World's cholera vaccine stash is empty-but relief is on its way.

A dramatic shortage of the oral vaccine may ease in the years ahead as more companies enter the market.

Vaccines are in short supply amid global cholera surge.

Climate change and pandemic may be fueling outbreaks.

High cholera vaccination coverage following emergency campaign in Haiti: Results from a cluster survey in three rural Communes in the South Department, 2017.

Oral cholera vaccine (OCV) has increasingly been used as an outbreak control measure, but vaccine shortages limit its application. A two-dose OCV campaign targeting residents aged over 1 year was launched in three rural Communes of Southern Haiti during an outbreak following Hurricane Matthew in October 2016. Door-to-door and fixed-site strategies were employed and mobile teams delivered vaccines to hard-to-reach communities. This was the first campaign to use the recently pre-qualified OCV, Euvichol. The study objective was to estimate post-campaign vaccination coverage in order to evaluate the campaign and guide future outbreak control strategies. We conducted a cluster survey with sampling based on random GPS points. We identified clusters of five households and included all members eligible for vaccination. Local residents collected data through face-to-face interviews. Coverage was estimated, accounting for the clustered sampling, and 95% confidence intervals calculated. 435 clusters, 2,100 households and 9,086 people were included (99% response rate). Across the three communes respectively, coverage by recall was: 80.7% (95% CI:76.8-84.1), 82.6% (78.1-86.4), and 82.3% (79.0-85.2) for two doses and 94.2% (90.8-96.4), 91.8% (87-94.9), and 93.8% (90.8-95.9) for at least one dose. Coverage varied by less than 9% across age groups and was similar among males and females. Participants obtained vaccines from door-to-door vaccinators (53%) and fixed sites (47%). Most participants heard about the campaign through community 'criers' (58%). Despite hard-to-reach communities, high coverage was achieved in all areas through combining different vaccine delivery strategies and extensive community mobilisation. Emergency OCV campaigns are a viable option for outbreak control and where possible multiple strategies should be used in combination. Euvichol will help alleviate the OCV shortage but effectiveness studies in outbreaks should be done.

The history of OCV in India and barriers remaining to programmatic introduction.

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.

Global oral cholera vaccine use, 2013-2018.

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.

Pathways to a policy for cholera control in India.

Cholera is endemic in southern Asia, but available control mechanisms have either not been applied or have been ineffective. Oral killed cholera vaccines are now available, are pre-qualified by the World Health Organization (WHO) and are being stock-piled by the Gavi Alliance. Although cholera vaccines have been tested, manufactured and licensed in India for several years, they are not in use in public health programmes for either endemic disease or outbreaks. The National Technical Advisory Group on Immunization (NTAGI) is the advisory body that considers disease burden, vaccine performance, cost-effectiveness and potential for introduction into national programmes, reporting to the Ministry of Health. The NTAGI also takes into account the recommendations of the WHO and is now considering cholera vaccines. Policies for cholera control are urgently needed, and the availability and affordability of an oral cholera vaccine in India offers new opportunities to control an important public health problem.

Comparing alternative cholera vaccination strategies in Maela refugee camp: using a transmission model in public health practice.

BACKGROUND: Cholera is a major public health concern in displaced-person camps, which often contend with overcrowding and scarcity of resources. Maela, the largest and longest-standing refugee camp in Thailand, located along the Thai-Burmese border, experienced four cholera outbreaks between 2005 and 2010. In 2013, a cholera vaccine campaign was implemented in the camp. To assist in the evaluation of the campaign and planning for subsequent campaigns, we developed a mathematical model of cholera in Maela. METHODS: We formulated a Susceptible-Infectious-Water-Recovered-based transmission model and estimated parameters using incidence data from 2010. We next evaluated the reduction in cases conferred by several immunization strategies, varying timing, effectiveness, and resources (i.e., vaccine availability). After the vaccine campaign, we generated case forecasts for the next year, to inform on-the-ground decision-making regarding whether a booster campaign was needed. RESULTS: We found that preexposure vaccination can substantially reduce the risk of cholera even when <50% of the population is given the full two-dose series. Additionally, the preferred number of doses per person should be considered in the context of one vs. two dose effectiveness and vaccine availability. For reactive vaccination, a trade-off between timing and effectiveness was revealed, indicating that it may be beneficial to give one dose to more people rather than two doses to fewer people, given that a two-dose schedule would incur a delay in administration of the second dose. Forecasting using realistic coverage levels predicted that there was no need for a booster campaign in 2014 (consistent with our predictions, there was not a cholera epidemic in 2014). CONCLUSIONS: Our analyses suggest that vaccination in conjunction with ongoing water sanitation and hygiene efforts provides an effective strategy for controlling cholera outbreaks in refugee camps. Effective preexposure vaccination depends on timing and effectiveness. If a camp is facing an outbreak, delayed distribution of vaccines can substantially alter the effectiveness of reactive vaccination, suggesting that quick distribution of vaccines may be more important than ensuring every individual receives both vaccine doses. Overall, this analysis illustrates how mathematical models can be applied in public health practice, to assist in evaluating alternative intervention strategies and inform decision-making.

