Research Projects : Export

Objective

Evaluate the effectiveness of the Case Area Targeted Intervention (CATI) approach in reducing the incidence of new cases during cholera outbreaks.  And in so doing, to determine factors that support optimal delivery and interventions for CATIs towards cholera reduction in humanitarian settings and fragile states.

Aim

The primary aim is to characterize the relationship between CATI activation time (time between case presentation at a cholera treatment facility and the start of the CATI intervention) and cholera incidence in the area covered by CATI interventions. Secondary aims include:

• Document procedures of implementing CATIs and develop recommendations to maximize their impact in future cholera outbreaks.
• Describe the integration of water, sanitation, and hygiene (WASH) and health activities delivered via CATI.
• Characterize the relationship between CATI completeness (in terms of coverage within the specified geographic area and activities implemented within households) and incidence of new cholera cases.
• Estimate CATI effectiveness using secondary parameters (e.g. reported diarrheal incidence, free chlorine residual (FCR) in the drinking water sample, and knowledge and practices to prevent cholera transmission).
• Document coordination mechanisms between Ministries, United Nations (UN) agencies, Clusters, and non-governmental organizations (NGOs) and develop recommendations for coordination in future responses.

Study Design

The proposed research will be conducted in future cholera outbreaks that take place in recognized humanitarian contexts in at least two different countries; locations will be selected based on where cholera outbreaks occur and the presence of a CATI implementing partner.  Organizations that frequently implement CATI interventions during cholera response that have agreed to partner with JHSPH include Action Against Hunger, Solidarités International, and Medair. Countries with humanitarian emergencies that are at high risk of cholera outbreaks include Democratic Republic of the Congo, Nigeria, Ethiopia, Mozambique and Yemen, though it is possible that other humanitarian contexts may serve as a research location if a cholera outbreak occurs and one of the aforementioned implementing partners responds with a CATI intervention.

The JHSPH IRB approval has classified this study as Non-Human Subjects Research.   Government or IRB approval will be attained prior to conducting the research.

The research team will be present at the site as soon as possible after the first cholera case has been documented and begin data collection as soon as feasible. If travel to the study location is not feasible for security reasons, the JHSPH research team will conduct the study remotely through the partner organization that is providing on-the-ground CATI response to the cholera outbreak.

Because the aim of the research is to evaluate CATIs as delivered by NGOs in response to a cholera outbreak, a randomized design is not possible. Thus, we will rely on comparison groups that will occur naturally, according to the outbreak size and capacity of the response organization. This will necessitate a flexible sampling approach.

We anticipate the primary comparison will be rapid vs. delayed CATI implementation (e.g. end stage of outbreak); however, it is also possible that areas with no CATI implementation could be used as a comparison group [in outbreaks where there is insufficient capacity to respond to all cases].  Additional points of comparison may include the delay between case presentation and CATI implementation:  e.g. CATI implemented within 24h, in 2 days, in 3 days, in 4 days, etc.

The proposed research is an observational study of cholera interventions implemented by NGOs in response to cholera outbreaks (i.e. no intervention is proposed).  The study will include the following components:

• Observation of CATI delivery
• Key informant interviews: 1) NGO staff members delivering the CATI intervention to characterize perceived strengths and weakness of the intervention, household selection, logistical processes and implementation challenges; 2) Humanitarian response managers from the partner NGO, UN agencies, national governments and other organizations engaged in the cholera response to ascertain perceptions of the response, coordination and CATI delivery and implementation
• Cholera treatment facility line lists: Information from cholera line lists is used to plan CATI interventions, where each individual on the line list (i.e. a cholera case) receives a household visit from a CATI team. The JHSPH study team will request line lists from health facilities [which may be augmented by the study team] to evaluate coverage of CATI interventions.
• Follow up survey: The household follow up survey will be conducted approximately 14 days after the presentation of the suspected cholera case at a cholera treatment facility. The exact sampling approach will depend on the density of housing in the community and the CATI implementation strategy. Household surveys will enquire about receipt of the CATI intervention, household composition, incidence of diarrhea and diarrhea care seeking among household members in the period since CATI implementation (or case presentation if there was no CATI), knowledge and practices of hygiene behaviors and observation of free chlorine level (FCR) in stored drinking water.

Cholera continues to pose a major global public health threat and is a marker of inequality and poverty as it reflects the lack of access to basic water and sanitation infrastructures. The risk of the spread of cholera is particularly high in humanitarian settings and fragile contexts.

