The World Health Organization (WHO) recommends oral cholera vaccines (OCVs) as a supplementary tool to conventional prevention of cholera. Dukoral, a killed whole-cell two-dose OCV, was used in a mass vaccination campaign in 2009 in Zanzibar. Public and private costs of illness (COI) due to endemic cholera and costs of the mass vaccination campaign were estimated to assess the cost-effectiveness of OCV for this particular campaign from both the health care provider and the societal perspective. Public and private COI were obtained from interviews with local experts, with patients from three outbreaks and from reports and record review. Cost data for the vaccination campaign were collected based on actual expenditure and planned budget data. A static cohort of 50,000 individuals was examined, including herd protection. Primary outcome measures were incremental cost-effectiveness ratios (ICER) per death, per case and per disability-adjusted life-year (DALY) averted. One-way sensitivity and threshold analyses were conducted. The ICER was evaluated with regard to WHO criteria for cost-effectiveness. Base-case ICERs were USD 750,000 per death averted, USD 6,000 per case averted and USD 30,000 per DALY averted, without differences between the health care provider and the societal perspective. Threshold analyses using Shanchol and assuming high incidence and case-fatality rate indicated that the purchase price per course would have to be as low as USD 1. 2 to render the mass vaccination campaign cost-effective from a health care provider perspective (societal perspective: USD 1. 3). Based on empirical and site-specific cost and effectiveness data from Zanzibar, the 2009 mass vaccination campaign was cost-ineffective mainly due to the relatively high OCV purchase price and a relatively low incidence. However, mass vaccination campaigns in Zanzibar to control endemic cholera may meet criteria for cost-effectiveness under certain circumstances, especially in high-incidence areas and at OCV prices below USD 1. 3.
Despite efforts to improve water supply and sanitation, cholera still represents a serious public health burden in low- and middle-income countries. In 2009, more than 220,000 cases and almost 5,000 deaths were reported to the World Health Organization (WHO) [1]. Due to underreporting and difficulties with surveillance, however, the true burden is likely in the range of 3 million cases and 100,000 deaths per year [2], [3]. A recent review of official cholera-related morbidity and mortality data from the WHO Africa region also indicated a potential economic burden of cholera for families and the health sector [4]. Cholera is an enteric bacterial disease caused by Vibrio cholerae serogroup O1 or O139 that usually occurs in sudden epidemics. Main features include acute, profuse watery diarrhea and vomiting that may lead to dehydration with concurrent electrolyte loss and eventually death if timely treatment is unavailable. Even though case-fatality rates (CFRs) may reach 50%, a rate below 1% has been achieved with proper case management [3], [5]. Treatment is based on prompt rehydration with oral rehydration solution (ORS) for mild to moderate cases and intravenous (IV) fluids for severe cases [3]. Antibiotics are recommended for severe, and also moderate cases, to reduce the duration of episodes and shedding of infectious V. cholerae [3], [6]. Traditionally, cholera control has been based on prevention (i. e. , adequate water supply, improved sanitation and health education, and timely treatment). The role of vaccination for cholera control has recently received increased attention from public health officials; the WHO recommends oral cholera vaccines (OCVs) as a supplementary public health tool to traditional prevention and treatment in endemic and epidemic settings [7]. A series of research studies, done as part of the Diseases of the Most Impoverished (DOMI) project coordinated by the International Vaccine Institute (IVI), evaluated the use of OCVs in Asia and Africa for control of endemic cholera. Private demand for cholera vaccines was examined through willingness-to-pay studies [8]–[11], costs of illness (COI) and mass vaccination data were collected [12]–[14], and cost-effectiveness and cost-benefit analyses were performed [15], [16]. Besides the recent article by Poulos et al. [13], published information about COI due to cholera is lacking even though patient-level data is needed for economic evaluations to improve local planning of cholera control. A joint initiative between the WHO, the IVI and the Ministry of Health of Zanzibar (MoH) implemented a mass vaccination campaign with an OCV in two selected cholera-endemic areas of Zanzibar in 2009. This intervention-cum-research project provided the opportunity to assess costs of immunization in an endemic setting. Public COI—defined as fixed and variable costs borne by the health care provider for setting up and running cholera treatment centers (CTCs) —were estimated from three outbreaks that happened in 2009 outside the mass vaccination target communities. Private direct COI—defined as medical and non-medical expenses related to patient treatment, and indirect COI—defined as loss of income borne by patients and their families—were elicited from a sample of patients admitted to CTCs during these outbreaks. This study aims to estimate (i) public and private COI due to cholera, (ii) costs of an oral cholera mass vaccination campaign, and (iii) the cost-effectiveness of using OCVs in endemic regions of Zanzibar from a health care provider and a societal perspective.
