Ukhiya) of Cox’s Bazar. According to the latest assessment, more than half (52%) of the total Rakhine state’s population has no access to the improved sanitation facility. Also, around 45% of the population has not access to or is not using improved water supply facility according to the SDG standards. Considering this risk assessment international co-ordination group (ICG) of WHO allocate 900,000 oral cholera vaccines from WHO stockpile to deploy among the FDMN. Therefore the objective of this study is to determine the effectiveness of OCV in a test-negative case control design among Forcibly Displaced Myanmar Nationals (FDMN) in Bangladesh.

“The vaccine effectiveness will be measured by comparing the ratio of odds of vaccination in the cholera positive patients and odds of vaccination in the cholera negative patients.
”

In 2012, the 65th World Health Assembly (WHA) declared the completion of poliomyelitis (polio) eradication to be a programmatic emergency for global public health. Cholera, another life-threatening infectious disease, is highly endemic and epidemic in many of the same parts of the world affected by polio.

Currently, no studies have been conducted to determine if any of the OPV and OCV can be co-administered without impacting the immunogenicity of either vaccine. Data on co-administration of the currently available whole-cell killed OCVs with other oral vaccines, specifically, oral polio vaccines is lacking.

Effective immunization with high coverage remains the key for interruption of polio transmission, and vaccination is a vital complementary strategy for cholera control. Given that OPV campaigns in most polio priority settings target a largely overlapping population as OCV campaigns, the results of this study are crucial and highly relevant for OPV-OCV vaccine administration policies. If able to be co-administered safely and effectively, combined OPV-OCV campaigns may potentially outline large cost-savings and eliminate potentially redundant administration costs and improve adherence.

Co-administration of oral polio vaccine (OPV) and oral cholera vaccine (OCV) will not decrease immunogenicity of either vaccine among children 1 – 3 years old.

Objectives

Primary

• To compare seroconversion for OPV types P1 and P3 when administered alone versus when administered with OCV on day 28 and 56 after vaccination.
• To compare vibriocidal antibody response (based on a ≥ 4-fold rise) to OCV when administered alone versus when co-administered with OPV on day 28 and day 56 after vaccination.

Secondary

• To determine safety of co-administration of OPV with OCV compared to OPV or OCV alone.

Methods

We propose to conduct an open-label, randomized controlled study in Dhaka, Bangladesh, among healthy children aged 1 – 3 years old who have received < 3 doses of OPV and has not received any dose of IPV or OCV at any time before enrolment based upon immunization card record or history from parents.

Outcome measures/variables

Primary

• Anti-polio virus antibodies type 1 and type 3 microneutralization titer when OPV and OCV are administered separately, and when given together.
• Vibriocidal antibody response to V. cholerae O1, serotype Ogawa and Inaba when OPV and OCV are administered separately and when given together.

Secondary

• Number of adverse events and serious adverse events between OPV and OCV when given alone versus when given concomitantly.

Effective immunization with high coverage remains the key for interruption of polio transmission, and vaccination is a vital complementary strategy for cholera control. Given that OPV campaigns in most polio priority settings target a largely overlapping population as OCV campaigns, the results of this study are crucial and highly relevant for OPV-OCV vaccine administration policies. If able to be co-administered safely and effectively, combined OPV-OCV campaigns may potentially outline large cost-savings and eliminate potentially redundant administration costs and improve adherence. Therefore, the main objectives of the study are:

• To compare seroconversion for OPV types P1 and P3 when administered alone versus when administered with OCV on day 28 and 56 after vaccination.
• To compare vibriocidal antibody response (based on a ≥ 4-fold rise) to OCV when administered alone versus when co-administered with OPV on day 28 and day 56 after vaccination.

• Anti-polio virus antibodies type 1 and type 3 microneutralization titer when OPV and OCV are administered separately, and when given together.
• Vibriocidal antibody response to V. cholerae O1, serotype Ogawa and Inaba when OPV and OCV are administered separately and when given together.