Cholera transmission risk is higher for cholera case household members and nearby households. Mass interventions to contain cholera outbreaks are not resource efficient.  Preventive interventions targeting cholera case-households and neighbors have been found effective in past outbreaks. These interventions are often referred to as case area targeted interventions (CATIs). CATIs predominantly include water, sanitation, and hygiene (WASH) activities but can also include epidemiological surveillance, and health (clinical) services, primarily oral vaccination and antibiotic chemoprophylaxis.

There are limited studies on the best practices and effectiveness of CATIs in humanitarian settings.   This study aims to identify those factors that support optimal delivery and interventions of these CATIs for cholera reduction in humanitarian settings and fragile states.  The study design centers around observing the CATI activities of partner organizations as they respond to a cholera outbreaks in known humanitarian or fragile settings.

There is limited evidence studying the mechanisms, composition, interventions, timing, effectiveness of CATIs in humanitarian settings. This proposed research for CATI in humanitarian settings will focus on variations in CATI implementation and timing, monitoring and evaluation, and coordination and integration with the aim of expanding available evidence that can be used to inform the development of operational guidance for CATI interventions in cholera response.

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.

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.

Burden

Cholera, caused by V. cholerae, is a killer disease. In Bangladesh, cholera occurs endemically at defined seasons resulting significant morbidity and mortality each year. V. cholerae is a native flora of the estuarine aquatic environment. The bacterium existing in the environment is found mostly in a dormant, non-cultivable state; and can regain active state and flourish to initiate the seasonal epidemics of cholera. Although seasonal cholera is driven by natural climate factors, the disease takes the turn of epidemic through rapid transmission of infectious V. cholerae via fecal-oral mode as marginal people relies on contaminated surface water for drinking and other domestic purposes.

Knowledge gap

We want to understand V. cholerae growth response, particularly what triggers the bacterium to be active from dormant non-culturable state, and if locally available no-cost items such as ashes could kill the infectious bacterium shed in stool to decontaminate the environment; the aim is to develop a sustainable method to prevent cholera transmission.

Relevance

This study will generate knowledge on V. cholerae growth responses, and no-cost method of stool decontamination, and the aim is prevent cholera transmission.

Hypothesis

• Climatic and human factors contribute to active growth of V. cholerae responsible for seasonal cholera to prevent cholera transmission
• Wood ashes might provide a sustainable method of stool decontamination to prevent V. cholerae transmission

Objectives

• Study the environmental and human factors activating naturally occurring non-cuturable V. cholerae that initiates seasonal cholera
• Test efficacy of wood ashes in decontaminating V. cholerae shed in stools to reduce cholera transmission

Methods

Water samples will be collected from four Mathbaria sites, and temperature, turbidity, pH, salinity, total dissolved solids and conductivity of water monitored bi-weekly during March-May and September-November and monthly for the rest of the year. Toxigenic V. cholerae will be isolated (Alam et al. 2006a) and characterized in terms of virulence adaptive polymorphisms (VAPs) and molecular fingerprinting. Also, laboratory microcosms will be constructed with two toxigenic V. cholerae to test growth response of the bacterium, and the role of cyanobacteria (Islam et al., 1990a; Islam et al., 1990b) and bile will be monitored at different temperatures, pH, salinity, and conductivity. In this study, efficacy of decontamination of discarded diarrheal stools carrying V. cholerae would be monitored and compared with commercially available disinfectant such as bleaching powder.

Outcome measures/variables

Growth response of V. cholerae to different climate factors, and the role of cyanobacteria and bile in microcosms would be an outcome to measure. V. cholerae burden in cholera stool at different concentrations and time of treatment with wood-ashes would also be an outcome measure.

Vibrio cholerae often escapes culturing methods while in a dormant and non-culturable state in the aquatic environment, although they can become actively growing to cause seasonal epidemicsof cholera. We designed this study to unveil the climate and/or natural no-cost substaces that could drive the growth responses of the bacterium to be able to aid diseases prevention in endemic settings.

Vibrio cholerae is an aquatic bacterium which passes the interepidemic period in a dormant and non-culturable state. The well-defined climate or natural factors driving the growth responses of the bacterium could aid in diseases prevention in endemic settings.