Written informed consent was obtained from all study participants interviewed for private costs of illness. Patients aged 18 years or older were directly interviewed while caregivers were interviewed if the patient was younger than 18 years. No incentives were provided to them. The protocol of this study was cleared by the WHO Research Ethics Review Committee and the MoH Ethics Committee. All data were handled confidentially and made anonymous before analysis. Zanzibar consists of two major islands, Unguja (also named Zanzibar) and Pemba, which are situated in the Indian Ocean about 40–60 km off the coast of Tanzania. Zanzibar, a semiautonomous polity within the United Republic of Tanzania, consists of five regions, which are subdivided into ten districts, 50 constituencies and 296 Shehias, the latter being the smallest administrative unit. The main islands cover ∼2,557 km2 (Unguja: ∼1,651 km2, Pemba ∼906 km2). The archipelago is inhabited by a fast-growing population of ∼1. 2 million Kiswahili-speaking Muslim people. Monthly mean per capita expenditure for all goods and services was TZS 21,000 (∼USD 18) in 2004/5 with a 2. 1% share for health-related expenditures [17]. Life expectancy at birth has risen from 47 years in 1988 to 57 years in 2002 [18]. The economy of the islands depends on agriculture (primarily cloves, coconuts/copra and seaweed), fishing and tourism. The public health care delivery structure in Zanzibar comprises two zones, Unguja and Pemba, each with three levels: the primary, the secondary and the tertiary level. Each zone is headed by a zonal medical officer. Most of the health care services are provided at the primary level through Primary Health Care Units (PHCU) (n = 124). The majority of these units is open during the day to outpatients and provides basic services. Primary Health Care Centers (PHCC) (n = 4) are additional facilities on the primary level; they operate on a 24-hours basis and can admit up to 30 patients. At the secondary level, three district hospitals (only in Pemba) are operational while the country' s only tertiary level hospital (Mnazi Mmoja) is located in the capital Stonetown in Unguja. The top causes of primary- and secondary-level outpatient visits in 2008 were upper respiratory tract infections (23%), pneumonia (10%), malaria (10%) and diarrhea (9%) [19]. In recent times, the first cholera outbreak with 411 cases and 51 deaths was reported in 1978 from two fishermen villages in Zanzibar [20]. More than a dozen outbreaks followed since then with almost annual episodes since the year 2000. Reyburn et al. reported an annual incidence of 0. 5 cases per 1,000 population based on a review of routine surveillance data for the years 1997 to 2007 [21], although the true incidence was likely higher due to underreporting. A seasonal pattern can be observed that follows the rainy seasons (usually from March to June and from October to December) during which widespread flooding occurs. Such deteriorating environmental conditions subsequently expose the majority of inhabitants on both islands to an increased risk of waterborne diseases due to the scarcity of safe drinking water supplies and a generally poor or lacking sanitation infrastructure in periurban and rural areas. Based on a consideration of areas of recent cholera activity, three Shehias per island, adjacent to each other, were selected as sites for the mass vaccination campaign. In Unguja, the Shehias of Chumbuni and Karakana in Urban district and Mtopepo in West district were targeted for the campaign; in Pemba, the Shehias of Kengeja, Mwambe and Shamiani, all located in the rural southeastern Mkoani district, were chosen. Dukoral, the only OCV that was pre-qualified by the WHO in 2009, was used in the mass vaccination campaign. Dukoral is a V. cholerae serogroup O1 whole-cell, killed vaccine containing recombinant cholera toxin (CT) B subunit protein; it has to be administered in two doses at least one week apart and requires a cold chain (2–8°C) [22]. This OCV was originally designed for immunologically naïve travelers from the north to tropical countries; it is licensed for use from two years of age and above and was shown to be 60–90% protective for up to three years [23]–[25]. One three-ml vial of Dukoral contains 1×1011 killed V. cholerae O1 (biotype classical and El Tor) and 1 mg of the CT B subunit protein in a suspension. Because the CT B subunit protein is not gastric acid-fast, the suspension has to be mixed with 1. 5 dl of drinking water and a buffer sachet containing effervescent granules of sodium bicarbonate before ingestion. Recipients need to fast one hour before and after ingestion. Table 1 describes cost components and sources of data collected for this study. Estimates for public COI were obtained from interviews with local experts and unvaccinated patients and from reports and record review. Cost data for the mass vaccination campaign were collected based on actual expenditure and planned budget data. Private direct and indirect costs were collected through interviews done with unvaccinated patients on Pemba. All costs are reported in 2009 USD from an economic perspective, based on mid-2009 exchange rates obtained from http: //www. oanda. com/currency/converter/. Based on a previous study for Bangladesh [29], a model was developed in Microsoft Excel to estimate the costs and health effects of a mass vaccination campaign program compared to standard