While there is ample evidence on the direct protection conferred by killed whole-cell oral cholera vaccines (OCV), there is limited evidence documenting the population-level impacts of mass vaccination on infection rates, disease incidence and mortality both due to the limited number of mass campaigns that have been conducted in cholera-endemic areas and due to the generally weak clinical surveillance systems for cholera. As more and more vaccines become available and endemic hotspots plan to use OCV, evidence on the population level impacts of mass vaccination are needed to help set expectations for the role OCV can play in short- to medium-term global reductions in cholera. Eastern Democratic Republic of Congo provides a unique setting to study the impacts of mass vaccination given the reporting of cholera cases throughout the year and the ambitious plans by the Ministry of Health to substantially reduce cholera burden in the years to come through improvements in water and sanitation and the use of OCV.

Relevance

Results from this study will allow for a better estimation of the impact of mass oral cholera vaccination campaigns deployed in Uvira (South Kivu) on the incidence of confirmed clinical cholera and mortality. To further understand both direct and indirect effects of vaccination while more explicitly accounting for changes in population movement, secular changes and waning vaccine protection, we will fit dynamic transmission models to data from Uvira. A better understanding of these effects will also aid in the country’s national plan for cholera elimination over 2018-2022.

Objectives

There are three main objectives of this study. The first is to estimate the impact of mass oral cholera vaccination campaigns deployed in the city of Uvira on the incidence of confirmed clinical cholera and cholera-related mortality from 2021 through 2026. The second is to describe V. cholerae contamination patterns and genetic diversity over time in patients, households, and the broader environment through microbiological analyses of clinical and environmental samples. The third and final objective is to describe changes in vaccine coverage, care seeking behavior, and serologically-derived V. cholerae infections rates in the city of Uvira from 2021 to 2026.

Methods and Outcome measures / Variables

This study has three main components; surveillance for medically attended cholera, follow-up studies in households of confirmed cholera cases with environmental surveillance and representative household surveys.

For clinical surveillance, systematic cholera confirmation through RDT, culture and qPCR will be continuously conducted over the study period at the primary sites in Uvira for diarrhea/cholera treatment; a cholera treatment centre (CTC) and cholera treatment unit (CTU).

For household follow-up studies, environmental sampling in households of confirmed cholera cases as well as matched controls, and at community water sources will be conducted by study staff in addition to laboratory testing for V. cholerae via culture-based and molecular methods.

Representative household surveys will be conducted each year, with blood collection done in a subset (3 of the years). Data on migration patterns, vaccine coverage, access to and use of WASH infrastructure, household mortality and other data will be collected from all participating individuals within households. We will test serum for a suite of antibodies related to previous V. cholerae O1 infection and use machine learning models to estimate seroincidence. ”

We aim to quantify the impact of the killed oral cholera vaccine (OCV) on cholera incidence and mortality over 6 years (2021-2026) in Uvira, Democratic Republic of Congo, a city with endemic cholera transmission. In addition, we hope to better understand how contamination patterns and genetic diversity of the cholera-causing bacteria change over time (pre- and post-vaccination) through analysis of clinical and environmental samples.

This study will help us better understand the impact of mass cholera vaccination programs to set expectations for decision makers and help understand when revaccination may be needed.

Background

Cholera is an acute dehydrating diarrheal illness caused by Vibrio cholerae infection, accounting for more than 3 million cases and 100,000 deaths a year globally. In endemic countries, young children bear a large burden of disease.

Knowledge gap

Despite this, currently available cholera vaccines achieve a lower efficacy and shorter duration of protection in young children than in adults for reasons that are poorly understood, while such differences in protection are not evident following natural infection. We have recently shown, in a cohort of Bangladeshi children, that younger children given oral cholera vaccine mount lower V. cholerae polysaccharide-specific antibody responses compared to older children and adults.

Relevance

Mucosal-associated invariant T (MAIT) cells are recently described innate-like T cells, representing 1-10% of circulating T cells, and found in abundance in the intestinal mucosa, mesenteric lymph nodes, and liver. MAIT cells are predominantly CD8+ and restricted by the non-polymorphic MHC-related protein 1 (MR1), and activated by pathogen-derived vitamin B metabolites. Despite their innate-like features, recent studies have found that MAIT cells have surprising heterogeneity in their TCR repertoire and can discriminate between pathogen-derived ligands in a clonotype-dependent manner.

