Meagan C. Fitzpatrick

Cost-effectiveness of canine vaccination to prevent human rabies in rural tanzania

Context Human rabies causes many deaths in resource-limited countries, and most are due to dog bites. Administration of postexposure prophylaxis is uncommon because of cost and limited access. Contribution Using a model of rabies transmission in 2 rural districts of Tanzania, the authors demonstrated that a campaign of annual rabies vaccination of dogs would be very cost- effective. Implication Annual canine rabies vaccination in sub-Saharan Africa could dramatically decrease the occurrence of this disease in humans. The Editors Rabies is a viral encephalitic disease of mammals that is responsible for an estimated 61000 human deaths each year (1), nearly one third of which occur in rural Africa (2). Once symptoms appear, rabies is almost universally fatal (3). Control of the disease in canines is a potential approach to reducing human rabies incidence because more than 99% of all human cases worldwide result from the bite of a domestic dog (4). Postexposure prophylaxis (PEP), including a series of vaccinations and administration of immunoglobulin, can prevent rabies after a dog bite. Worldwide, more than 7.5 million rabies PEP regimens are delivered annually (5) at an estimated cost of more than

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1.5 billion (1). Given that a disproportionate rabies burden occurs in sub-Saharan Africa, these costs often fall to the countries that are least able to afford them. In addition, PEP is frequently unavailable in rural areas within the 24-hour period recommended for treatment initiation after exposure to rabies (6). Concerns about program costs and the efficient use of health resources have been identified as major barriers to the implementation of canine vaccination programs (7). One-time canine rabies vaccination campaigns have been evaluated as cost-effective prevention against human rabies in urban Chad (8). However, more than 75% of rabies deaths in Africa occur in rural areas (2), and disease dynamics vary between these 2 settings because of different densities and contact patterns among humans, dogs, and other wildlife (9). Additionally, high birth and death rates in domestic dogs as well as reintroduction of rabies from dogs or wildlife in neighboring, unvaccinated regions make it unlikely that a 1-time vaccination campaign will control canine rabies in rural Africa indefinitely (10). Therefore, we evaluated the cost-effectiveness of rabies control in rural Africa through a strategy of annual canine vaccination campaigns. Methods We developed a mathematical model of rabies transmission to estimate the epidemiologic effects, clinical benefits, economic costs, and cost-effectiveness of canine vaccination coverage strategies ranging from 0% to 95% in rural Tanzania. No vaccination, which is the status quo in most parts of Tanzania, was considered the baseline for our analysis. Outcome measures included numbers of dogs vaccinated, incidence of human rabies, and economic costs (in 2010 U.S. dollars). The analysis was conducted from the perspective of a health policymaker, and we therefore considered health burden in terms of life-years, which in this context were equal to disability-adjusted life-years given that rabies is inevitably fatal. Thus, the entire health burden accrues from deaths rather than illnesses. We assessed economic costs associated with both a canine vaccination campaign and PEP to prevent rabies in exposed persons. In conformity with World Health Organization guidelines (11) and other recommendations for best practices (12), cost-effectiveness outcomes were reported across both 1- and 10-year time horizons on a present-value basis with a 3% annual discount rate. We evaluated the robustness of the results to model inputs, using both probabilistic uncertainty analysis and 1-way sensitivity analysis. We applied World Health Organization recommendations (13, 14) to denote strategies with incremental cost-effectiveness ratios less than the per-capita gross domestic product (GDP) for a life-year saved (GDP,

Potential for Rabies Control through Dog Vaccination in Wildlife-Abundant Communities of Tanzania

1430 for Tanzania [15]) as very cost-effective and ratios less than 3 times the per-capita GDP (

