Mathematical Modeling of Endemic Cholera Transmission.

Mathematical modeling can be used to project the impact of mass vaccination on cholera transmission. Here, we discuss 2 examples for which indirect protection from mass vaccination needs to be considered. In the first, we show that nonvaccinees can be protected by mass vaccination campaigns. This additional benefit of indirect protection improves the cost-effectiveness of mass vaccination. In the second, we model the use of mass vaccination to eliminate cholera. In this case, a high population level of immunity, including contributions from infection and vaccination, is required to reach the "herd immunity" threshold needed to stop transmission and achieve elimination.

Costing oral cholera vaccine delivery using a generic oral cholera vaccine delivery planning and costing tool (CholTool).

Cholera is both an endemic and epidemic disease in many low and middle-income countries (LMICs). Strategies for cholera control include improving water, sanitation, and hygiene; providing early and effective treatment; and deploying oral cholera vaccine (OCV). This last strategy is relatively new, and countries considering its introduction are interested in knowing the potential cost not only of the vaccine, but also the cost of introduction. This paper describes the costing of OCV introduction in LMICs using a publicly available Excel-based tool known as the CholTool. It includes estimates of delivery cost categories which cover not only the service delivery costs (e.g. vaccine procurement, handling, storage, and transport; vaccination administration, monitoring supervision, and field support), but also the programmatic costs associated with introducing a new vaccine (i.e. microplanning, communication and training materials development, sensitization/social mobilization, and personnel training) to ensure that a comprehensive estimate is provided with health payer perspective. CholTool takes the user through a structured sequence of interlinked modules containing input parameter cells (assumptions), decision cells (variable selections), and formulas (calculations) to produce customized cost estimates based on standardized methods. The tool provides both financial and economic cost estimates, to ensure that both costs are available for consideration. Four examples of applications of CholTool are presented in three countries- one in Ethiopia, two in Malawi and one in Nepal. The estimates of economic delivery cost per dose (including service delivery and programmatic costs) were (in USD 2016): $2.89 in Ethiopia, $3.04 in Malawi1, $3.35 in Malawi2 and $3.06 in Nepal. A cost projection conducted before the campaign using the tool and a retrospective costing using the tool in Nepal resulted in no significant difference between economic delivery costs per dose.

Willingness to pay for oral cholera vaccines in urban Bangladesh.

INTRODUCTION: Cholera is a highly infectious disease and remains a serious public health burden in Bangladesh. The objective of the study was to measure the private demand for oral cholera vaccines (OCV) in Bangladesh and to investigate the key determinants of this demand, reflected in the household's willingness to pay (WTP) for oral cholera vaccine. METHODS: A contingent valuation method was employed in an urban setting of Bangladesh during December 2015 to January 2016. All respondents (N = 1051) received a description of World Health Organization (WHO) prequalified OCV, Shanchol™. Interviews were conducted with either the head of households or their spouse or a major economic contributor of the households. Respondents were asked about how much at maximum they were willing to pay for OCV for their own and their household members' protection. Results are presented as the average and median of the reported maximum WTP of the respondents with standard deviations and 95% confidence interval. Natural log-linear regression model was employed to examine the factors influencing participants' WTP for OCV. RESULTS: About 99% of the respondents expressed WTP for OCV with a maximum mean and median WTP per vaccination (2 doses) of US$ 2.23 and US$ 1.92 respectively. On the household level with an average number of 4.62 members, the estimated mean WTP was US$ 10 (median: US$ 7.69) which represents the perceived demand for OCV of a household to vaccinate against cholera. CONCLUSIONS: The demand of vaccination further indicates that there is a potential scope for recovering a certain portion of the expenditure of immunization program by introducing direct user fees for future cholera vaccination in Bangladesh. Findings from this study will be useful for the policy-makers to make decision on cost-recovery in future oral cholera vaccination programs in Bangladesh and in similar countries.

Implications and measurement of herd protection (indirect effects) for enteric vaccine development.