In collaboration with scientists at the University of Utah, we have examined both peripheral and duodenal MAIT cells in humans with severe cholera. We found that MAIT cells are activated in both the peripheral and mucosal compartments during cholera infection, and that they are associated with higher class-switched V. cholerae polysaccharide-specific antibody responses. Additionally, in a set of in vitro studies using primary MAIT cells and MAIT clones expanded from healthy individuals, we have shown that MAIT cells promote B cell differentiation and antibody production. We have also used transcriptomic analysis to demonstrate that activated MAIT cells have increased expression of CD40L and APRIL, factors known to play a role in B cell activation. Thus, we hypothesize that in mucosal infection and vaccination, MAIT cells play an important role in bridging innate and adaptive immune responses, including a possible effect on polysaccharide-specific responses.

Building on these data, and taking advantage of our longstanding collaboration with scientists at the University of Utah and Harvard Medical School, we propose to use V. cholerae as a prototypical human enteric pathogen to understand the adaptive capacity and B cell impact of MAIT cells during enteric infection and vaccination.

Hypothesis

We will test the hypothesis that a subset of MAIT cells, when activated following infection or vaccination, undergo clonal expansion and provide help to B cells through MR1-dependent and -independent interactions to enhance polysaccharide-specific antibody production.

Objectives

The objective of this study is:

• To characterize clonal expansions of MAIT cells during human cholera infection and vaccination;
• To determine the mechanisms through which MAIT cells affect B cell maturation.

Methods

Isolation of PBMCs from blood by density gradient centrifugation from younger and older children vaccinees and infected younger children and clonal expansion of single sorted MAIT cells.

Outcome measures/variables

Generation of clones from the vaccinees and infected persons with Cholera.

Currently available cholera vaccines achieve a lower efficacy and shorter duration of protection in young children than in adults for reasons that are poorly understood, while such differences in protection are not evident following natural infection. We have recently shown, in a cohort of Bangladeshi children, that younger children given oral cholera vaccine mount lower V. cholerae polysaccharide-specific antibody responses compared to older children and adults.

The objective of this study is:

• To characterize clonal expansions of MAIT cells during human cholera infection and vaccination;
• To determine the mechanisms through which MAIT cells affect B cell maturation.

Generation of MAIT cell clones from the vaccinees and infected persons with cholera may help to understand and use those as therapeutics for control of cholera.

The prevention of cholera has become a high priority in the global community. Immunization with OCV is the most effective means of preventing cholera infection and it’s consequences. The World Health Organization (WHO) has warned of a growing risk of a cholera epidemic at the Rohingya camps in Bangladesh where people are sheltered in dire conditions. The camps do not have safe drinking water and lacked sufficient sanitation and hygiene; filthy water and faeces flowed openly through the camps. Risk of waterborne diseases is very high, especially there is increasing the risk of cholera in these camp. Over a million Forcibly Displaced Myanmar Nationals (FDMNs) have been residing in different camps of Ukhia and Teknaf, the two upazilla of Cox’s Bazar. Around the camps, the Bangladeshi host population are also living in close proximity to the FDMNs. The risk of cholera and other diarrhoeal diseases are similarly present for the host community and the fragile population. Moreover, according to WHO, a total number of 782 cases with 11 deaths have been reported in 2016 from Myanmer when the case fatality rate was 1.4%. Interventions like vaccination are being scaled-up as the situation remains critical and challenging. In addition, an impact evaluation of the effectiveness of the mass OCV campaigns carried out between October 2017 to December 2018 is ongoing. This has been carried out in 13 sites in Teknaf (n=2) and Ukhia (n=11). But information related to cholera burden among the FDMNs and host community is necessary to detect epidemics and outbreaks which will leverage cholera containment through vaccination and WASH activities. The objective of this study to carry out cholera surveillance at selected health facilities in Ukhiya and Teknaf Upazila, Cox’sbazar to gather information regarding cholera burden among fragile population (FDMN) and host community.