A Cost-Effectiveness Tool for Informing Policies on Zika Virus Control

4290) as cost-effective. We compared pastoral (Ngorongoro) and agro-pastoral (Serengeti) districts in rural Tanzania as representative of 2 major settlement patterns and canine densities in rural Africa. Although both are sparsely populated compared with cities, agro-pastoral areas generally consist of larger, more closely located villages than found in pastoral areas. Canine density, measured as dogs per square kilometer, was nearly 7 times higher in Serengeti than Ngorongoro. Rabies in Serengeti was endemic, with cases continuously observed, whereas rabies in Ngorongoro was epidemic, with no observed cases between outbreaks (16, 17). Additionally, pilot rabies vaccination campaigns in the 2 districts have required different strategies to achieve high coverage (18). Both districts border Serengeti National Park and are home to abundant and diverse wildlife populations. Although rabies cannot persist solely in wildlife in either district (16), we addressed concerns that vaccination coverage that had been sufficient for control in some regions may be insufficient in these wildlife-rich areas (7) by explicitly including wildlife hosts and their contribution to transmission in our dynamic model. Additional details and a map of these districts are included in the Appendix and Figure 1 of Supplement 1. Supplement 1. Figures We compared our model output with the incidence of canine and human rabies in these 2 districts before large-scale annual vaccination campaigns began. Because of past sporadic vaccination efforts, 5% to 10% of dogs in these districts had been previously vaccinated when the annual canine incidence was 1% to 2%. For human rabies, we had previously estimated an incidence of 1.48 to 4.28 deaths per 100000 people in Ngorongoro before large-scale implementation of canine vaccination, resulting in 2 to 6 rabies deaths per year for the district (22). From animal-bite injury data and availability of PEP, we had estimated that the incidence of human rabies in unvaccinated areas near Serengeti was 4.9 annual deaths (95% CI, 2.9 to 7.2) per 100000 persons in the late 1990s (23), leading to 5 to 13 human cases of rabies annually. Costs of Vaccination We parameterized the costs in our analysis using field data that we collected during annual vaccination campaigns in Serengeti and Ngorongoro and from published literature (18). We considered only the direct costs of vaccination because dogs are often brought to vaccination stations by children and the average income loss from bringing a dog to the central point was therefore considered to be minimal. We generated functions of cost with increasing vaccination coverage. The costs varied between the 2 districts. In the agro-pastoralist district of Serengeti, central-point vaccination campaigns were sufficient to achieve high coverage, whereas in the more sparsely populated pastoral district of Ngorongoro, central-point vaccination campaigns must be supplemented with door-to-door vaccinators to achieve high coverage, increasing the costs per dog vaccinated in Ngorongoro compared with those in Serengeti. We estimated costs as a function of coverage level, taking into account both the fixed costs of program start-up and the decreasing efficiency associated with searching for additional dogs to vaccinate as coverage levels increase (Appendix). Costs of Disease An untreated rabies bite to a human was estimated to result in the loss of 31.4 life-years on average (2), taking into account the typical age-distribution of persons with rabies. Monetary losses accrue through the cost of PEP, estimated to be

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111.29 per regimen (24), which includes both direct costs of treatment and indirect costs of transportation and lost income for the days on which treatment is administered. We assumed that a full course of PEP was 100% effective, which was both consistent with clinical data (6) and conservative given that this assumption would bias against canine vaccination. When persons who did not receive PEP progressed to rabies, we considered only the health burden because medical care is not effective and usually not provided in rural African settings. We constructed a probability tree to model the chain of events leading from a rabid dog to PEP, a case of rabies, or neither (Table 2 of Supplement 2 and Figure 1). We did not consider transmission from wildlife to humans because this represented fewer than 1% of human cases (4). However, our previous findings did show that mass vaccination of domestic dogs could concomitantly eliminate disease from wildlife (16), and this would potentially be an additional benefit for conservation (25, 26) as well as human health. Figure 1. Rabies transmission model. Our dynamic compartmental model is stratified by host type. Rabid dogs are linked to human deaths through a probability tree of human health outcomes. The equations governing the movement between classes are given in Table 1 of Supplement 2. PEP = postexposure prophylaxis. Supplement 2. Tables Data collected through contact tracing of all rabies cases detected from January 2002 through December 2006 (16, 17) were used to estimate that each rabid dog bites 0.51 humans (Appendix). We estimated that each rabid dog led to an average of

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36.89 in costs from PEP administration and a loss of 1.07 human life-years (Table 2 of Supplement 2). To estimate the cost of disease for each strategy that we considered, we multiplied each of these measures by the canine rabies incidence predicted through simulation. We calculated the cumulative economic cost of disease and vaccination on 2 time scales, annually and over a decade. Cost-Effectiveness Within each district, any strategy that had both greater monetary cost and more lives lost than some other strategy or combination of strategies was considered to be dominated by the latter strategy. For each nondominated scenario, we calculated the inc

One Health approach to cost-effective rabies control in India.