Burden

Cholera is a deadly disease with approximately 3-5 million cases and over 1,00,000 deaths annually worldwide. Of the 1.3 billion people at risk worldwide, 66 million are in Bangladesh equating to approximately 40% of the Bangladeshi population. In addition, refugee movement bring increased risk from this disease. Bangladesh is one of the Least Developed Countries list of ODA recipients and together with India has the largest population at risk of Cholera. Rapid diagnosis and early detection of outbreaks are key aspects to fight cholera. Moreover, the indiscriminate use of wide-spectrum antibiotics creates the additional threat of antibacterial resistance (ABR) in V. cholerae population.

Knowledge gap

Microbiological testing is resource-intensive, and outbreak detection is mostly based on unreliable reports of cholera-like diarrhoea cases from local hospitals. Advances in diagnostics, treatment selection and outbreak tracking are much-needed for progressing towards eliminating cholera as a public health threat by 2030, a recently proclaimed objective by the WHO-backed Global Taskforce for Cholera Control.

Relevance

The aggregation of geo-localised clinical, environmental, and societal information collected for the development of the diagnostic and early prediction systems, and the additional data continuously collected during the deployment and operation of such systems, will constitute an invaluable databank shareable across follow-on and collaborative projects and eventually across countries.

Hypothesis

Significant changes in understanding transmission dynamics of antimicrobial resistant V. cholerae in Bangladesh by big data mining and machine learning with better local community decision making to improve diagnosis and treatment of cholera.

Objectives

The specific objectives of this project are as follows:

• Develop a portable, real-time diagnostics solution for cholera infection caused by antimicrobial resistant V. cholerae
• Develop a surveillance system to identify hot spots with higher likelihood of outbreak
• Development of a shareable databank

Methods

Samples will be collected from Dhaka Hospital, Mathbaria Thana Health Complex, Cox’s Bazar Hospital and Rohingya camp. Immediate after collection, samples will be subjected to RDT. If the sample is positive for either V. cholerae O1 or O139 then one aliquot will be stored at -80°C freezer at icddr,b for future use and another aliquot will be transferred to NSU, Bangladesh for further analysis (Alam et al. 2006a). Water samples will also be collected from 6 sites each, for Dhaka city, Mathbaria, and Cox’s Bazar. Toxigenic V. cholerae will be isolated from stool and water samples following standard culture methods, and characterized for antibiotic resistance (Alam et al. 2006b, c). Both types of samples will be subjected to Nanopore genome sequencing.

Outcome measures/variables

Through the collaboration this proposal brings expertise together to work on public health. This will enable a much-needed multidisciplinary research programme to diagnose cholera using Nanopore genome sequencing, treatment selection, epidemiological forecasting for infection and antibacterial resistance, ultimately contributing to improving health, welfare and economic growth of Bangladesh.

Data mining and machine learning appear to offer better resolution for improving accuracy of diagnosis of a pathogen. The portable real-time nannopore sequencing device could provide diagnostic solution at field level. We designed this big data mining and machine learning study to improve diagnostics and treatment selection for cholera infection caused by antimicrobial resistant V. cholerae.

A portable real-time diagnostics solution for cholera infection caused by antimicrobial resistant V. cholerae with big data mining and machine learning to improve diagnostics and treatment selection.

Cholera is an acute watery diarrhoeal disease that can lead to severe dehydration and death in less than 16 hours. It is an important public health problem in Asia, Africa and Latin America. Globally 1.3-4 million cases and 21,000-143,000 deaths occur annually due to cholera1. Accurate diagnosis of cholera early in an epidemic is critical to reduce morbidity and mortality. Rapid diagnostic tests (RDTs) have the potential to provide immediate objective findings early in outbreaks in settings that lack conventional microbiology laboratories. Several lateral flow immunoassay-based RDTs are commercially available and target V. cholerae O1 and/or O139 specific antigens. However, the RDT performance metrics are unpredictable for unknown reasons which has resulted in limited adoption. We are specifically interested in the widely used RDT sold under the name of Crystal VC (Span Diagnostics, India) that was developed by the Institute Pasteur.

While limitations with current RDTs may include production and operator problems, there are multiple biologic reasons why the RDT may fail when deployed in field settings. One explanation is that the concentration of Vibrio cholerae may fall below the limit of detection when the bacteria are preyed upon by viruses called lytic vibriophages. This predation is dynamic to the ratio of predator / prey. We have shown that vibriophage (ICP1) negatively impacts the RDT (see preliminary data section).