The icddr,b and IVI have collaborated on multiple research projects addressing the epidemiology of vaccines for cholera. This is in addition to each institution`s individual work on cholera and typhoid fever. To date, papers with significant global health impact been published on these studies, yet, the papers are relatively few in number in relation to the size and richness of the data available from the studies. Computerized datasets from these projects have been cleaned, archived, and documented, and are available for analyses. These datasets thus constitute an important resource for further analyses and publications addressing critical issues related to control of cholera and typhoid by both vaccine and non-vaccine (WASH) measures.

The purpose of this proposal is to:

• To answer scientific questions and publish manuscripts in the international scientific journals using existing computerized and curetted datasets for analyses of the epidemiology of cholera and typhoid, as well as the effectiveness of vaccine and WASH control measures for the control of these disease.
• To form a working group consisting of both senior and junior scientists from each institution, together with selected experts from outside the institutions, to exploit the untapped existing computerized and curetted datasets.

We will achieve the objectives by forming working groups consisting of senior and junior scientists together with a steering committee composed of selected experts from outside the institutions, to analyze the existing datasets and to submit manuscripts based on these analyses for publication in the international scientific literature. We will also present the findings at international scientific meetings and forums. In addition, after completion of the proposal in the 2 year period targeted for the study, the results will be shared with Institute for Health Metrics and Evaluation (IHME), as necessary, to strengthen the cholera and typhoid fever disease burden data.

The vaccine effectiveness will be measured by comparing the ratio of odds of vaccination in the cholera positive patients and odds of vaccination in the cholera negative patients.

To prevent cholera epidemics and empower local public health service for sustainable cholera and other vaccine-preventable disease surveillance and control.The MOCA project was conducted in Cuamba Municipality District where cholera is found to be endemic and period outbreaks occur including the recent cholera epidemic in 2015.

Strengthened local capacity for cholera/diarrheal surveillance and laboratory diagnosis.

Prevention of cholera infection in vulnerable populations in Mozambique. Generation of data on the occurrence of cholera and other vaccine-preventable non-cholera diarrheal infections. Capacity-building of African scientists in the field of public health research collaborations particularly on diarrheal disease and cholera surveillance activities.

The objective of this study is to test the safety and immunogenicity of HaitiV – a novel live-attenuated cholera vaccine. Pre-clinical data suggest that HaitiV can provide rapid (within a day), single-dose, long-lived protection from cholera. The key goals of the study are 1) creation of a GMP lot of HaitiV for use in human studies and development and approval of an investigator sponsored Investigational New Drug application to conduct a first-inhuman Phase I trial of HaitiV; 2) determination of the maximum tolerated dose and safety profile of HaitiV; and 3) identification of the most immunogenic HaitiV dose. These studies will provide the pivotal data required for future development of this vaccine, including human challenge studies and field trials in cholera endemic regions.

Cholera remains an important challenge to global public health. Killed cholera vaccines have shown promise as tools for cholera control, but these vaccines have limitations, including minimal activity in children and delay in eliciting protection. In contrast to killed cholera vaccines, HaitiV, our novel highly engineered live-attenuated cholera vaccine, leverages the unusual capacity of the cholera pathogen to replicate in and colonize the human small intestine. Our pre-clinical studies in animal models have shown that administration of this live vaccine confers rapid protection to animals prior to engendering protective immune responses to a range of Vibrio cholerae antigens. Such rapid protection could have major impact on reactive cholera vaccine campaigns, curtailing epidemic spread. The vaccine also has great promise to provide single-dose long-lived protection in children as well as adults. Thus, completion of the proposed first-in-human trial of HaitiV could propel the development of a transformative new tool for global cholera control.

This study will yield critical data about a new agent for cholera control.

Background

Globally, the risk of small-scale cholera outbreaks propagating rapidly and enlarging extensively remains substantial. As opposed to relying on mass, community-wide approaches, cholera control strategies could focus on proactively containing the first clusters. Case-area targeted interventions (CATI) are based on the premise that early cluster detection can trigger a rapid, localised response in the high-risk radius around one or several households to reduce transmission sufficiently to extinguish the outbreak or reduce its spread. Current evidence supports a high-risk spatiotemporal zone of 100 to 250 meters around case-households for 7 days.

