Research Article: Controlling Endemic Cholera with Oral Vaccines

Date Published: November 27, 2007

Publisher: Public Library of Science

Author(s): Ira M Longini, Azhar Nizam, Mohammad Ali, Mohammad Yunus, Neeta Shenvi, John D Clemens, Lorenz von Seidlein

Abstract: BackgroundAlthough advances in rehydration therapy have made cholera a treatable disease with low case-fatality in settings with appropriate medical care, cholera continues to impose considerable mortality in the world’s most impoverished populations. Internationally licensed, killed whole-cell based oral cholera vaccines (OCVs) have been available for over a decade, but have not been used for the control of cholera. Recently, these vaccines were shown to confer significant levels of herd protection, suggesting that the protective potential of these vaccines has been underestimated and that these vaccines may be highly effective in cholera control when deployed in mass immunization programs. We used a large-scale stochastic simulation model to investigate the possibility of controlling endemic cholera with OCVs.Methods and FindingsWe construct a large-scale, stochastic cholera transmission model of Matlab, Bangladesh. We find that cholera transmission could be controlled in endemic areas with 50% coverage with OCVs. At this level of coverage, the model predicts that there would be an 89% (95% confidence interval [CI] 72%–98%) reduction in cholera cases among the unvaccinated, and a 93% (95% CI 82%–99%) reduction overall in the entire population. Even a more modest coverage of 30% would result in a 76% (95% CI 44%–95%) reduction in cholera incidence for the population area covered. For populations that have less natural immunity than the population of Matlab, 70% coverage would probably be necessary for cholera control, i.e., an annual incidence rate of ≤ 1 case per 1,000 people in the population.ConclusionsEndemic cholera could be reduced to an annual incidence rate of ≤ 1 case per 1,000 people in endemic areas with biennial vaccination with OCVs if coverage could reach 50%–70% depending on the level of prior immunity in the population. These vaccination efforts could be targeted with careful use of ecological data.

Partial Text: The global burden of cholera remains substantial. In 2005, 131,943 cases and 2,272 deaths were reported to the WHO, and recently major, sustained epidemics have been reported in West Africa [1]. These statistics are gross underestimates, as many cholera-endemic countries do not report cholera to the WHO, including Bangladesh, which has among the highest rates of cholera in the world. More realistic estimates of the global burden of cholera mortality place the figure at 100,000–150,000 deaths per year. This high burden occurs because cholera targets the most impoverished populations, which often lack access to centers that can appropriately administer life-saving rehydration therapy.

In the mid-1980s, a randomized controlled vaccine trial with OCV in Matlab, Bangladesh, yielded 70% direct vaccine efficacy for up to two years [2,3]. We use information about Matlab, Bangladesh to construct a model of the population as it was in 1985, consisting of 183,826 participants. These individuals were mapped into families and families were distributed in “baris,” i.e., patrilineally related household clusters [7]. In the model, baris are further clustered into subregions of about 6 km2 that are considered to be the geographic cholera transmission areas. The model (see Figures S1–S5 and Texts S1 and S2) represents the number of contacts that a typical person makes with sources of potential cholera transmission in the course of a day. The age and bari size distributions of the population are based on data from Ali et al. [7]. Women and children are assumed to come into contact with sources of infection in the subregion where they live, while working males are assumed to make contact with infective sources in the subregion where they live as well as where they work. The population structure and movement distance function are given in Text S1.

We calibrated the simulation model using cholera incidence data observed in the first year of the vaccine trial (Table 1) over a 180 d period in order to capture all the cholera transmission during the large annual cholera outbreak. This was done by varying the transmission probability, π (see Figure S6 and Text S2), such that the differences between the observed incidence rates and the simulated incidence rates in Table 1 were minimized. The estimated reproductive number was 5.0 with a standard deviation of 3.3 (see Text S2). A summary of the parameters and their baseline values are shown in Table S1. The vaccine coverage levels in the target population and the effective coverage in the entire population from the trial are summarized in Table 1. We assume that vaccinated people receive an effective regimen of two doses. The observed cholera incidence rates among the unvaccinated ranged from a high of 7.0 cases/1,000 over 180 d for the subregions with the lowest coverage in the target population, centered at 14%, to 1.5 cases/1,000 for the highest coverage, centered at 58%. The observed cholera incidence rates among the vaccinated ranged from a high of 2.7 cases/1,000 for the subregions with the lowest coverage to 1.3 cases/1,000 for the highest coverage. We set the vaccine efficacy (VE) for susceptibility to VES = 0.7 [2,3] and for infectiousness to VEI = 0.5. The simulated incidence rates provided a good fit to the data based on a χ2 goodness-of-fit test for frequency data (p = 0.84, 9 degrees of freedom). Figure 3A–3D show the number of cases over time comparing the unvaccinated to the vaccinated populations. Videos S1 and S2 show the spatial–temporal epidemics at different coverage levels. For effectiveness measures, we compare the intervention subregions to hypothetical subregions that receive no vaccine, i.e., f = 0. Table 2 shows the indirect, total, and overall effectiveness estimated by the model for possible coverage levels when comparing coverages in the entire population, 2 y of age and older, ranging from 10% to 90% compared to no vaccination. For example, the average indirect effectiveness, comparing a population with a coverage of 30% to one with no vaccination, is 70% (also see Figure S7). This indicates that on average, the cholera incidence among unvaccinated people in a population with 30% coverage would be reduced by 70% compared with a completely unvaccinated population. At this level of coverage, the total effectiveness of 90% indicates high protection for a vaccinated person in a population with 30% vaccination coverage, while the overall effectiveness of 76% indicates a good overall reduction in risk to the overall population. According to the model, around 40 cases of cholera are prevented per 1,000-dose regimens of vaccine at low coverage and 13 cases at high coverage. At coverage levels of 50% and higher, all levels of effectiveness exceed 85%, resulting in the nearly total control, i.e., an overall annual cholera incidence of about 1 case per 1,000 people, of cholera transmission.

The results of this modeling study indicate that 50% coverage with OCV could control cholera transmission in endemic areas such as Matlab, Bangladesh through a combination of direct and indirect effects.. At this level of coverage, the model predicts an 89% reduction in cholera cases even among the unvaccinated, and a 93% reduction overall in the entire population. These results would apply only where cholera is endemic and population levels of immunity are relatively high. According to our simulations, areas where susceptibility is 2–2.5 as great as Matlab would need to have vaccine coverage of at least 70% to achieve cholera control. Since vaccine-induced protection with current OCV begins to wane after about two years, populations would have to be vaccinated biennially. This could be done in advance of the cholera season for regions that have clear seasonality. Alternatively, environmental predictors of cholera outbreaks could be sampled in regions where such a prediction capacity exists, and then vaccination could take place in advance of expected outbreaks. In environmental studies of cholera outbreak predictors in rural Bangladesh, increases in cholera incidence can be predicted several weeks in advance by water temperature, water depth, rainfall, conductivity, and copepod counts [14]. Such predictors have been developed for Bangladesh and parts of Latin America, but also need to be developed for other regions with substantial risk, especially in Africa. Rapid mass vaccination could take place after such predictors indicate that outbreaks are likely. Further research needs to be carried out on environmental predictors of cholera incidence to make such an assessment reliable. For endemic cholera, population-level immunity is relatively high, making control possible with relatively low vaccine coverage levels. For epidemic cholera, where population level immunity may not be high, rapid vaccination could also be beneficial, but further study would be required to determine the higher coverage levels necessary to obtain substantial indirect protection.



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