Cholera

The global OCV stockpile was established in 2013 to ensure rapid availability of OCV as part of effective cholera outbreak response. As of the end of March 2024, 127 million doses of OCV have been approved and shipped to 28 countries for use in reactive campaigns.  

In January 2023, the WHO classified the global resurgence of cholera as a grade 3 emergency. The global capacity to respond to multiple concurrent outbreaks continues to be strained due to the global lack of resources, including shortages of the Oral Cholera Vaccine (OCV), as well as overstretched public health and medical personnel.

Current guidelines for OCV allocation are based on the potential impact of vaccination, as well as feasibility of a vaccination campaign and stockpile availability. Aside from a few individual case studies, there has been no comprehensive analysis of the impact of previous emergency OCV deployments. A multi-country retrospective analysis of reactive OCV campaigns will provide critical evidence for informing guidelines for OCV campaign planning, allocation and implementation.

The overall aim of this study is therefore to generate evidence for efficient planning and implementation of reactive OCV campaigns by quantifying their short- and long-term impact on cholera transmission and persistence.

Primary objectives

• Assess the short-term population-level impact of historic reactive OCV campaigns and evaluate the impact of campaign timing on outbreak size and duration.
• Quantify the mid-to-long-term population-level impact of reactive OCV campaigns on cholera incidence and persistence.
• Evaluate methods for estimating individual-level protection of OCV vaccination against infection and severe outcomes using routinely-collected surveillance data.
• Propose evidence-based criteria for planning of reactive OCV campaigns, including timing, number of doses and target coverage.
• Conduct workshops with country-based collaborators and stakeholders to develop frameworks for planning and implementing effective OCV campaigns.

Country

Democratic Republic of the Congo, Niger, Nigeria, Malawi, Mozambique, Somalia, Ethiopia, Zambia

Status

Launch of the study

Tentative end Date

November 2025

Our role

Study Coordination  

Partners

Programme National d'Élimination du Choléra, DRC; Programme Elargi de Vaccination, DRC; Ethiopian Public Health Institute; Ministère de la Santé Publique, de la Population et des Affaires Sociales (MSPPAS), Niger; Nigeria Centre for Disease Control; National Primary Health Care Development Agency, Nigeria; Malawi World Health Organisation Country Office; Malawi Ministry of Health; Public Health Institute of Malawi; Blantyre Institute for Community Outreach; National Institute of Health, Mozambique; Somalia World Health Organisation Country Office; Somalia Ministry of Health; Zambia National Public Health Institute; Zambia Ministry of Health, Johns Hopkins University; Médecins Sans Frontières; World Health Organisation

Although extensive work on defining the theoretical basis of potential sampling schemes to estimate incidence has been done by the GTFCC, the practical deployment strategies for RDTs to support incidence measurement in field conditions require further refinement. First, after RDT deployment to the health facilities the respective people must be trained in the use of RDT and interpretation of the result for surveillance. For example, a field-applicable method is required to identify the scaling up of the RDT positivity rate in a sample of suspected cases to incidence estimates for all suspected cases and correcting for sensitivity and specificity. Before a successful integration of RDT into routine surveillance, more research on different strategies and their implementation is necessary for different scenarios. Moreover, the ideal sampling strategy must be adaptable to field conditions, based on the most commonly used RDTs. Furthermore they should be implemented by MoH staff without much supervision and follow-up in cholera outbreak settings with limited resources. Hence, the study will contribute to further refine the use of RDTs for cholera surveillance with a strong focus on the implementation in real world conditions. 

Objective 

• Assess the performance and feasibility of different cholera RDTs and their implementation into new surveillance strategies under a variety of real-world deployment conditions.
• Derive and compare estimates of the true clinical incidence of cholera based on RDTs using different sampling schemes.

Methods 

This study will be an observational, mixed-methods study.

Country 

DRC and Niger

Status

Launch of the study

Tentative end Date 

2024 

Our role  

Study Coordination  

Partners 

MSF, DRC Ministry oh health, GAVI

Manufacturers of oral cholera vaccine (OCV) recommend a 7- or 14-days interval between two doses. To carry out two rounds of mass vaccination within this delay is not always feasible and many campaigns implemented to date have used a longer interval. Recent evidence indicates that an extended interval between OCV doses might result in equivalent seroconversion rates and in an improved boosting of mucosal immune responses following the second dose. 

Objective 

We aim to demonstrate the non-inferiority of the humoral immune response between individuals receiving a second Euvichol-Plus® pre-qualified OCV dose either 6 or 12 months after the initial dose and individuals receiving a second pre-qualified OCV dose 14 days after the initial dose. The humoral immune response will be assessed as the post-vaccination titer of serum vibriocidal antibodies at 14 days post-2nd dose vaccination. Secondary outcomes include the comparison of the overall rate of vibriocidal seroconversion 14 days after either the first or the second vaccine dose. A subsample of individuals ≥ 18 years will have additional serological evaluation to characterize the kinetics of their antibody responses up to 6 months after the second OCV vaccine dose. Although the vaccine is safe, occurrence of adverse events and serious adverse events following vaccination will be assessed (safety evaluation).  