treatment in CTCs in Zanzibar. A static cohort of 50,000 individuals, reflecting the target population of the 2009 mass vaccination campaign in Zanzibar, was examined from a health care provider and a societal perspective. Input parameters for inclusion in the model were related to vaccine characteristics and vaccination costs, burden and impact of cholera, and public and private COI. Private providers were not considered since the majority of patients would visit public facilities in case of an outbreak [26]. Indirect effects due to herd protection were also included in the model since they may play a considerable role in the overall impact of cholera vaccination [30] and were shown to make community-based programs in three Asian and one African setting cost-effective [15]. The base-case model considered costs and effects of a one-time vaccination program over the duration of protection (i. e. , three years). The annual number of cases without vaccination was obtained by multiplying the population size times the annualized cholera incidence obtained from surveillance of diarrhea cases with laboratory confirmation for cholera in the study area [31]. The annual number of cases under the vaccination program was derived from adding up direct and indirect effects of the vaccination program: direct effects were calculated by multiplying the annual incidence of cases without vaccination with (1 – protective efficacy among vaccinated people [PE]), coverage, and population size; indirect effects were calculated by multiplying the annual incidence of cases without vaccination with (1 – protective efficacy among unvaccinated people [PEU]), (1 – coverage), and population size. The variable PEU was derived using the concepts and a formula from Longini et al. [30] (p. 1778). It calculates what they refer to as “indirect vaccine effectiveness” = 1− (r01/r02), where r01 is the cholera incidence among unvaccinated people within a vaccinated sub-region and r02 is the cholera incidence in an unvaccinated sub-region. In the absence of incidence data among unvaccinated people from the mass vaccination campaign area, the incidence rate of 2. 34 cases per 1,000 population (after annualizing, Khatib et al. [31]) calculated from people that resided in the lowest quintile of surrounding coverage (i. e. , <39%) in a cluster with a radius of 400 m around vaccinated households was used as proxy for r02. Khatib et al. showed that herd protection effects mainly existed within that radius. A longer distance from the household of the vaccinated person was considered to dilute the benefit of herd protection. The incidence of 1. 29 cases per 1,000 population (after annualizing) among all unvaccinated people was used as an approximation for r01 [31]. This leads to a base-case estimate of PEU = 45%. The number of annual deaths without a vaccination program was calculated by multiplying the CFR with the annual number of cases without vaccination. The number of deaths with a vaccination program was calculated by using the CFR times the annual number of cases under the vaccination program. Incremental cost-effectiveness ratios (ICER) calculated as incremental costs per death, per case and per disability-adjusted life-year (DALY) averted were used as outcome measures. Incremental costs were calculated as the difference between costs of the vaccination program and public COI saved due to the vaccination from the health care provider perspective. Private direct COI saved were added in the base-case model adopting the societal perspective. Private indirect COI saved were not included in the base-case model [32]. The number of deaths, cases or DALYs averted was equal to the difference in numbers with and without the vaccination program. DALYs, which are an aggregate measure combining morbidity (i. e. , years of life lived with disability) and mortality (years of life lost), were calculated according to Jeuland et al. [15], assuming no age weighing. Since no disability weights are available for cholera, the disability weight of 0. 11 for diarrheal diseases [33] was used. Life expectancy at the average age of onset of 18 years based on patient data was obtained from WHO life tables for Tanzania [34]. The vaccine was directly purchased from the manufacturer at a UN price. Future effects were discounted at a rate of 3. 0% for the base case. Campaign costs were not discounted since the mass campaign happened over one single year. Cost-effectiveness was examined according to widely-used WHO criteria that define an intervention as ‘cost-effective’ if the ICER is less than three times per capita gross domestic product (GDP) per DALY averted and as ‘highly cost-effective’ if the ICER is less than per capita GDP per DALY averted [35]. One-way sensitivity analyses were done to estimate the influence of changes in potentially influential input parameters on model outcomes. Such key parameters included vaccine purchase price and delivery costs, protective efficacy (PE, PEU), duration of protection, incidence, CFR and so forth [15]. Plausible ranges were based on public health considerations (for vaccine purchase price and delivery costs, incidence), guidelines (discount rate) and variation for local data (PE, PEU, CFR, number of ill days, public and private COI). Base-case values and plausible ranges are presented in Table 2. Threshold analyses examined at which vaccine purchase price the intervention would become cost-effective.
