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The authors have declared that no competing interests exist.

Conceived and designed the experiments: DTD CT MEH IML DLC. Performed the experiments: DTD. Analyzed the data: DTD. Contributed reagents/materials/analysis tools: DTD. Wrote the paper: DTD CT MEH IML DLC.

Killed, oral cholera vaccines have proven safe and effective, and several large-scale mass cholera vaccination efforts have demonstrated the feasibility of widespread deployment. This study uses a mathematical model of cholera transmission in Bangladesh to examine the effectiveness of potential vaccination strategies.

We developed an age-structured mathematical model of cholera transmission and calibrated it to reproduce the dynamics of cholera in Matlab, Bangladesh. We used the model to predict the effectiveness of different cholera vaccination strategies over a period of 20 years. We explored vaccination programs that targeted one of three increasingly focused age groups (the entire vaccine-eligible population of age one year and older, children of ages 1 to 14 years, or preschoolers of ages 1 to 4 years) and that could occur either as campaigns recurring every five years or as continuous ongoing vaccination efforts. Our modeling results suggest that vaccinating 70% of the population would avert 90% of cholera cases in the first year but that campaign and continuous vaccination strategies differ in effectiveness over 20 years. Maintaining 70% coverage of the population would be sufficient to prevent sustained transmission of endemic cholera in Matlab, while vaccinating periodically every five years is less effective. Selectively vaccinating children 1–14 years old would prevent the most cholera cases per vaccine administered in both campaign and continuous strategies.

We conclude that continuous mass vaccination would be more effective against endemic cholera than periodic campaigns. Vaccinating children averts more cases per dose than vaccinating all age groups, although vaccinating only children is unlikely to control endemic cholera in Bangladesh. Careful consideration must be made before generalizing these results to other regions.

Bangladesh has a high burden of cholera and may become the first country to use cholera vaccine on a large scale. Mass cholera vaccination may be hard to justify to international funding agencies because of the modest efficacy of existing vaccines and their limited duration of protection. However, mass cholera vaccination can induce high levels of indirect protection in a population, i.e., protecting even unvaccinated individuals by lowering cholera incidence, and a case for cost-effective cholera vaccination could be made. Mathematical modeling is one way to predict the magnitude of indirect protection conferred by a proposed vaccination program. Here, we predict the effectiveness of various mass cholera vaccination strategies in Bangladesh using a mathematical model. We found that maintaining high levels of vaccination coverage in children could be very effective in reducing the burden of cholera, and secondary transmission of cholera would virtually stop when 70% of the population is vaccinated. Mathematical modeling may play a key role in planning widespread cholera vaccination efforts in Bangladesh and other countries.

Oral cholera vaccines are safe and effective

It can be difficult to justify the widespread use of OCVs on economic grounds because: OCVs confer only moderate protection for a few years

Matlab is a rural community of approximately 220,000 people 30 kilometers southeast of Dhaka

We developed an age-structured mathematical model of cholera transmission. Compartments in the model are unvaccinated susceptible (S), vaccinated susceptible (V), symptomatically infected (I), asymptomatically infected (A), or recovered and immune (R) from cholera (

Individuals are aggregated in compartments by cholera status as susceptible unvaccinated (S), susceptible vaccinated (V), cholera cases (I), asymptomatically infected (A), and recovered (R). The concentration of ^{V}) is presented in

The model aggregates the population in compartments by disease status and age. Age cohorts represent children under 2 years old, pre-school aged children (2 to 4 years old), school aged children (5 to 14 years old), and adults (15 years old and older). Younger age groups are assumed to be more susceptible to infection

Frequency-dependent transmission rates are assumed for infections acquired through short cycle transmission (person-to-person) while a saturation (Holling type II

Infected individuals recover after five days on average and are immune to infection until they transition back to the susceptible state after an average of 3 years

The model is calibrated to fit the dynamics of cholera cases recorded between 1997 and 2001 in Matlab. The proportion of recovered individuals at the beginning of 1997 is estimated based on time-series data of cholera incidence in Matlab

A) Reported cholera cases per month in Matlab, Bangladesh from March 1997 to December 2001. B) Distribution of the reported cholera during this period by age group.

Vaccinated susceptibles in the model are protected for an average of five years. Adults and children 5 years and older are 65% less likely to become infected upon exposure to cholera than unvaccinated individuals and children 1–4 years are 40% less likely to become infected

We modeled vaccination programs that target one of three age groups: the entire vaccine-eligible population (those one year old and older), all children (ages one to fourteen years), and preschoolers (ages one to four years). We did not model the vaccination of those under one year old, since no vaccine is currently licensed for that age group

We modeled three distinct schedules for vaccinating these target populations: one-time campaign, periodic campaigns, and continuous vaccination. For the one-time campaign, a proportion of the targeted population is vaccinated at the start of the first year only. For the periodic campaigns, every five years a proportion of all susceptible and recovered individuals are vaccinated. The period between campaigns was chosen to match the duration of vaccine protection. The continuous vaccination strategy is an approximation of an annual vaccination program. In this strategy, a proportion of the targeted population is vaccinated at the beginning of the first year, then starting in the second year the unvaccinated susceptible and recovered individuals are vaccinated at a fixed rate for the duration of the simulation. A detailed description of the implementations of all vaccination strategies in the model is in