Babesia microti and Borrelia burgdorferi, the respective causative agents of human babesiosis and Lyme disease, are maintained in their enzootic cycles by the blacklegged tick (Ixodes scapularis) and use the white-footed mouse (Peromyscus leucopus) as primary reservoir host. The geographic range of both pathogens has expanded in the United States, but the spread of babesiosis has lagged behind that of Lyme disease. Several studies have estimated the basic reproduction number (R 0) for B. microti to be below the threshold for persistence (<1), a finding that is inconsistent with the persistence and geographic expansion of this pathogen. We tested the hypothesis that host coinfection with B. burgdorferi increases the likelihood of B. microti transmission and establishment in new areas. We fed I. scapularis larva on P. leucopus mice that had been infected in the laboratory with B. microti and/or B. burgdorferi. We observed that coinfection in mice increases the frequency of B. microti infected ticks. To identify the ecological variables that would increase the probability of B. microti establishment in the field, we integrated our laboratory data with field data on tick burden and feeding activity in an R 0 model. Our model predicts that high prevalence of B. burgdorferi infected mice lowers the ecological threshold for B. microti establishment, especially at sites where larval burden on P. leucopus is lower and where larvae feed simultaneously or soon after nymphs infect mice, when most of the transmission enhancement due to coinfection occurs. Our studies suggest that B. burgdorferi contributes to the emergence and expansion of B. microti and provides a model to predict the ecological factors that are sufficient for emergence of B. microti in the wild.

Optimizing the impact of low-efficacy influenza vaccines

Canine vaccination has been successful in controlling rabies in diverse settings worldwide. However, concerns remain that coverage levels which have previously been sufficient might be insufficient in systems where transmission occurs both between and within populations of domestic dogs and other carnivores. To evaluate the effectiveness of vaccination targeted at domestic dogs when wildlife also contributes to transmission, we applied a next-generation matrix model based on contract tracing data from the Ngorongoro and Serengeti Districts in northwest Tanzania. We calculated corresponding values of R 0, and determined, for policy purposes, the probabilities that various annual vaccination targets would control the disease, taking into account the empirical uncertainty in our field data. We found that transition rate estimates and corresponding probabilities of vaccination-based control indicate that rabies transmission in this region is driven by transmission within domestic dogs. Different patterns of rabies transmission between the two districts exist, with wildlife playing a more important part in Ngorongoro and leading to higher recommended coverage levels in that district. Nonetheless, our findings indicate that an annual dog vaccination campaign achieving the WHO-recommended target of 70% will control rabies in both districts with a high level of certainty. Our results support the feasibility of controlling rabies in Tanzania through dog vaccination.

Evaluating Vaccination Strategies for Zika Virus in the Americas

Background As Zika virus continues to spread, decisions regarding resource allocations to control the outbreak underscore the need for a tool to weigh policies according to their cost and the health burden they could avert. For example, to combat the current Zika outbreak the US President requested the allocation of

Optimal frequency of rabies vaccination campaigns in Sub-Saharan Africa

1.8 billion from Congress in February 2016. Methodology/Principal Findings Illustrated through an interactive tool, we evaluated how the number of Zika cases averted, the period during pregnancy in which Zika infection poses a risk of microcephaly, and probabilities of microcephaly and Guillain-Barré Syndrome (GBS) impact the cost at which an intervention is cost-effective. From Northeast Brazilian microcephaly incidence data, we estimated the probability of microcephaly in infants born to Zika-infected women (0.49% to 2.10%). We also estimated the probability of GBS arising from Zika infections in Brazil (0.02% to 0.06%) and Colombia (0.08%). We calculated that each microcephaly and GBS case incurs the loss of 29.95 DALYs and 1.25 DALYs per case, as well as direct medical costs for Latin America and the Caribbean of