Table 3 presents the fixed and variable mean public COI at the three CTC sites. Fixed costs of USD 51 accounted for 85% of public COI, with mean fixed costs ranging from USD 21 to USD 88. Direct and indirect human resources costs accounted for the majority of fixed costs; they were highest in Kiuyu Minungwini (86%), medium in Micheweni (85%) and lowest in Chumbuni (80%). The remaining fixed costs were used for setting up and running the centers. Health care personnel working in Unguja received higher top up payments than in Pemba, but the latter were given food to cater for themselves while on shift. Variable costs of USD 9. 2 were mainly driven by IV fluid use as patients were administered on average 8. 8 liters, which cost USD 7. 1. Further details on public variable costs for treatment can be found as supporting information in Table S1. A total of 95 individuals were interviewed. All but one of the interviewed patients had been admitted at the CTC at Micheweni PHCC. Total direct and indirect mean private COI amounted to USD 43, with almost three-fourth (USD 32) being indirect costs (i. e. , productivity losses to the patient or caregiver and other household members) (Table 4). Among direct costs, which amounted to USD 11, feeding the patient at the CTC accounted for the biggest share (USD 8. 3,19% of total costs). Other direct costs, incurred for treatment (mainly for plastic sheets needed to cover cots), transport and communication, were reported each by less than 3%. Total mass vaccination campaign costs amounted to USD 760,000, with USD 510,000 (68%) spent on vaccine purchase and USD 240,000 (32%) on delivery (Table 5). The vaccine was purchased from SBL Vaccin AB, Sweden, at a price of USD 10 per course (2 doses). Delivery costs comprised transport of the vaccine from Stockholm to Zanzibar and procurement of cups and water required for the buffer solution (6. 0% of campaign costs), the work of two experienced international consultants (14%), training of locally recruited implementers (1. 3%) and the implementation (social mobilization and vaccination) itself (10%). More details on delivery costs are presented as supporting information in Table S2. At a vaccine purchase price of USD 10 per course, the estimated total costs per fully immunized individual amounted to USD 30, with mean costs per vaccine course of USD 21 and mean costs for delivery of USD 9. 7. The latter amounted to USD 5. 3 after exclusion of services from international consultants, lowering the overall total costs per fully immunized individual to USD 26. Mean costs were adjusted for actual coverage of 50%, relating to 23,921 fully immunized individuals out of a population denominator of 48,178 used in the analysis by Khatib et al. [31].