We define the overall effectiveness of mass vaccination to be the number of cholera cases prevented (i.e., the difference in the number of cases in a simulation without vaccination and the number of cases in a simulation with mass vaccination) divided by the number of cases when there is no vaccination

Seasonal cholera transmission was simulated in a rural population in Bangladesh using a mathematical model calibrated to reproduce the two annual peaks (

We compare the effectiveness over 20 years of one-time mass vaccination, recurring campaigns every five years, and continuous vaccination targeting 70% of all individuals one year old and older (

The one-time vaccination targets 70% of the vaccine-eligible population (those one year old and older) for vaccination, the 5-year campaigns target 70% of the population every 5 years, and the continuous vaccination strategy targets 70% of the population at the beginning of the first year then vaccinates at a constant rate starting in year 2. Vaccine is less effective for children aged 1–4 (40% efficacy) than for older children and adults (65% efficacy). Temporal dynamics of A) the fraction of the population protected by vaccine; B) annual cholera cases; C) the overall effectiveness in terms of prevented fraction of cholera cases when different vaccination strategies are implemented; and D) total number of vaccinations for different strategies over 10 and 20 years.

Because protection conferred by vaccination lasts five years, one might choose to conduct campaigns once every five years for logistical reasons. However, susceptibility in the population accumulates between campaigns and the proportion of the population protected by vaccine drops to 20%–25% due to the waning of vaccine efficacy and the birth of new susceptible individuals (

To avoid the fluctuations in vaccination coverage associated with 5-year campaigns, we modeled continuous vaccination in which people are vaccinated at a constant rate throughout the year every year after year 1. When calibrated to use nearly the same amount of vaccine as the 5-year campaigns (

We compared the effectiveness of targeting different age groups with campaigns every five years. Our modeling results suggest that vaccinating everyone (100% of) one year old and older at 5-year intervals would prevent 89% of cholera cases over 20 years (

A) Overall effectiveness and B) vaccinations per case prevented by mass vaccination campaigns that occur every 5 years. C) Overall effectiveness and D) vaccinations per case prevented by continuous vaccination. We assume that the vaccine protects for an average of 5 years and is less effective among children from ages 1 to 4 years (40% efficacy) than among older individuals (65% efficacy). Overall effectiveness is the prevented fraction of cholera cases over 20 years. The boxes represent the interquartile range and the whiskers cover 90% of the results from 100 simulations per scenario with parameters of seasonal environmental exposure sampled from ranges in

Continuous vaccination is associated with higher overall effectiveness than the 5-year campaigns. Coverage above 70% of the general population is sufficient to virtually interrupt onward transmission of cholera (

If vaccine efficacy in young children were as high as that in adults, then children ages 1 to 4 years old would be the most efficient age group to target, and vaccinating 70% of them every 5 years would have a VPC of 7, and maintaining 70% coverage with continuous vaccination would have a VPC of 6.5 (Figure S4 in

Simulated cholera epidemics are sensitive to the assumed proportion of cases that seek treatment. An alternative scenario was calibrated assuming 25% of cholera cases seek treatment in Matlab, resulting in a lower underlying disease burden than the main analysis, which assumed a 10% reporting rate. This alternative scenario projects substantially smaller epidemics and consequently stronger impact of all vaccination programs (Figures S6 and S7 in

We used a mathematical model to explore the potential effectiveness of mass cholera vaccination in rural Bangladesh and believe that the results apply more broadly to cholera endemic areas in Bangladesh. With the model, we were able to predict the overall effectiveness, which includes indirect effects, of different mass vaccination strategies. Our results indicate that maintaining 60% or higher vaccine coverage in the population would stop cholera transmission, which is consistent with an earlier modeling study

We found that vaccinating all vaccine-eligible children, ages 1–14 years, requires the fewest number of vaccinations per case averted compared to vaccinating preschool-aged children (1–4 years) or the general population (ages 1 year and older). Although preschool-aged children have the greatest burden of cholera, represented by both disease incidence and mortality

Delivering OCV to children could build upon existing delivery mechanisms like the Expanded Programme on Immunization (EPI) or National Immunization Days

Previous cost-effectiveness studies have found that untargeted mass cholera vaccination in Bangladesh may not be effective unless one accounts for indirect protection

There are several limitations to this study. The model was calibrated to match the demographic and epidemiologic characteristics of cholera in Matlab, Bangladesh; so extrapolating the results from this study to other settings requires careful consideration. We modeled transmission of cholera in an endemic setting where the incidence is much higher in children than adults. However, data from cholera outbreaks in non-endemic settings suggest a more even distribution of cholera incidence by age

The model was not intended for the prediction of cholera activity for a particular year. We calibrated the model using five years of data from Matlab, assuming that the epidemiology of cholera will not change substantially, so the 20-year projections described here should be considered average outcomes over this time horizon. We assumed that current demographic trends, sanitation levels, and climate would remain constant over the next 20 years, but changes in population movement, development, rainfall, the frequency of severe flooding events, sea level, and ocean temperature could change the epidemiology of cholera

There is growing momentum toward incorporating oral cholera vaccine into cholera control and outbreak response planning. Field and feasibility trials have been conducted in urban and rural Bangladesh and there appears to be interest to include targeted OCV use as part of comprehensive cholera control strategies

1. Model Description. 2. Forces of Infection. 3. Modeling Vaccination Strategies

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