Dengue is a systemic viral infection transmitted between humans by Aedes mosquitoes. For some patients, dengue is a life-threatening illness. There are currently no licensed vaccines or specific therapeutics, and substantial vector control efforts have not stopped its rapid emergence and global spread. The contemporary worldwide distribution of the risk of dengue virus infection and its public health burden are poorly known. Here we undertake an exhaustive assembly of known records of dengue occurrence worldwide, and use a formal modelling framework to map the global distribution of dengue risk. We then pair the resulting risk map with detailed longitudinal information from dengue cohort studies and population surfaces to infer the public health burden of dengue in 2010. We predict dengue to be ubiquitous throughout the tropics, with local spatial variations in risk influenced strongly by rainfall, temperature and the degree of urbanization. Using cartographic approaches, we estimate there to be 390 million (95% credible interval 284-528) dengue infections per year, of which 96 million (67-136) manifest apparently (any level of disease severity). This infection total is more than three times the dengue burden estimate of the World Health Organization. Stratification of our estimates by country allows comparison with national dengue reporting, after taking into account the probability of an apparent infection being formally reported. The most notable differences are discussed. These new risk maps and infection estimates provide novel insights into the global, regional and national public health burden imposed by dengue. We anticipate that they will provide a starting point for a wider discussion about the global impact of this disease and will help to guide improvements in disease control strategies using vaccine, drug and vector control methods, and in their economic evaluation.

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The global distribution and burden of dengue

Genetic manipulations of insect populations for pest control have been advocated for some time, but there are few cases where manipulated individuals have been released in the field and no cases where they have successfully invaded target populations. Population transformation using the intracellular bacterium Wolbachia is particularly attractive because this maternally-inherited agent provides a powerful mechanism to invade natural populations through cytoplasmic incompatibility. When Wolbachia are introduced into mosquitoes, they interfere with pathogen transmission and influence key life history traits such as lifespan. Here we describe how the wMel Wolbachia infection, introduced into the dengue vector Aedes aegypti from Drosophila melanogaster, successfully invaded two natural A. aegypti populations in Australia, reaching near-fixation in a few months following releases of wMel-infected A. aegypti adults. Models with plausible parameter values indicate that Wolbachia-infected mosquitoes suffered relatively small fitness costs, leading to an unstable equilibrium frequency <30% that must be exceeded for invasion. These findings demonstrate that Wolbachia-based strategies can be deployed as a practical approach to dengue suppression with potential for area-wide implementation.

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Successful establishment of Wolbachia in Aedes populations to suppress dengue transmission

Most studies on the ability of insect populations to transmit pathogens consider only constant temperatures and do not account for realistic daily temperature fluctuations that can impact vector–pathogen interactions. Here, we show that diurnal temperature range (DTR) affects two important parameters underlying dengue virus (DENV) transmission by Aedes aegypti. In two independent experiments using different DENV serotypes, mosquitoes were less susceptible to virus infection and died faster under larger DTR around the same mean temperature. Large DTR (20 °C) decreased the probability of midgut infection, but not duration of the virus extrinsic incubation period (EIP), compared with moderate DTR (10 °C) or constant temperature. A thermodynamic model predicted that at mean temperatures 18 °C, larger DTR reduces DENV transmission. The negative impact of DTR on Ae. aegypti survival indicates that large temperature fluctuations will reduce the probability of vector survival through EIP and expectation of infectious life. Seasonal variation in the amplitude of daily temperature fluctuations helps to explain seasonal forcing of DENV transmission at locations where average temperature does not vary seasonally and mosquito abundance is not associated with dengue incidence. Mosquitoes lived longer and were more likely to become infected under moderate temperature fluctuations, which is typical of the high DENV transmission season than under large temperature fluctuations, which is typical of the low DENV transmission season. Our findings reveal the importance of considering short-term temperature variations when studying DENV transmission dynamics.