We hypothesize that the prompt application of CATI will reduce household transmission and transmission in the wider ring. This will result in reduced incidence in the ring and reduced clustering of cases. The local focus of CATI will enable active case-finding and sustained uptake of interventions. This will result in prompt access to care for detected cases, and reduced mortality and community transmission.

Methods

We propose to evaluate the effectiveness of a CATI strategy using an observational study design during an acute cholera epidemic, with clearly-defined measures of the effectiveness of the CATI package. In addition, we intend to evaluate the feasibility, costs, and process of implementing this approach. The CATI package delivered by Médecins Sans Frontières’ (MSF) will incorporate key transmission-reducing interventions (including household-level water, sanitation, and hygiene measures, active case-finding, antibiotic chemoprophylaxis, and, single-dose oral cholera vaccination (OCV)) which aim to rapidly reduce the risk of infection in the household and in the ring around the primary case household. MSF will decide on the contents of the CATI package used, the radius of intervention and the prioritization strategy used if the caseload is higher than the operational capacity, based on national policies, the local context, and operational considerations. In scenarios where preventative vaccination has been recently conducted or is planned, CATI and its evaluation will focus on implementation before and during the mass campaign, or in areas where vaccination coverage was sub-optimal.

The study design is based on comparing the effects of CATIs that rapidly provide protection in averting later generations of cases when compared with progressively-delayed CATIs. A regression analysis will be used to model the observed incidence of enriched RDT-positive cholera as a function of the delay to intervention (in days). The delay will reflect the inverse strength of rapid response. Groups, as a function of their delays to intervention, will serve as internal controls.

Case-area targeted interventions (CATI) are based on the premise that early cluster detection can trigger a rapid, localised response in the high-risk radius around one or several households to reduce transmission sufficiently to extinguish the outbreak or reduce its spread.

We propose to evaluate the effectiveness of a CATI strategy using an observational study design during an acute cholera epidemic, with clearly-defined measures of the effectiveness of the CATI package. In addition, we intend to evaluate the feasibility, costs, and process of implementing this approach. The CATI package delivered by Médecins Sans Frontières’ (MSF) will incorporate key transmission-reducing interventions (including household-level water, sanitation, and hygiene measures, active case-finding, antibiotic chemoprophylaxis, and, single-dose oral cholera vaccination (OCV) ) which aim to rapidly reduce the risk of infection in the household and in the ring around the primary case household.

CATI has been highlighted as a major component of the GTFCC’s global research agenda. Therefore, conducting a rigorous prospective evaluation of the effectiveness of CATI, which includes OCV and explains the pathway to impact, is an important and timely question for outbreak control.

Cholera outbreaks caused by Vibrio cholerae are endemic in Kenya and the East Africa region accounting for nearly 10% of all cases reported from sub-Saharan Africa and the case-fatality rates remain above 2.5%, which is unacceptably high. Cholera is spread through consumption of fecally contaminated water or food. Investigating the relationship between cholera occurrence in terms of dominant hotspots and various environmental and human factors associated with the hotspots is important for managing cases and preventing future outbreaks. Whereas WASH interventions have been recommended by various studies as a control strategy for Cholera, the critical intervention pathways that have the most significant public health impact are not known.

The current research aims to study hotspots identified from previous outbreaks and from ongoing outbreaks in Kenya using drone technology to map areas for immediate sampling, exposure risks and most critical transmission pathways surveillance. Using SANIPATH techniques in identifying critical environmental and human factors associated with hotspots, we are deploying novel techniques including Whole Genome Sequencing (WGS) and bioinformatics partnering with relevant governmental agencies that will deploy our rapid detection and tracking techniques of these hotspots in a bid to innovatively establish preventive measures for infection emergence and spread. Data analysis will be done using basic descriptive statistics (percentages, means, standard deviations, modes) and the latest version of SAS software suite (SAS Institute Inc.) Ethical approval has been sought from Scientific Ethics Review Unit (SERU) in Kenya Medical Research Institute

Cholera is a disease caused and spread by germs that you get by eating or drinking contaminated food or water.