Diarrhea remains one of the top five causes of disease and death among young children in developing nations. Fortunately, scientists are making progress developing vaccines against enterotoxigenic E. coli (ETEC) and Shigella, two of the leading diarrhea pathogens. As vaccine developers start to consider field efficacy trials of these vaccines, they should be aware of the importance of evaluating not only vaccine direct effects on the immunized, but also the herd effects that vaccination can afford to the unimmunized in a community. In a workshop held at the conference titled "Vaccines against Shigella and ETEC (VASE)", we described to participants what herd effects are and we presented on methods used in cholera and rotavirus studies that could be useful for future ETEC and Shigella vaccine trials conducted in low and middle-income nations. We also presented evidence on the effects of vaccine herd effects for estimates of vaccine cost-effectiveness.

Evaluating the costs of cholera illness and cost-effectiveness of a single dose oral vaccination campaign in Lusaka, Zambia.

INTRODUCTION: In 2016, for the very first time, the Ministry of Health in Zambia implemented a reactive outbreak response to control the spread of cholera and vaccinated at-risk populations with a single dose of Shancol-an oral cholera vaccine (OCV). This study aimed to assess the costs of cholera illness and determine the cost-effectiveness of the 2016 vaccination campaign. METHODOLOGY: From April to June 2017, we conducted a retrospective cost and cost-effectiveness analysis in three peri-urban areas of Lusaka. To estimate costs of illness from a household perspective, a systematic random sample of 189 in-patients confirmed with V. cholera were identified from Cholera Treatment Centre registers and interviewed for out-of-pocket costs. Vaccine delivery and health systems costs were extracted from financial records at the District Health Office and health facilities. The cost of cholera treatment was derived by multiplying the subsidized cost of drugs by the quantity administered to patients during hospitalisation. The cost-effectiveness analysis measured incremental cost-effectiveness ratio-cost per case averted, cost per life saved and cost per DALY averted-for a single dose OCV. RESULTS: The mean cost per administered vaccine was US$1.72. Treatment costs per hospitalized episode were US$14.49-US$18.03 for patients ≤15 years old and US$17.66-US$35.16 for older patients. Whereas households incurred costs on non-medical items such as communication, beverages, food and transport during illness, a large proportion of medical costs were borne by the health system. Assuming vaccine effectiveness of 88.9% and 63%, a life expectancy of 62 years and Gross Domestic Product (GDP) per capita of US$1,500, the costs per case averted were estimated US$369-US$532. Costs per life year saved ranged from US$18,515-US$27,976. The total cost per DALY averted was estimated between US$698-US$1,006 for patients ≤15 years old and US$666-US$1,000 for older patients. CONCLUSION: Our study determined that reactive vaccination campaign with a single dose of Shancol for cholera control in densely populated areas of Lusaka was cost-effective.

Feasibility, coverage and cost of oral cholera vaccination conducted by icddr,b using the existing national immunization service delivery mechanism in rural setting Keraniganj, Bangladesh.

Background: Cholera is a considerable health burden in developing country settings including Bangladesh. The oral cholera vaccine (OCV) is a preventative tool to control the disease. The objective of this study was to describe whether the International Centre for Diarrheal Disease Research, Bangladesh (icddr,b), could provide the OCV to rural communities using existing government infrastructure. Methods: The study was conducted in rural sub-district Keraniganj, 20 km from the capital city Dhaka. All listed participants one year and above in age (excluding pregnant women) were offered two doses of OCV at a 14 day interval. Existing government facilities were used to deliver and also maintain the cold chain required for the vaccine. All events related to vaccination were recorded at the 17 vaccination sites to evaluate the coverage and feasibility of OCV program. Results: A total of 29,029 individuals received the 1st dose (90% of target) and 26,611 individuals received the 2nd dose (83% of target and 92% of 1st dose individuals) of OCV. The highest vaccination coverage was in younger children (1-9 years) and the lowest was amongst 18-29-year age group. Somewhat better coverage was seen amongst the female participants than males (92% vs. 88% for the 1st dose and 93% vs. 90% for the 2nd dose). The cost of vaccine cost was calculated as US$1.00 per dose plus freight, insurance, and transportation and the total vaccine delivery cost was US$70,957. Conclusion: This was a project undertaken using existing public health program resources to collect empirical evidence on the use of a mass OCV campaign in the rural setting. Mass vaccination with the OCV is feasible in the rural setting using existing governmental vaccine delivery systems in Bangladesh.