Methods 

The study is an open-label, randomized, controlled, non-inferiority immunogenicity trial comparing the humoral immune responses to OCV in two interventions arms (6 and 12 months interval between OCV doses) compared with a control arm (standard 14-day interval). In each arm, we aim to recruit 152 individuals aged 1 to 39 year-old eligible for OCV vaccination from the general population (ie. 456 individuals in total). 

Country 

Republic of Guinea 

Status

Recruitment ongoing

Tentative end Date 

2024 

Our role  

Study Coordination  

Partners 

MSF OCB, Ministry of Health Republic of Guinea, Massachusetts General Hospital, Grieg Foundation 

Cholera remains a global health threat, persisting in settings with inadequate water, sanitation and hygiene (WASH) access. Killed oral cholera vaccines (OCV), in combination with WASH improvements, have become a standard component in cholera control programs. Most available evidence on OCV impact has been related to individual-level protection from clinical disease. Mass vaccination campaigns have the potential to also reduce transmission and occurrence of pandemic Vibrio cholerae in the environment. In 2020, mass OCV campaigns were deployed in cholera endemic regions of the Democratic Republic of the Congo. The study, scheduled to run for 2 years and assess the impact of mass OCV deployment in Goma and rural Ex-Katanga, has been amended and extended to 2024. 

The transformed project will aim to evaluate the strategies and impact of major preventive vaccination campaigns against OCV in different cholera outbreak contexts in DRC, and will include various activities: 1. Continued clinical surveillance of cholera in sites targeted by different vaccination strategies. 2. Case-cohort study in Goma with the aim of reinforcing estimates of vaccine efficacy 3. Regular surveys, including vaccination coverage, mortality, incidence of cholera symptoms and influencing factors, registration of population movements and access to care 4. Qualitative approach (focus groups and in-depth interviews).

Methods

Our protocols combine (1) clinical surveillance, (2) serological surveys, and (3) household follow-ups. We will collaborate with health authorities to strengthen clinical surveillance systems. Culture of V. cholerae, molecular assays and cholera serology will be conducted in North Kivu (including optimisation of a qPCR assay for the simultaneous detection and differentiation of toxigenic V. cholerae O1 and O139). A sequence of serological surveys will be conducted at each study sites to assess cholera infection rates in the community, providing a measure of transmission independent of infection severity and health-seeking behaviour. Finally, a series of follow-up visits to the households of confirmed cholera cases will be conducted estimate household secondary attack rates and cholera shedding time among vaccinated and non-vaccinated persons. Environmental samples will be collected from households and water sources to monitor changes in V. cholerae detection frequency. Clinical, household, and environmental isolates will be sequenced to better understand V. cholerae circulation within households and study sites.

For the amended part of the project, this will be a prospective observational study, following a case-cohort design, with a dynamic aspect to control for certain biases.

Objective

The study is expected to generate evidence on the long-term epidemiological and environmental impacts of mass OCV administration. The combination of clinical surveillance, serological surveys, and household contacts and environmental sampling will also contribute to improving our understanding of cholera transmission dynamics in endemic settings characteristic of transmission hotspots and inform articulated WASH-OCV strategies.

Objective of the amended project
Evaluate the impact of major preventive cholera vaccination campaigns by calculating vaccine effectiveness and monitoring appropriate indicators, in an urban cholera outbreak in the Democratic Republic of Congo (DRC).

Country

Democratic Republic of the Congo

Tentative end date

2025

Our role

Sponsor of the study. Conception, implementation, analysis, publications

Partners

Ministry of Health DRC, PNECHOL, INRB, MSF OCP

This study is funded by the Wellcome, UKaid and the Foreign and Commonwealth and Development Office (FCDO). 

Case-Area Targeted Intervention to contain or shorten the duration of cholera outbreaks (CATI)

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.

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 MSF will incorporate key transmission-reducing interventions (including household-level water, sanitation, and hygiene measures, active case-finding, antibiotic chemoprophylaxis, and/or 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.

The study design is based on comparing the effects of CATIs that rapidly provide protection in averting later generations of cases when compared with CATIs delayed by operational constraints (delays will not be assigned nor randomized). 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.

Country

DRC, Cameroun, Zimbabwe

Tentative End date

December 2021

Our Role

Study design, Coordination, Implementation, Analysis

Who's Involved

OCG, OCB, OCP, OCBA, OCA

LSHTM