We are investigating areas in Mukuru slums that may harbor high concentration of these germs, e.g. sewers, open drainages, homesteads and water supply chains etc. We are using satellite imaging technologies to map areas of high risk for cholera, then get samples to investigate presence of these germs in the lab at KEMRI. This will help manage those with the disease as well as prevent future occurrence of the disease.

Work with local governments and communities to make evidence-based intervention decisions and co-design and implement WASH and/or OCV campaigns as appropriate for the local context; and

Build capacity in regional academic institutions and health ministries for applied public health research to strengthen cholera prevention and control programs.

Diarrheal diseases are one of the most common causes of morbidity and mortality in the world today. It is estimated that a child dies of diarrhea approximately every 15-30 seconds; almost all of these deaths occur in the developing world. One of the, causative organisms, Vibrio cholerae, causes severe secretory diarrhea in humans. A prototypical mucosal infection, V. cholerae does not invade the intestinal epithelium and serves as an excellent model for the study of mucosal immunity and vaccination. The study focuses on defining the mechanisms of protective immunity to infection with V. cholerae so as to understand the requisites for the development of a protective cholera vaccine.

The central hypothesis of this proposal is that V. cholerae expresses specific proteins during early human infection, which generate immune responses that are protective on subsequent exposure; that these proteins may not be adequately expressed during colonization with currently available vaccine strains, and that these differences may explain the generally lessened efficacy of current vaccine approaches. As a result of this study, we hope to assess immune responses following cholera vaccination with the killed oral vaccines (Dukoral and/or Shanchol), and compare with responses to those seen following natural cholera. In order, to assess the duration of immunity to known cholera virulence factors, we will determine antigen-specific memory B cells circulating in human blood, to examine the longevity of B cell immunologic memory. To determine the mucosal immune responses, we will follow the immune responses using duodenal biopsies from patients recovered from cholera and correlate the duration of antigen-specific, antibody-secreting cells over a period of one year.

In addition to cholera patients, we will also study household contacts to assess innate and acquired immune responses early after exposure in household contacts of cholera patients, to determine correlates of subsequent protective immunity to cholera. The study planned is a continuation of investigations of immune responses in cholera (Pr#2005-030).

Yes, that impact the development of immune responses following cholera or that influence the development of clinical illness following exposure to the organism.

Burden

Cholera is life threatening disease that remains one of the major causes of deaths in the developing countries. Although more than 200 serogroups of V. cholerae reported so far, serogroup O1 and O139 are the major pathogenic strains. Serogroup O1 has two biotypes, classical and El Tor. The classical biotype caused first six cholera pandemics in the Ganges Delta of Bay of Bengal and the other parts of the world. The El Tor biotype of V. cholerae initiated the ongoing 7th pandemic in early 1960s. The El Tor biotype was displaced for a short while in late 1992 when an explosive cholera epidemic occurred by V. cholerae O139 synonym Bengal. O139 however, failed to continue as the predominant epidemic strain and thus V. cholerae El Tor continued to cause the ongoing 7th pandemic.

Knowledge gap

A retrospective study on V. cholerae strains isolated between 1991 and 1997 showed that the biotypes Classical, El Tor, and El Tor variants were involved in endemic cholera in Mexico and ET prototype (wild type) were involved in Peru. We are not aware about the present status of cholera bacteria in different parts of Latin America so; a follow-up study on V. cholerae isolated from 1998 to 2012 was designed.

Hypothesis

The V. cholerae strains causing endemic cholera between 1998 and 2012 in Mexico and other countries of Latin America might not be different in terms of biotype, phenotype, molecular, and phylogenetic properties compared with Asia and Africa.

Objectives

The aim of this study is to determine the prevalent sero-biotypes, molecular status and clonal nature of V. cholerae isolated in Mexico and other Latin American countries and compare those characteristics with the strains isolated from Gangetic Bengal and Africa.