Oral cholera vaccination coverage after the first global stockpile deployment in Haiti, 2014.

INTRODUCTION: In 2014, an oral cholera vaccine (OCV) campaign targeting 185,314 persons aged ≥1 years was conducted in 3 departments via fixed post and door-to-door strategies. This was the first use of the global OCV stockpile in Haiti. METHODS: We conducted a multi-stage cluster survey to assess departmental OCV coverage. Target population estimates were projected from the 2003 Haiti population census with adjustments for population growth and estimated proportion of pregnant women. In the three departments, we sampled 30/106 enumeration areas (EAs) in Artibonite, 30/244 EAs in Centre, and 20/29 EAs in Ouest; 20 households were systematically sampled in each EA. Household and individual interviews using a standard questionnaire were conducted in each selected household; data on OCV receipt were obtained from vaccination card or verbal report. We calculated OCV campaign coverage estimates and 95% confidence intervals (CIs) accounting for survey design. RESULTS: Overall two-dose OCV coverage was 70% (95% CI: 60, 79), 63% (95% CI: 55, 71), and 44% (95% CI: 35, 53) in Artibonite, Centre, and Ouest, respectively. Two-dose coverage was higher in the 1-4 years age group than among those ≥ 15 years in Artibonite (difference: 11%; 95% CI: 5%, 17%) and Ouest (difference: 12%; 95% CI: 3, 20). A higher percentage of children aged 5-14 years received both recommended doses than did those ≥ 15 years (Artibonite: 14% (95% CI: 8%, 19%) difference; Centre: 11% difference (95% CI: 5%, 17%); Ouest: 10% difference (95% CI: 2%, 17%). The most common reason for not receiving any OCV dose was being absent during the campaign or not having heard about vaccination activities. CONCLUSIONS: While coverage estimates in Artibonite and Centre were comparable with other OCV campaigns in Haiti and elsewhere, inadequate social mobilization and outdated population estimates might have contributed to lower coverage in Ouest.

The Euvichol story - Development and licensure of a safe, effective and affordable oral cholera vaccine through global public private partnerships.

Cholera, a diarrheal disease primarily affecting vulnerable populations in developing countries, is estimated to cause disease in more than 2.5 million people and kill almost 100,000 annually. An oral cholera vaccine (OCV) has been available globally since 2001; the demand for this vaccine from affected countries has however been very low, due to various factors including vaccine price and mode of administration. The low demand for the vaccine and limited commercial incentives to invest in research and development of vaccines for developing country markets has kept the global supply of OCVs down. Since 1999, the International Vaccine Institute has been committed to make safe, effective and affordable OCVs accessible. Through a variety of partnerships with collaborators in Sweden, Vietnam, India and South Korea, and with public and private funding, IVI facilitated development and production of two affordable and WHO-prequalified OCVs and together with other stakeholders accelerated the introduction of these vaccines for the global public-sector market.

Prolonging herd immunity to cholera via vaccination: Accounting for human mobility and waning vaccine effects.

BACKGROUND: Oral cholera vaccination is an approach to preventing outbreaks in at-risk settings and controlling cholera in endemic settings. However, vaccine-derived herd immunity may be short-lived due to interactions between human mobility and imperfect or waning vaccine efficacy. As the supply and utilization of oral cholera vaccines grows, critical questions related to herd immunity are emerging, including: who should be targeted; when should revaccination be performed; and why have cholera outbreaks occurred in recently vaccinated populations? METHODS AND FINDINGS: We use mathematical models to simulate routine and mass oral cholera vaccination in populations with varying degrees of migration, transmission intensity, and vaccine coverage. We show that migration and waning vaccine efficacy strongly influence the duration of herd immunity while birth and death rates have relatively minimal impacts. As compared to either periodic mass vaccination or routine vaccination alone, a community could be protected longer by a blended "Mass and Maintain" strategy. We show that vaccination may be best targeted at populations with intermediate degrees of mobility as compared to communities with very high or very low population turnover. Using a case study of an internally displaced person camp in South Sudan which underwent high-coverage mass vaccination in 2014 and 2015, we show that waning vaccine direct effects and high population turnover rendered the camp over 80% susceptible at the time of the cholera outbreak beginning in October 2016. CONCLUSIONS: Oral cholera vaccines can be powerful tools for quickly protecting a population for a period of time that depends critically on vaccine coverage, vaccine efficacy over time, and the rate of population turnover through human mobility. Due to waning herd immunity, epidemics in vaccinated communities are possible but become less likely through complementary interventions or data-driven revaccination strategies.

Characterization of Interventional Studies of the Cholera Epidemic in Haiti.