The impact and cost-effectiveness of controlling cholera through the use of oral cholera vaccines in urban Bangladesh: A disease modeling and economic analysis.

BACKGROUND: Cholera remains an important public health problem in major cities in Bangladesh, especially in slum areas. In response to growing interest among local policymakers to control this disease, this study estimated the impact and cost-effectiveness of preventive cholera vaccination over a ten-year period in a high-risk slum population in Dhaka to inform decisions about the use of oral cholera vaccines as a key tool in reducing cholera risk in such populations. METHODOLOGY/PRINCIPAL FINDINGS: Assuming use of a two-dose killed whole-cell oral cholera vaccine to be produced locally, the number of cholera cases and deaths averted was estimated for three target group options (1-4 year olds, 1-14 year olds, and all persons 1+), using cholera incidence data from Dhaka, estimates of vaccination coverage rates from the literature, and a dynamic model of cholera transmission based on data from Matlab, which incorporates herd effects. Local estimates of vaccination costs minus savings in treatment costs, were used to obtain incremental cost-effectiveness ratios for one- and ten-dose vial sizes. Vaccinating 1-14 year olds every three years, combined with annual routine vaccination of children, would be the most cost-effective strategy, reducing incidence in this population by 45% (assuming 10% annual migration), and costing was $823 (2015 USD) for single dose vials and $591 (2015 USD) for ten-dose vials per disability-adjusted life year (DALY) averted. Vaccinating all ages one year and above would reduce incidence by >90%, but would be 50% less cost-effective ($894-1,234/DALY averted). Limiting vaccination to 1-4 year olds would be the least cost-effective strategy (preventing only 7% of cases and costing $1,276-$1,731/DALY averted), due to the limited herd effects of vaccinating this small population and the lower vaccine efficacy in this age group. CONCLUSIONS/SIGNIFICANCE: Providing cholera vaccine to slum populations in Dhaka through periodic vaccination campaigns would significantly reduce cholera incidence and inequities, and be especially cost-effective if all 1-14 year olds are targeted.

Feasibility and costs of a targeted cholera vaccination campaign in Ethiopia.

Shanchol™, a WHO-prequalified oral cholera vaccine (OCV), has been used to control endemic cholera in Asia, as well as in emergencies and outbreaks elsewhere. The vaccine has not been used by public health systems in cholera-endemic settings of Africa although several outbreak response campaigns have been conducted. Here we present experiences from a mass vaccination campaign in a cholera-endemic setting of Ethiopia in which Shanchol™ was introduced through the public health system. The vaccination site was selected based on cholera cases reported in previous years. Social mobilization involved sensitization of community leaders, household visits, and mass distribution of banners, posters and leaflets. The vaccination was implemented after careful microplanning of logistics and cold chain, manpower, transportation, vaccine supply and supervision and monitoring of adverse events. Vaccine administration was recorded on individual vaccination cards. Vaccine delivery costs were collected and analyzed after vaccination. As there was no experience with Shanchol™ in Ethiopia, a bridging trial was conducted to demonstrate safety and immunogenicity of the vaccine in the local population prior to the mass vaccination. Oral cholera vaccination was conducted in two rounds of four days each in February 2015 and March 2015 in 10 selected villages of Shashemenae rural district of Ethiopia. A total of 62,161 people targeted. 47,137 people (76%) received the first dose, and 40,707 (65%) received two doses. The financial cost of the vaccination campaign was estimated at US $2·60 per dose or US $5·64 per fully immunized person. The cost of vaccine delivery excluding vaccine procurement was $0·68 per dose or $1·48 per fully immunized person. The study demonstrates that mass cholera vaccination administered through the public health system in Ethiopia is feasible, can be implemented through the existing health system at an affordable cost, and the vaccine is acceptable to the community. The lessons from this study are useful for deploying OCV in other African endemic settings through the public health system and may guide future immunization policy decisions.