Our primary research question is if the incorporation of antibodies that detect both V. cholerae and lytic vibriophage into a Rapid Diagnostic Test (RDT) will address limitations in the current RDTs used when cholera patients harbor lytic vibriophage. This novel RDT may represent a model for diagnostic tool development for enteric and nonenteric infectious diseases. To develop this RDT and answer this question we propose the following specific aims:

Aim 1

Identify lytic vibriophage structural and non-structural proteins that are antigenically unique in diarrheal stool. We hypothesize that lytic vibriophage express structural and non-structural proteins that are antigenically unique. These proteins can be used to generate a monoclonal antibodies (mAb) that can then be incorporated into an improved RDT. We will take two approaches to identify unique immunogenic vibriophage proteins with specific focus on ICP1 because it has been shown to be most common in multiple locations.
1.1 Reverse vaccinology by genomic analysis, cloning, expression, and testing immunogenicity
1.2 Proteomic analysis of immunogenic proteins separated by 2-D gel electrophoresis and MALDI-TOF

Aim 2

Produce monoclonal antibodies (mAbs) against unique lytic vibriophage protein. The vibriophage proteins identified in Aim 1 will be used to raise mAbs using both hybridoma and in vivo ascites techniques.
2.1 Immunize animal model with vibriophage proteins and screen for antibody producing hybridoma clones
2.2 Propagate selected hybridoma cells in vivo using ascites method for mAb production and affinity purification

Aim 3

Produce, test and select candidate RDTs by highest performance metrics. The monoclonal antibodies produced by hybridoma technology will be used to develop an immune-assay based lateral flow test; this test will include the existing (or equivalent) commercial mAb for V. cholerae O1 LPS. Several RDTs with different mAb candidates will be evaluated.
3.1 Conjugate colloidal gold to mAb and assemble the lateral flow strip
3.2 Evaluate the performance of the RDTs against commercially available RDTs with a clinical sample library

It is likely that rapid diagnostic tests (RDTs) for cholera intermittently fail because lytic vibriophage destroy the Vibrio cholerae target. In this proposal, we are adding an antibody to the lytic vibriophage (ICP1) to the RDT. The goal is that detection of the vibriophage can serve as a proxy for Vibrio cholerae, and therefore, increase sensitivity of the RDT when vibriophage are present.

This revised RDT will address sensitivity concerns and intermittent performance of current RDTs when lytic vibriophage are present. This new RDT will not address limitations when antibiotics are present, and therefore patient reports on antibiotic consumption need to be consider when evaluating RDT results, even with the new RDT.

For over ten years, we have sought how best to develop decision-support tools for clinicians treating diarrhoeal disease. This is important because of a need to rapidly train large numbers of providers during cholera outbreaks, rapidly re-educate when guidelines change, address inappropriate antibiotic use, and allow for differences in epidemiology by season and place. We have built tools in both paper and digital formats, and evaluated their impact in clinical trials. Now, we are collaboratively building digital tools that depend on models developed through machine learning. In a large international collaboration, we have built and evaluated improved algorithms to assess dehydration for children and adults (project led by A. Levine at Brown University) and provide a probability that a patient has only a viral disease based on real-time weather, clinical and epidemiologic data (project led by D. Leung at Utah University). In addition to helping to improve cholera response, these tools represent a significant shift in how clinical decision-support might be in 10 years.

The impact of this research is to first improve rehydration and antibiotic guideline adherence. Secondly, the impact is to make possible dynamic decision-support that is responsive to where and when the patient is being treated.

In this project, we are working to complete a systematic review (stratifying cholera WASH evidence by context), and to convene a working group to inform WASH components of National Cholera Control Plan development.

The project aims to inform National Cholera Control Plan Development.

In this project, we:

• analyzed monitoring data collected by partners in Nigeria during cholera;
• completed key informant interviews with people collecting and inputing data;
• suggested improvements to the monitoring tools and Kobo platform.

The project aimed to assist in cholera monitoring in Nigeria.

In this project we:

• conducted three mixed-methods, multi-country evaluations of water trucking in humanitarian responses;
• developed methods, and conducted large- and small-scale laboratory studies on how to clean jerricans, containers, and taps (water storage containers) to prevent biofilm development or remove biofilms;
• developed a protocol to determine the most appropriate chlorine tablet for a particular emergency context.

The project provided key information on efficacy, effectiveness, and guidance for bucket chlorination, water trucking, jerrican cleaning, and chlorine tablet selection.

In this project, we evaluated a program where Red Crescent volunteers staffed ORPs locally in conflict-affected areas. It was found volunteers could effectively staff the ORPs, provide ORS to minor cases, and refer moderate/sever cases. However, the mobile phone based monitoring system was not effectively established.

