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Oral cholera vaccines consisting of killed whole cells have been available for many years, but they have not been used extensively in populations with endemic disease. An inexpensive, locally produced oral killed-whole-cell vaccine has been used in high-risk areas in Vietnam. To expand the use of this vaccine, it was modified to comply with WHO standards. We assessed the efficacy and safety of this modified vaccine in a population with endemic cholera. In this double-blind trial, 107 774 non-pregnant residents of Kolkata, India, aged 1 year or older, were cluster-randomised by dwelling to receive two doses of either modified killed-whole-cell cholera vaccine (n=52 212; 1966 clusters) or heat-killed Escherichia coli K12 placebo (n=55 562; 1967 clusters), both delivered orally. Randomisation was done by computer-generated sequence in blocks of four. The primary endpoint was prevention of episodes of culture-confirmed Vibrio cholerae O1 diarrhoea severe enough for the patient to seek treatment in a health-care facility. We undertook an interim, per-protocol analysis at 2 years of follow-up that included individuals who received two completely ingested doses of vaccine or placebo. We assessed first episodes of cholera that occurred between 14 days and 730 days after receipt of the second dose. This study is registered with ClinicalTrials.gov, number NCT00289224. 31 932 participants assigned to vaccine (1721 clusters) and 34 968 assigned to placebo (1757 clusters) received two doses of study treatment. There were 20 episodes of cholera in the vaccine group and 68 episodes in the placebo group (protective efficacy 67%; one-tailed 99% CI, lower bound 35%, p<0·0001). The vaccine protected individuals in age-groups 1·0–4·9 years, 5·0–14·9 years, and 15 years and older, and protective efficacy did not differ significantly between age-groups (p=0·28). We recorded no vaccine-related serious adverse events. This modified killed-whole-cell oral vaccine, compliant with WHO standards, is safe, provides protection against clinically significant cholera in an endemic setting, and can be used in children aged 1·0–4·9 years, who are at highest risk of developing cholera in endemic settings. Bill & Melinda Gates Foundation, Swedish International Development Cooperation Agency, Governments of South Korea, Sweden, and Kuwait.

Vaccination is a key intervention to prevent and control cholera in conjunction with water, sanitation and hygiene activities. An oral cholera vaccine (OCV) stockpile was established by the World Health Organization (WHO) in 2013. We reviewed its use from July 2013 to all of 2018 in order to assess its role in cholera control. We computed information related to OCV deployments and campaigns conducted including setting, target population, timelines, delivery strategy, reported adverse events, coverage achieved, and costs. In 2013–2018, a total of 83,509,941 OCV doses have been requested by 24 countries, of which 55,409,160 were approved and 36,066,010 eventually shipped in 83 deployments, resulting in 104 vaccination campaigns in 22 countries. OCVs had in general high uptake (mean administrative coverage 1st dose campaign at 90.3%; 2nd dose campaign at 88.2%; mean survey-estimated two-dose coverage at 69.9%, at least one dose at 84.6%) No serious adverse events were reported. Campaigns were organized quickly (five days median duration). In emergency settings, the longest delay was from the occurrence of the emergency to requesting OCV (median: 26 days). The mean cost of administering one dose of vaccine was 2.98 USD. The OCV stockpile is an important public health resource. OCVs were generally well accepted by the population and their use demonstrated to be safe and feasible in all settings. OCV was an inexpensive intervention, although timing was a limiting factor for emergency use. The dynamic created by the establishment of the OCV stockpile has played a role in the increased use of the vaccine by setting in motion a virtuous cycle by which better monitoring and evaluation leads to better campaign organization, better cholera control, and more requests being generated. Further work is needed to improve timeliness of response and contextualize strategies for OCV delivery in the various settings.