Impact of daily temperature fluctuations on dengue virus transmission by Aedes aegypti

Vaccine efficacy (VE) estimates are crucial for assessing the suitability of dengue vaccine candidates for public health implementation, but efficacy trials are subject to a known bias to estimate VE toward the null if heterogeneous exposure is not accounted for in the analysis of trial data. In light of many well-characterized sources of heterogeneity in dengue virus (DENV) transmission, our goal was to estimate the potential magnitude of this bias in VE estimates for a hypothetical dengue vaccine. To ensure that we realistically modeled heterogeneous exposure, we simulated city-wide DENV transmission and vaccine trial protocols using an agent-based model calibrated with entomological and epidemiological data from long-term field studies in Iquitos, Peru. By simulating a vaccine with a true VE of 0.8 in 1,000 replicate trials each designed to attain 90% power, we found that conventional methods underestimated VE by as much as 21% due to heterogeneous exposure. Accounting for the number of exposures in the vaccine and placebo arms eliminated this bias completely, and the more realistic option of including a frailty term to model exposure as a random effect reduced this bias partially. We also discovered a distinct bias in VE estimates away from the null due to lower detectability of primary DENV infections among seronegative individuals in the vaccinated group. This difference in detectability resulted from our assumption that primary infections in vaccinees who are seronegative at baseline resemble secondary infections, which experience a shorter window of detectable viremia due to a quicker immune response. This resulted in an artefactual finding that VE estimates for the seronegative group were approximately 1% greater than for the seropositive group. Simulation models of vaccine trials that account for these factors can be used to anticipate the extent of bias in field trials and to aid in their interpretation.

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Biased efficacy estimates in phase-III dengue vaccine trials due to heterogeneous exposure and differential detectability of primary infections across trial arms.

Background 
Human movement is a key behavioral factor in many vector-borne disease systems because it influences exposure to vectors and thus the transmission of pathogens. Human movement transcends spatial and temporal scales with different influences on disease dynamics. Here we develop a conceptual model to evaluate the importance of variation in exposure due to individual human movements for pathogen transmission, focusing on mosquito-borne dengue virus.


Methodology and Principal Findings 
We develop a model showing that the relevance of human movement at a particular scale depends on vector behavior. Focusing on the day-biting Aedes aegypti, we illustrate how vector biting behavior combined with fine-scale movements of individual humans engaged in their regular daily routine can influence transmission. Using a simple example, we estimate a transmission rate (R0) of 1.3 when exposure is assumed to occur only in the home versus 3.75 when exposure at multiple locations—e.g., market, friend's—due to movement is considered. Movement also influences for which sites and individuals risk is greatest. For the example considered, intriguingly, our model predicts little correspondence between vector abundance in a site and estimated R0 for that site when movement is considered. This illustrates the importance of human movement for understanding and predicting the dynamics of a disease like dengue. To encourage investigation of human movement and disease, we review methods currently available to study human movement and, based on our experience studying dengue in Peru, discuss several important questions to address when designing a study.


Conclusions/Significance 
Human movement is a critical, understudied behavioral component underlying the transmission dynamics of many vector-borne pathogens. Understanding movement will facilitate identification of key individuals and sites in the transmission of pathogens such as dengue, which then may provide targets for surveillance, intervention, and improved disease prevention.

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The Role of Human Movement in the Transmission of Vector-Borne Pathogens

Knowledge of mosquito dispersal is critical for vector-borne disease control and prevention strategies and for understanding population structure and pathogen dissemination. We determined Aedes aegypti flight range and dispersal patterns from 21 mark-release-recapture experiments conducted over 11 years (1991-2002) in Puerto Rico and Thailand. Dispersal was compared by release location, sex, age, season, and village. For all experiments, the majority of mosquitoes were collected from their release house or adjacent house. Inter-village movement was detected rarely, with a few mosquitoes moving a maximum of 512 meters from one Thai village to the next. Average dispersal distances were similar for males and females and females released indoors versus outdoors. The movement of Ae. aegypti was not influenced by season or age, but differed by village. Results demonstrate that adult Ae. aegypti disperse relatively short distances, suggesting that people rather than mosquitoes are the primary mode of dengue virus dissemination within and among communities.

Dispersal of the dengue vector Aedes aegypti within and between rural communities.

A knowledge, attitude, and practice (KAP) survey and an extensive entomologic survey were conducted in two sub-districts of Kamphaeng Phet province, Thailand, to test the hypothesis that correct dengue knowledge and practice reduce dengue vector populations. We found a negative association between respondents' knowledge of preventive measures and the number of unprotected containers in and around their houses. Knowledge of development sites was positively associated with unprotected containers. No relationships existed between knowledge of dengue and adult mosquito reduction practices. A higher number of unprotected containers increased the likelihood of the house being infested with one or more adult Aedes aegypti. Surprisingly, houses of respondents that used mosquito coils or had screening on doors and windows were significantly more likely to be infested (odds ratio =2.0) with adult Ae. aegypti. We conclude that there is a direct link between knowledge on dengue prevention and container protection practices, whereas measures against adult mosquitoes are used only when people experience a mosquito nuisance problem.

