Research Projects : Export

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.

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.

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.