Background The global resurgence of cholera, a diarrhoeal disease, has resulted in vaccine demand that exceeds the currently available supply resulting in global calls for next generation cholera vaccines. DuoChol is a novel, thermostable, low-cost oral cholera vaccine capsule currently in development which has the potential to introduce programmatic benefits and efficiencies in cholera vaccination campaigns. Objectives This qualitative study aimed to identify country-specific challenges in handling, distributing, and storing cholera vaccines and to assess the feasibility, acceptability, and policy implications of vaccine capsules compared to current products and practices in vaccination campaigns. Methods Using the World Health Organization’s Vaccine Innovation Framework, consultations were conducted with 81 immunization programme stakeholders from Bangladesh, Ethiopia, Kenya, Mozambique and Tanzania. Results Key barriers to cholera vaccination include challenges in disbursing funds to subnational levels and the need for surged resources, such as additional health workers and cold chain equipment, during campaigns. Stakeholders discussed attributes of the novel vaccine such as improved thermostability and presentation which could reduce or eliminate the existing barriers. Conclusions The stakeholders highlighted that vaccine capsules are desirable for use in the general population as they have the potential to have many advantages over the current practice. However, for children who are not able to swallow the capsule, the currently available liquid oral cholera vaccine may be more desirable. To make an eventual informed decision about whether to recommend use of the vaccine capsule, national stakeholders requested the generation of evidence derived from pilot studies.

The frequency and magnitude of infectious disease outbreaks are expected to rise. Although emergency vaccine stockpiles have emerged as a strategy to hedge against sporadic demand and accelerate response efforts, their long-term management is complex. This study investigates the role of global emergency vaccine stockpiles in achieving public health goals over time and underlying health system structures that drive their performance, with an application to cholera. A qualitative study design was used, combining insights from literature and semi-structured interviews with experts engaged in stockpile-related activities. A systems analysis, using qualitative causal loop diagrams, helps explain global stockpile behavior and discuss leverage points for change. It includes identifying system elements, important relationship between them, and resulting feedback loops. Despite expanding the stockpile for oral cholera vaccines, growing supply shortages since 2021 can partly be explained by increased demand due to a surge in outbreaks and the accumulation of evidence on vaccine effectiveness. These supply constraints have led to delays fulfilling vaccine orders for reactive campaigns and a pause on preventive use, leaving populations vulnerable. Despite ongoing efforts to scale-up production, a continued challenge is designing effective risk-sharing policies to attract manufacturers given uncertainty in demand forecasts and erratic orders. In literature, the time-dependent and complex environmental, social, demographic, and structural drivers that underpin the emergence and spread of disease are rarely jointly considered, making it difficult to anticipate the changing role and use of stockpiles relative to other preparedness strategies. Over time, global emergency vaccine stockpiles can support the transition from reactive to proactive strategies, helping achieve evolving public health goals towards disease elimination. As disease epidemiology, vaccination strategies, uptake, and supply markets evolve asynchronously, there is a need for decision-support tools that better integrate supply and demand dynamics, hence expanding traditionally narrow model boundaries.

Following decades of progress, recent years have seen a resurgence of cholera. This has led to unprecedented demand for vaccines from the global emergency stockpile of oral cholera vaccines (OCVs), for outbreak and humanitarian use. As a consequence of chronic supply shortages, preventive vaccination has been suspended since 2022. Although strategic demand scenarios have been published for OCV, models that integrate OCV supply and demand across long time horizons are lacking. Therefore, a quantitative system dynamics model is presented to simulate OCV market dynamics between 2013–2035. The model considers the evolving OCV supply landscape as well as the impact of preventive efforts. Building on stakeholder-driven scenario design, simulations help identify leverage points to improve OCV market health and assess the individual and combined effect of interventions on accelerating cholera control. Specifically, country adoption of preventive vaccination programs and complementary investments in water and sanitation infrastructure are critical to reduce the risk of cholera. Although more resource-intensive, re-vaccination of at-risk populations helps sustain outbreak prevention. It also offers potential benefits such as increasing long-term demand predictability and the overall market size. These serve as important incentives to maintain supplier diversity, thus improving market health. However, since many cholera endemic countries rely on donor support to access OCV, budget constraints associated with reduced development aid can jeopardize programmatic ambitions. Interventions such as the use of rapid diagnostic tests and price competition of procurement can help meet country needs. Finally, market dynamics are influenced by the policies around when to resume preventive OCV use in endemic countries and 2-dose reactive vaccination. Specifically, inventory policies based on the current available stock level versus incoming stock in transit are compared. Aligning OCV supply with demand, both in time and quantity, will be critical to address immediate needs and support broader multi-sectoral activities towards cholera elimination.