It is recommended to continue using volunteers to staff ORP.

Burden

Diarrhea is the second most leading causes of deaths in children under 5 years of age globally, with an estimated 800,000 deaths annually. On an average, a child in Bangladesh suffers from 3-5 episodes of diarrhea per year. Children suffering from frequent and recurrent diarrhea suffer from food wasting, and the ultimate result is severe malnutrition and growth stunting. Once stunted, its effects typically become permanent, and children may never regain the height lost as a result of stunting. Previous studies have identified lack of caregiver hand washing with soap and treatment of household drinking water, poor water storage practices, and lack of caregivers knowledge about diarrhea prevention as important risk factors for diarrheal disease in paediatric populations. Water, sanitation, and hygiene (WASH) interventions promoting household chlorination of drinking water and hand washing with soap have the potential to reduce diarrheal disease incidence in children less than five years of age an estimated 30 to 40%. Furthermore, Community Based WASH interventions are expensive and often difficult to implement in an urban context in low resource settings. Our team has recently developed a Hospital Based WASH intervention which is entitled CHoBI7 (Cholera Hospital-Based Intervention for 7 days). The CHoBI7 intervention was initially designed to reduce cholera infection among family members of hospitalized cholera cases during the one week high risk period after the case presents at the hospital. This low cost Hospital Based WASH intervention resulted in a significant reduction in the incidence of symptomatic cholera, and a 47% percent reduction in the incidence of cholera infection among household members of hospitalized cholera cases. Furthermore, we observed sustained uptake of the promoted hand washing with soap and water treatment behaviours among intervention households 6 to 12 months after the intervention was delivered.

Knowledge gap

Despite successful intervention in our just concluded hospital based study we still do not understand if all the procedures involved can be integrated into the services provided for hospitalized diarrhea patients at health facilities of Bangladesh and the promoted hand washing with soap and water and water treatment behaviour would be a long lasting practice in the community.

Hypothesis

Based on what we have learned from our just concluded Hospital Based WASH intervention study entitled “Cholera Hospital-Based Intervention for 7 day” (CHoBI7), we hypothesize that developing and evaluating scalable approaches might help this innovative and low cost CHoBI7 intervention to be integrated into the services provided for hospitalized diarrhea patients at the health facilities of Bangladesh. We also hypothesize that evaluating the ability of the CHoBI7 intervention, which could lead to a sustained uptake of the promoted hand washing with soap and water treatment behaviours might reduce the burden of diarrheal diseases over time.

Objective 1

To Develop scalable approaches to integrate the CHoBI7 intervention in urban health facilities through formative research and engagement of key stakeholders.

Objective 3

Investigate the effectiveness of the developed scalable approaches for program delivery of CHoBI7 in terms of: (1) reductions in diarrheal disease prevalence during the 12 months period after the index diarrhea patient in the health facility receives the intervention; and (2) sustained high uptake of hand washing with soap and water treatment practices at 1 week, 1 month, 3 months, 6 months, 9 months, and 12 months post intervention.

Objective 3

Calculate the cost effectiveness of upscaling the CHoBI7 intervention in terms of cost per Disability Adjusted Life Year (DALY) averted and case and death averted for cholera and moderate to severe diarrhea episodes.

Objective 4

Investigate the feasibility of implementing the proposed low cost approaches for program delivery of CHoBI7 as part of the National Emerging and Re-emerging Diseases Program through identification of potential barriers to successful implementation, and engagement with key government stakeholders.

Objective 5

Disseminate the findings of CHoBI7 intervention implementation and evaluation activities and our recent CHoBI7 efficacy trial at the household, health facility, and national and local government levels through the creation of a website, policy planning workshops with government leaders, development of policy briefs, publishing finding in peer reviewed scientific journals, and presentations at international scientific meetings.