Global economic evaluation of oral cholera vaccine: A systematic review.

World Health Organization recommends oral cholera vaccine (OCV) to prevent and control cholera, but requires cost-effectiveness evidence. This review aimed to provide a critical appraisal and summary of global economic evaluation (EE) studies involving OCV to guide future EE study. Full EE studies, published from inception to December 2015, evaluating OCV against cholera disease were included. The included studies were appraised using WHO guide for standardization of EE of immunization programs. Out of 14 included studies, almost all (13/14) were in low- and middle-income countries. Most studies (11/14) evaluated mass vaccination program. Most of the studies (9/14) incorporated herd protective effect. The most common influential parameters were cholera incidence, OCV coverage, herd protection and OCV price. OCV vaccination is likely to be cost-effective when targeted at the population with high-risk of cholera and poor access to health care facilities when herd protection effect is incorporated and OCV price is low.

Cost Evaluation of a Government-Conducted Oral Cholera Vaccination Campaign-Haiti, 2013.

The devastating 2010 cholera epidemic in Haiti prompted the government to introduce oral cholera vaccine (OCV) in two high-risk areas of Haiti. We evaluated the direct costs associated with the government's first vaccine campaign implemented in August-September 2013. We analyzed data for major cost categories and assessed the efficiency of available campaign resources to vaccinate the target population. For a target population of 107,906 persons, campaign costs totaled $624,000 and 215,295 OCV doses were dispensed. The total vaccine and operational cost was $2.90 per dose; vaccine alone cost $1.85 per dose, vaccine delivery and administration $0.70 per dose, and vaccine storage and transport $0.35 per dose. Resources were greater than needed-our analyses suggested that approximately 2.5-6 times as many persons could have been vaccinated during this campaign without increasing the resources allocated for vaccine delivery and administration. These results can inform future OCV campaigns in Haiti.

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.

Oral Cholera Vaccination Delivery Cost in Low- and Middle-Income Countries: An Analysis Based on Systematic Review.

BACKGROUND: Use of the oral cholera vaccine (OCV) is a vital short-term strategy to control cholera in endemic areas with poor water and sanitation infrastructure. Identifying, estimating, and categorizing the delivery costs of OCV campaigns are useful in analyzing cost-effectiveness, understanding vaccine affordability, and in planning and decision making by program managers and policy makers. OBJECTIVES: To review and re-estimate oral cholera vaccination program costs and propose a new standardized categorization that can help in collation, analysis, and comparison of delivery costs across countries. DATA SOURCES: Peer reviewed publications listed in PubMed database, Google Scholar and World Health Organization (WHO) websites and unpublished data from organizations involved in oral cholera vaccination. STUDY ELIGIBILITY CRITERIA: The publications and reports containing oral cholera vaccination delivery costs, conducted in low- and middle-income countries based on World Bank Classification. Limits are humans and publication date before December 31st, 2014. PARTICIPANTS: No participants are involved, only costs are collected. INTERVENTION: Oral cholera vaccination and cost estimation. STUDY APPRAISAL AND SYNTHESIS METHOD: A systematic review was conducted using pre-defined inclusion and exclusion criteria. Cost items were categorized into four main cost groups: vaccination program preparation, vaccine administration, adverse events following immunization and vaccine procurement; the first three groups constituting the vaccine delivery costs. The costs were re-estimated in 2014 US dollars (US$) and in international dollar (I$). RESULTS: Ten studies were identified and included in the analysis. The vaccine delivery costs ranged from US$0.36 to US$ 6.32 (in US$2014) which was equivalent to I$ 0.99 to I$ 16.81 (in I$2014). The vaccine procurement costs ranged from US$ 0.29 to US$ 29.70 (in US$2014), which was equivalent to I$ 0.72 to I$ 78.96 (in I$2014). The delivery costs in routine immunization systems were lowest from US$ 0.36 (in US$2014) equivalent to I$ 0.99 (in I$2014). LIMITATIONS: The reported cost categories are not standardized at collection point and may lead to misclassification. Costs for some OCV campaigns are not available and analysis does not include direct and indirect costs to vaccine recipients. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Vaccine delivery cost estimation is needed for budgeting and economic analysis of vaccination programs. The cost categorization methodology presented in this study is helpful in collecting OCV delivery costs in a standardized manner, comparing delivery costs, planning vaccination campaigns and informing decision-making.