Methods

150 V. cholerae strains (both clinical and environmental) which included 89 strains isolated in Mexico, 45 in Peru, 12 in Brazil, and 6 in Guatemala will be analyzed by culture method, serogrouping and antibiogram. V. cholerae strains will also be subjected to detection of marker genes such as ompW, wbeO1, wbfO139, ctxA and ctxB by PCR. Extensive molecular characterizations using multi-locus genome screening and DNA fingerprinting (phylogeny) by PFGE will also be done.

Outcome measures/variables

This study will generate valuable information on nature (clonal types) of cholera bacteria, their transmission patterns world-wide. This is important because updated information on phenotypic, molecular, and phylogenetic characteristics of V. cholerae associated with cholera in Mexico and other Latin American countries are lacking.

The V. cholerae strains causing endemic cholera between 1998 and 2012 in Mexico and other countries of Latin America might not be different in terms of biotype, phenotype, molecular, and phylogenetic properties compared with Asia and Africa.

This project focuses on defining O-specific polysaccharide (OSP) responses during cholera and development of vaccines protective against cholera and enteric infection.

Immune responses that mediate protection against cholera target the sugar (OSP) that coats the bacteria that causes cholera. Young children in particular do not develop high level or durable immune responses against this sugar after oral cholera vaccination. Understanding and improving these responses will be critical in development of next generation cholera vaccines that can protect young children against cholera, and that can be incorporated in EPI schedules.

Informs development of next generation cholera vaccines for use in children under 5 years of age.

Cholera is a major source of under 5 yrs. mortality globally; the existing oral vaccine is not effective for this age group. A Cholera Conjugate Vaccine (CCV) is under development with partnership between MGH Harvard (USA), Eubiologics & IVI (latter two in Korea) to address this need; it has the O-specific Polysaccharide antigen from Vibrio cholerae O1 Inaba El Tor strain conjugated to a recombinant tetanus toxoid heavy chain fragment (rTTHc) using a novel conjugation chemistry.

The study Drug Product materials are produced under a separate RIGHT Fund grant, using Drug Substance (DS; OSP–rTT-Hc Conjugate) produced through an optimized, scaled-up process at Eubiologics for use in preclinical animal toxicology study before its human clinical trial.

The proposal will help to complete (a) the toxicology study; (b) formulation of two additional DP batches for generating stability data; and (c) to complete an IND application for CCV’s phase 1 clinical trial.

Cholera is a disease of inequity that continues to disproportionately affect the world’s poorest and most vulnerable people. An oral cholera vaccine (OCV) is available and in use around the world, but it has lower efficacy in young children than in adults and a relatively short duration of protection necessitating re-vaccination every few years. We are developing a new conjugate vaccine that offers the promise of improved efficacy in all age groups, including those less than 5 years, and an extended duration of protection, thus reducing the requirements for repetitive vaccination to sustain population immunity. It can be implemented in place of OCV or as a complementary tool to prevent or limit outbreaks in high risk settings, and build enduring population immunity that will cost-effectively control cholera over the decades required to build definitive public health capacities in at risk countries.

Data from this project will enable the filing of an investigational new drug application to conduct a phase 1 trial of the CCV.

Our goal is to identify the best strategies to control the ongoing cholera outbreaks in the Republic of Yemen (ROY). To do so, we will evaluate previous interventions to inform and improve their implementation currently and in the future. These include use of oral cholera vaccines (OCV), water sanitation and hygiene (WaSH) strategies and acute watery diarrhea (AWD)/cholera-related messaging strategies.

Understand what interventions worked and what did not work to prevent cholera in Yemen. Also, recommend interventions that are possible.

Our findings of what works and why (or what did not work and why) will help guide policy and decision makers understand the factors impacting the success and challenges of the cholera integrated response plan intervention strategies for scale up programs. Consequently, we would have identified the optimal combination of interventions for AWD/cholera affected districts in ROY

There are currently two WHO pre-qualified oral cholera vaccines in the Gavi supported stockpile and available to eligible countries for emergency or routine preventive use. Both derive from the same basic technology and contain five antigenic components. This project seeks to simplify the formulation of the oral cholera vaccine to reduce the number of components and simplify the production. Guided by input from experts in cholera, vaccine developers and regulators, a simplified formulation will be produced and evaluated in a phase III, multicenter, observer-blinded, randomized, active controlled trial to determine immune non-inferiority, safety and lot-to-lot consistency of Oral Cholera Vaccine-Simplified (OCV-S) compared to ShancholTM in 1 to 40 year old healthy Nepalese participants. If successful, the simplified formulation will reduce product unit cost and expand production capability of manufacturers.