The worst cholera outbreaks in 20 years are highlighting the dire shortage of vaccine supplies and the problems of vaccine inequity and manufacturing. Jane Feinmann reports

Shortages of vaccines for epidemic diseases, such as cholera, meningitis, and yellow fever, have become common over the past decade, hampering efforts to control outbreaks through mass reactive vaccination campaigns. Additionally, various epidemiological, political, and logistical challenges, which are poorly documented in the literature, often lead to delays in reactive campaigns, ultimately reducing the effect of vaccination. In June 2015, a cholera outbreak occurred in Juba, South Sudan, and because of the global shortage of oral cholera vaccine, authorities were unable to secure sufficient doses to vaccinate the entire at-risk population—approximately 1 million people. In this Personal View, we document the first public health use of a reduced, single-dose regimen of oral cholera vaccine, and show the details of the decision-making process and timeline. We also make recommendations to help improve reactive vaccination campaigns against cholera, and discuss the importance of new and flexible context-specific dose regimens and vaccination strategies.

* A global oral cholera vaccine (OCV) stockpile was established in 2013 to improve rapid access to the vaccine in outbreaks and emergencies in which cholera risk is high. The first deployment from the global OCV stockpile was to South Sudan in 2014 because of high cholera risk from massive population displacements within the civil war.

Cholera-endemic Eastern India has played an important role in the development of oral cholera vaccines (OCV) through conduct of pivotal trials in Kolkata which led to the registration of the first low-cost bivalent killed whole cell OCV in India in 2009, and subsequent prequalification by the World Health Organization prequalification in 2011. Odisha hosted an influential early demonstration project for use of the vaccine in a high-risk population and provided data and lessons that were crucial input in the Vaccine Investment Strategy developed by Gavi, the Vaccine Alliance in 2013. With Gavi’s decision to finance an OCV stockpile, the demand for OCV surged and vaccine has been deployed with great success worldwide in areas of need in response to outbreaks and disasters, most notably in Africa. However, although India is considered one of the highest burden countries, no further use of OCV has occurred since the demonstration project in Odisha in 2011. In this paper we will summarize the important contributions of India to the development and use of OCV and discuss the possible barriers to OCV introduction as a public health tool to control cholera.

Improving water and sanitation is the preferred choice for cholera control in the long-term. Nevertheless, vaccination is an available tool that has been shown to be a cost-effective option for cholera prevention in endemic countries or during outbreaks. In 2011 the first low-cost oral cholera vaccine for international use was given prequalification by the World Health Organization (WHO). To increase and prioritize use of the vaccine, WHO created a global stockpile in 2013 from which countries may request oral cholera vaccine for reactive campaigns. WHO has issued specific guidelines for applying for the vaccine, which was previously in short supply (despite prequalification for a second oral vaccine in 2015). The addition of a third WHO-prequalified oral cholera vaccine in 2016 is expected to increase the global stockpile considerably and alleviate supply issues. However, prioritization and best use of the vaccine (e.g. how, when and where to use) will remain challenges. We describe 12 past oral cholera vaccine campaigns, conducted in settings with varying burdens of cholera. These case studies illustrate three key challenges faced in the use of the oral cholera vaccines: regulatory hurdles, cold chain logistics and vaccine coverage and uptake. To pave the way for the introduction of current and future oral cholera vaccines, we discuss operational challenges and make recommendations for future research with respect to each of these challenges.