How low an effect of a preventive measure against diarrhoea are travellers willing to pay for?: A survey of Norwegian travellers.

BACKGROUND: Traveller's diarrhoea (TD) is the most common infectious problem for travellers, and we lack effective ways of preventing it, apart from antibiotic prophylaxis. This study aims to quantify the risk reduction of a hypothetic TD vaccine Norwegian travellers are willing to pay for. METHODS: 1204 clients at Reiseklinikken responded to a questionnaire asking what level of effectiveness would be required of a hypothetical vaccine against TD costing US$65. RESULTS: 18.7% of the respondents would buy the vaccine even if it was only 20% effective. Among respondents older than 50 years, the proportion was 28.8%. CONCLUSIONS: Our findings should encourage the development of vaccines and other preventive measures against travellers' diarrhoea.

Evidence for CVD 103-HgR as an effective single-dose oral cholera vaccine.

We propose the ideal oral cholera vaccine (OCV) should be an inexpensive, single, oral dose that rapidly confers immunity for a long duration, and is well tolerated by individuals vulnerable to cholera. Vaccine trials in industrialized countries of a single oral dose of 5 × 10(8) colony forming units (CFU) of the live, attenuated cholera strain CVD 103-HgR have shown 88-97% serum vibriocidal antibody seroconversion rates, a correlate of protection and documented vaccine efficacy of ≥80% using volunteer challenge studies with wild-type cholera. For individuals of developing countries, a 5 × 10(9) CFU dose of CVD 103-HgR is necessary to elicit similar antibody responses. Presently, a reformulation of CVD 103-HgR is in late-stage clinical development for prospective US FDA licensure; making a cholera vaccine for US travelers potentially accessible in 2016. The availability of CVD 103-HgR should be a welcome addition to the currently available OCVs.

Estimating the cost of cholera-vaccine delivery from the societal point of view: A case of introduction of cholera vaccine in Bangladesh.

Cholera is a major global public health problem that causes both epidemic and endemic disease. The World Health Organization recommends oral cholera vaccines as a public health tool in addition to traditional prevention practices and treatments in both epidemic and endemic settings. In many developing countries like Bangladesh, the major issue concerns the affordability of this vaccine. In February 2011, a feasibility study entitled, "Introduction of Cholera Vaccine in Bangladesh (ICVB)", was conducted for a vaccination campaign using inactivated whole-cell cholera vaccine (Shanchol) in a high risk area of Mirpur, Dhaka. Empirical data obtained from this trial was used to determine the vaccination cost for a fully immunized person from the societal perspective. A total of 123,661 people were fully vaccinated receiving two doses of the vaccine, while 18,178 people received one dose of the same vaccine. The total cost for vaccine delivery was US$ 492,238 giving a total vaccination cost per fully-vaccinated individual of US$ 3.98. The purchase cost of the vaccine accounted for 58% of the overall cost of vaccination. Attempts to reduce the per-dose cost of the vaccine are likely to have a large impact on the cost of similar vaccination campaigns in the future.