Oral Cholera vaccine is currently in high demand with limited supply. If successful, this formulation simplification will reduce unit cost and expand supply availability of all current manufacturers using this technology.

Introduction: Adamawa and Bauchi are cholera endemic states in the north-east region of Nigeria, each with local government areas classified as cholera hotspots. Ineffective implementation of multi-sectoral cholera interventions in both states could make obtaining the global target for cholera control in Nigeria out of reach. A major contributing factor to this challenge is fragility of the region due to persistent Boko Haram insurgency activities, often characterised by the destruction of health infrastruture and displacement of communities to areas with suboptimal living conditions. Given the complexity of disease control in such a fragile setting, this study aims to systematically examine the barriers and/or facilitators influencing the implementation of existing cholera interventions in these states.

Methods: The study will use a systems dynamic approach. First, we will conduct a health facility survey to determine the current health system capacity to support multi-sectoral cholera interventions, and conduct key informant interviews with purposely selected state and national cholera stakeholders to identify the context-specific facilitators and barriers to the implementation of cholera interventions in these states. We will then conduct nine group model building workshops (four in both the Adamawa and Bauchi states and one in Abuja) among cholera stakeholders similar to those recruited for the interviews.

Conclusion: By engaging diverse and relevant cholera stakeholders, including community members, this study has the potential to provide a rich understanding of context-specific factors influencing the implementation of multi-sectoral cholera interventions in a fragile region of Nigeria, with a view to achieve sustainable progress towards cholera control in the country.

Adamawa and Bauchi states are cholera endemic states in the north-east region of Nigeria, each with some local government areas classified as cholera hotspots or high burden areas. However, the prevailing activities of armed conflict, as perpetuated by Boko-Haram, in the region could make the implementation of multi-sectoral cholera interventions ineffective. Moreover, addressing disease burden in such fragile settings is particularly challenging. Thus, this study aims to systematically examine the barriers and/or facilitators influencing the implementation of existing cholera interventions in these states.

To achieve these objectives, the study will use a systems dynamic approach, by first conducting a health facility survey to determine the current health system capacity to support multi-sectoral cholera interventions, as well as conducting key informant interviews with purposely selected cholera stakeholders at various levels of government. These research activities will then be followed by a series of participatory workshops (four in both Adamawa and Bauchi states and one in Abuja) among participants with similar characteristics as those in the key informant interviews. It is worth noting that findings from the first phase of the study will be informing the workshop activities.

Overall, by engaging diverse and relevant cholera stakeholders, including community members, this study has the potential to provide a rich understanding of context-specific factors influencing the implementation of multi-sectoral cholera interventions in a fragile region of Nigeria, with a view to achieve sustainable progress towards cholera control in the country.

Nationally, the study would be providing context-specific findings, generated in collaboration with various cholera stakeholders including policymakers and community representatives. Globally, the study is designed around the GTFCC’s global strategic framework, thereby making the potential findings of direct relevance to cholera global stakeholders.

This project will compare the vibriocidal titers in subjects who receive a second dose of oral cholera vaccine (Shanchol), two weeks, 6 months or 11.5 months after the first dose. The primary outcome is the geometric mean vibriocidal titer two weeks after the second dose. Additional follow-up serum samples will determine the persistence of the vibriocidal titers.

This will provide guidance when the second dose of OCV is delayed.

This project will evaluate the vibriocidal responses following receipt of oral cholera vaccine (Shanchol) when the second dose is given either 2 weeks or 6 months following the first dose. The primary outcome is the change in geometric mean vibriocidal titers two weeks after the second dose, but additional serum samples will be obtained to determine longevity of the increased titers.

Assurance of a non-inferior vibriocidal response when the second dose of OCV is delayed will provide guidance for timing of the second dose.