In October 2010, the Haitian Ministry of Public Health and Population (MSPP; Port au Prince, Haiti) reported a cholera epidemic caused by contamination of the Artibonite River by a United Nation Stabilization Mission camp. Interventional studies of the subsequent responses, including a descriptive Methods section and systematic approach, may be useful in facilitating comparisons and applying lessons learned to future outbreaks. The purpose of this study was to examine publicly available documents relating to the 2010 cholera outbreak to answer: (1) What information is publicly available on interventional studies conducted during the epidemic, and what was/were the impact(s)? and (2) Can the interventions be compared, and what lessons can be learned from their comparison? A PubMed (National Center for Biotechnology Information, National Institutes of Health; Bethesda, Maryland USA) search was conducted using the parameters "Haiti" and "cholera." Studies were categorized as "interventional research," "epidemiological research," or "other." A distinction was made between studies and narrative reports. The PubMed search yielded 171 papers, 59 (34.0%) of which were epidemiological and 12 (7.0%) were interventional studies. The remaining 100 papers (59.0%) comprised largely of narrative, anecdotal descriptions. An expanded examination of publications by the World Health Organization (WHO; Geneva, Switzerland), the Center for Research in the Epidemiology of Disasters (CRED; Brussels, Belgium), United States Agency for International Development (USAID; Washington, DC USA)-Development Experience Clearinghouse (DEC), and US National Library of Medicine's (NLM; Bethesda, Maryland USA) Disaster Literature databases yielded no additional interventional studies. The unstructured formats and differing levels of detail prohibited comparisons between interventions, even between those with a similar approach. Only two (17.0%) interventional studies included any impact data, although neither commented whether the intervention improved health or reduced incidence or mortality related to cholera. Agreed frameworks for guiding responses and subsequent reporting are needed to ensure reports contain sufficient detail to draw conclusions for the definition of best practices and for the design of future interventions. Miller J , Birnbaum ML . Characterization of interventional studies of the cholera epidemic in Haiti. Prehosp Disaster Med. 2018;33(2):176-181.

Lessons learnt from 12 oral cholera vaccine campaigns in resource-poor settings.

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.

Améliorer l'accès à l'eau et à l'assainissement est le meilleur moyen de lutter contre le choléra à long terme. Néanmoins, la vaccination s'avère être un outil accessible et rentable pour la prévention du choléra dans les pays où cette maladie est endémique ou pendant des épidémies. En 2011, l'Organisation mondiale de la Santé (OMS) a présélectionné le premier vaccin anticholérique oral à faible coût destiné à un usage international. Afin de favoriser et de hiérarchiser l'usage de ce vaccin, l'OMS a créé en 2013 une réserve mondiale auprès de laquelle les pays peuvent demander des vaccins anticholériques oraux et mettre en œuvre des campagnes réactives. L'OMS a publié des directives spécifiques pour demander ce vaccin, qui n'était auparavant disponible qu'en quantité limitée (malgré la présélection d'un second vaccin oral en 2015). L'ajout, en 2016, d'un troisième vaccin anticholérique oral présélectionné par l'OMS devrait permettre d'augmenter sensiblement les réserves mondiales et d'atténuer les problèmes d'approvisionnement. Il restera cependant à traiter les questions de la hiérarchisation et du meilleur usage du vaccin (par ex., comment, à quel moment et à quel endroit l'utiliser). Nous décrivons ici 12 campagnes de vaccination orale contre le choléra qui ont été menées dans des régions diversement touchées par cette maladie. Ces études de cas illustrent trois grands défis qui se posent lors de l'utilisation de vaccins anticholériques oraux: les obstacles règlementaires, la logistique de la chaîne du froid et la couverture ainsi que le taux de vaccination. Afin de préparer l'introduction de vaccins anticholériques oraux, existants et futurs, nous examinons les difficultés opérationnelles et formulons des recommandations concernant de futurs travaux de recherche sur chacune de ces difficultés.

La mejora del agua y el saneamiento es la opción preferida para el control del cólera a largo plazo. Sin embargo, la vacunación es una herramienta disponible que ha demostrado ser una alternativa rentable para la prevención del cólera en países endémicos o durante brotes. En 2011, la Organización Mundial de la Salud (OMS) precalificó la primera vacuna anticolérica oral de bajo coste para uso internacional. Para aumentar y priorizar el uso de la vacuna, en 2013 la OMS creó una reserva global de la cual los países podían solicitar vacunas anticoléricas orales para campañas reactivas. La OMS ha publicado directrices específicas para la aplicación de la vacuna, cuyo suministro era escaso anteriormente (a pesar de la precalificación para una segunda vacuna oral en 2015). Está previsto que el hecho de añadir una tercera vacuna anticolérica oral precalificada por la OMS en 2016 aumente las reservas globales de forma considerable y reduzca los problemas de suministro. No obstante, la priorización y el buen uso de la vacuna (por ejemplo, cómo, cuándo y dónde utilizarla) seguirán siendo asuntos importantes. Se describen 12 campañas anteriores de vacunación oral contra el cólera, realizadas en entornos con distintos niveles de cólera. Estos estudios de casos ilustran los tres problemas principales que surgen al utilizar vacunas anticoléricas orales: obstáculos reglamentarios, logística de la gestión de la cadena de frío y cobertura y aceptación de la vacuna. Para allanar el terreno en la introducción de vacunas anticoléricas orales en el presente y en el futuro, se analizan las dificultades operativas y se presentan recomendaciones para futuras investigaciones con respecto a estos problemas.

Adapting to the global shortage of cholera vaccines: targeted single dose cholera vaccine in response to an outbreak in South Sudan.

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.