Dengue knowledge and practices and their impact on aedes aegypti populations in kamphaeng phet, thailand

A hierarchical population genetic study was conducted among 19 Aedes aegypti populations in Thailand from Chiang Mai in the north to Songkhla province in the south. Single-strand conformation polymorphism analysis was used to examine variation in a 359-basepair region of the NADH dehydrogenase subunit 4 mitochondrial DNA gene (ND4). Seven haplotypes were detected in two lineages previously identified in ND4 haplotypes from North America. Gene flow estimates and highly significant variation among populations within 25 kilometers implicated genetic drift and vector control efforts as major factors in genetic structure. Mantel regression analysis demonstrated no isolation by distance. Urban areas were relatively panmictic, while suburban/rural sites exhibited more restricted gene flow. Significant genetic structure among groups of collections > 100 kilometers apart is consistent with recent (approximately 50 year) expansion of Ae. aegypti from highly populated areas accompanied by founder effects, but could also reflect the overall low genetic diversity in ND4 in Thailand.

Genetic structure of aedes aegypti populations in thailand using mitochondrial dna

The assumption that mosquito survival remains constant and that it is independent of age was tested with free-ranging Aedes aegypti (L.) (Diptera: Culicidae) by using a "synthetic cohort" mark-release-recapture method. Mosquito age cohorts (1-2, 3-4, and 19-20 d) were released simultaneously in homes in rural Thai villages during dry and rainy seasons (2002). Significant age-dependent effects were detected during the dry and rainy seasons. More young than older mosquitoes were recaptured (1-4 versus 5-20 d). The best predictive fit for recaptures was obtained using a quadratic function of age. Our results provide the first field-based evidence for age-dependent Ae. aegypti mortality in which the death rate increases with advancing age and highlight the need for research on ecological and epidemiological aspects of this process.

Age-Dependent Survival of the Dengue Vector Aedes aegypti (Diptera: Culicidae) Demonstrated by Simultaneous Release–Recapture of Different Age Cohorts

In 1999 and 2000 we evaluated a lethal ovitrap (LO) for the control of Aedes aegypti (L.) in three villages in Ratchaburi Province, Thailand. Two blocks of 50 houses (a minimum of 250 m apart) served as treatment and control sites in each village, with each house in the treatment area receiving 10 LOs. Thirty houses in the center of each treatment and control block were selected as sampling sites, with larval and adult mosquito sampling initiated when LOs were placed. Sampling was conducted weekly in 10 of the 30 houses at each site, with each block of 10 houses sampled every third week. Sampling continued for 30 wk. Efficacy of the LO was evaluated by determining number of containers with larvae and/or pupae per house and number of adult mosquitoes collected inside each house. In 1999, the LO had a negligible impact on all measures of Ae. aegypti abundance that were assessed; however, fungal contamination of insecticide-impregnated strips may have been responsible for the low efficacy. In 2000, significant suppression was achieved based on changes in multiple entomologic criteria (containers with larvae, containers with pupae, and number of adult Ae. aegypti); however, control was not absolute and neither immature nor adult Ae. aegypti were ever eliminated completely. We conclude that the LO can reduce adult Ae. aegypti populations in Thailand; however, efficacy of the LO is lower than desired due primarily to the high number of alternative oviposition sites. LO efficacy may be improved when used as part of an integrated control program that places emphasis on reduction of adjacent larval habitats. Further studies are required to assess this issue.

https://bioone.org/journals/Journal-of-Medical-Entomology/volume-40/issue-4/0022-2585-40.4.455/Field-Evaluation-of-a-Lethal-Ovitrap-for-the-Control-of/10.1603/0022-2585-40.4.455.pdf

Ratana Sithiprasasna

Papers

Dispersal of the dengue vector Aedes aegypti within and between rural communities.

Dengue knowledge and practices and their impact on aedes aegypti populations in kamphaeng phet, thailand

Genetic structure of aedes aegypti populations in thailand using mitochondrial dna

Age-Dependent Survival of the Dengue Vector Aedes aegypti (Diptera: Culicidae) Demonstrated by Simultaneous Release–Recapture of Different Age Cohorts

Field evaluation of a lethal ovitrap for the control of Aedes aegypti (Diptera: Culicidae) in Thailand.