This study has several limitations. First, due to limited data availability, this cost-effectiveness analysis assessed the value for money of a population-wide OCV campaign and not of a targeted approach for high-risk or specific age groups, which might make the intervention cost-effective as shown by Jeuland et al. for school-based programs in Kolkata and Beira [15]. However, threshold analyses using Shanchol indicated that scenarios targeting high-risk groups may become cost-effective in Zanzibar if the OCV was procured at a price below USD 1. 3, a level acceptable by many public health policy makers in Asia [36]. Second, it may be argued that the assumption of a preference for health facilities during a cholera outbreak may not necessarily reflect actual behavior as patients could also be negatively influenced by accessibility problems. Local observation and informal interviews, however, support this assumption, and the dense primary health care system reduces transport issues (according to the 2004/5 household budget survey, mean distance to a health care center in the urban and rural area was 0. 4 and 1. 7 km, respectively [17]) and because treatment for diarrhea is free. Third, non-diarrhea patients were usually not treated or admitted by their local public health care facility during the time it operated as a CTC. People seeking treatment for non-diarrheal diseases (e. g. , for malaria) during an ongoing cholera outbreak will have to bear extra direct and indirect costs related to additional travel or potential serious complications due to delayed treatment. These additional costs have not been included in the cost-effectiveness analysis due to a lack of relevant data; future studies in the area are advised to collect estimates on the costs of patients who are not able to get treatment at their usual center to assess the relevance of this ‘crowding out’ effect on cost-effectiveness. Fourth, the ICER might have been overestimated because waning has not been included in the estimate for PE. Jeuland et al. have adjusted their estimate in year 3 down by 17% [15]. However, since this represents a limited effect, and since sensitivity analysis included a minimum PE of 47%, omission of waning as input parameter in the model is likely to have only a limited effect. Fifth, threshold analysis for Shanchol did not consider potential savings due to the probably easier and faster administration of this new vaccine by oral syringe; this may have resulted in more favorable cost-effectiveness, but any beneficial effect will likely be limited because delivery costs influenced the ICER only to a small extent. Sixth, even though uncertainty in input parameters was considered in one-way sensitivity analyses, no full probabilistic uncertainty and sensitivity analysis was conducted which would provide a more complete picture of the distribution of possible outcomes and may find that some combinations of assumptions lead to greater cost-effectiveness than identified in the one-way sensitivity analysis [38]. Finally, a cost-benefit analysis may provide more useful information to local policy makers than a cost-effectiveness analysis because it explicitly characterizes the monetary value of prevented disease. However, willingness-to-pay data were not available for Zanzibar and contingent valuation exercises were beyond the scope of this study. Also, since campaign coverage with the free OCV in Zanzibar was merely 50% overall [31] and the community demanded a free vaccine [51], not making the OCV available for free in future campaigns would further jeopardize vaccine effectiveness and thus make such a program even less economical. The analysis presented here suggests that costs averted by a mass vaccination campaign with an OCV in endemic areas of Zanzibar were negligible when compared to standard treatment in decentralized cholera treatment centers. Mass vaccination was not cost-effective based on empirical data and the stated assumptions, mainly due to the relatively high purchase price and the relatively low cholera incidence in Zanzibar. However, mass vaccination campaigns in Zanzibar for endemic cholera control may meet WHO criteria for cost-effectiveness under certain circumstances, especially in high-incidence areas and when OCV prices are reduced to levels below USD 1. 3.
Despite efforts to improve water supply and sanitation, cholera still represents a serious burden in developing countries. Use of oral cholera vaccines (OCVs) in endemic and epidemic situations has recently shown a promising potential to mitigate this burden. To provide local decision-makers with specific information on OCV use for cholera control, we assessed the costs and benefits of a mass vaccination campaign that was conducted in 2009 in selected endemic areas of Zanzibar. We estimated the cost-effectiveness of OCVs by collecting health care provider and household costs of illness from cholera outbreaks and costs of the mass vaccination campaign that used the two-dose OCV Dukoral. Cost-effectiveness was expressed as the incremental costs of the one-off vaccination program per case, per death and per disability-adjusted life-year averted, over a three-year time period. Our model showed that the 2009 mass vaccination campaign in Zanzibar was not cost-effective, mainly due to the high OCV price (USD 10) and the relatively low incidence. Threshold analyses with Shanchol, the second OCV that is recommended by the WHO, indicated that mass vaccination in Zanzibar to control endemic cholera may become cost-effective if done in higher incidence areas and when OCV prices are reduced to levels below USD 1. 3.
medicine
public health and epidemiology
social and behavioral sciences
cost-effectiveness analysis
non-clinical medicine
neglected tropical diseases
cost effectiveness
immunizations
infectious diseases
cholera
health economics
public health
economics
socioeconomic aspects of health
Costs of Illness Due to Cholera, Costs of Immunization and Cost-Effectiveness of an Oral Cholera Mass Vaccination Campaign in Zanzibar