Methods

Diarrheal patients admitted to icddr,b Dhaka Hospital or Mugda General Hospital would be screened and enrolled according to inclusion criteria. Diarrhea patients will be recruited after they received ORS or intravenous rehydration. Household members would be recruited those accompanying the diarrhea patient to the hospital and reside in the home of the enrolled diarrhea patient. Written informed consent would be taken from the patients and their HHC before enrolment. A baseline questionnaire will then be administered to each enrolled diarrhea patient and enrolled accompanying household members (adult and child), stool sample will be collected, and anthropometric measurements will be performed. After the baseline questionnaire is administered to the index diarrhea patient and accompanying household members, they will then be randomized to their respective study arm (Control Arm/Health Facility Based Dissemination Arm / Health Facility Based Dissemination and Home Visits Arm) based on the day they arrive to the hospital. The first arm will receive the standard message given to hospitalized diarrhea patients in health facilities in Bangladesh on the use of oral rehydration solution (ORS) (Control Arm). The second arm will receive the standard message plus Health Facility Based Dissemination of CHoBI 7 (Health Facility Based Dissemination-Only Arm) and bi-weekly (every two weeks) follow-up phone calls or text messaging. The third arm will receive the standard message plus Health Facility Based Dissemination of CHoBI 7 plus two home visits (Health Facility Based Dissemination and Home Visits Arm) and biweekly follow-up phone calls or text messaging. These Randomized Control Trial activities would be 12 Months in duration in each enrolled household. Stool samples would be collected from the HHC on different time period, household drinking water would also be collected and direct observation (5 hr long) would also be performed.

Outcome measures/variables

Develop low cost effective strategies for delivering CHoBI7 in urban health facilities which can be integrated into the National Emerging and Re-emerging Diseases Program.

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

Cholera epidemics occur frequently in low-income countries affected by concurrent humanitarian crises. Evaluations of these epidemic response remains largely unpublished and there is a need to generate evidence on response efforts to inform future programmes. This review of MSF cholera epidemic responses aimed to describe the main characteristics of the cholera epidemics and related responses in these three countries, to identify challenges to the effectiveness and feasibility of different intervention strategies based on available data; and to make recommendations for epidemic prevention and control practice and policy.

Methods

Case studies from the Democratic Republic of Congo, Malawi and Mozambique were purposively selected by MSF for this review due to the documented burden of cholera in each of the countries, frequency of cholera outbreaks, and risk of concurrent humanitarian crises. Data were extracted on the characteristics of the epidemics; time between alert and response; and, the delivery of health and water, sanitation and hygiene (WASH) interventions. A Theory of Change for cholera response programmes was built to assess factors that affected implementation of the responses.

Results and conclusions

A total of 20 epidemic response reports were identified, 15 in DRC, one in Malawi and four in Mozambique. All contexts experienced concurrent humanitarian crises, either armed conflict or natural disasters. Across the three countries, median time between the date of alert and date of the start of the response by MSF was 23 days (IQR 14-41). Almost all responses targeted interventions community-wide, and all responses implemented in-patient treatment of suspected cholera cases in either established HCFs or temporary cholera treatment units (CTUs). In three responses, interventions were delivered as case-area targeted interventions (CATI) and four responses targeted households of admitted suspected cholera cases. CATI or delivery of interventions to households of admitted suspected cases occurred from 2017 onwards only. Overall, 74 factors affecting implementation were identified across reports including delayed supplies of materials, insufficient quantities of materials were delivered for effective programme delivery and limited or lack of coordination with local government or other agencies. Based on this review, the following recommendations are made to improve cholera prevention and control efforts: conduct rigorous and structured evaluations of cholera response programmes; explore improved models for epidemic preparedness, including rapid mobilisation of supplies and deployment of trained staff; invest in and strengthen partnerships with national and local government and other agencies as part of epidemic preparedness activities; and to standardise reporting templates within and across countries to provide consistent and accessible data by internal and external staff and collate learnings.

Based on this review, the following recommendations are made to improve cholera prevention and control efforts: conduct rigorous and structured evaluations of cholera response programmes; explore improved models for epidemic preparedness, including rapid mobilisation of supplies and deployment of trained staff; invest in and strengthen partnerships with national and local government and other agencies as part of epidemic preparedness activities; and to standardise reporting templates within and across countries to provide consistent and accessible data by internal and external staff and collate learnings.

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.

Our project will use genomic data and a detailed understanding of pathogen evolution to deliver a robust, rapid, accurate and cost-effective pathogen detection kit for use in the field. Current methods are unsuitable for detection as they are slow, inaccurate and cannot be field deployed. Our work has already changed the basic understanding of how cholera spreads and identified high and low epidemic risks that are the cornerstones of disease prevention. By making robust molecular indicator kits adapted to field settings we are able to rapidly probe the likely behaviour of cholera strains and provide actionable data that can make a direct contribution to a major human health challenge.

This project will help fasten decision making in cholera outbreak control by indicating the risk associated with the type of cholera detected.

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

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.