PREEMPTIVE INTERVENTION OF MOSQUITO-BORNE VIRAL DISEASE

• Sponsoring Institution: National Institute of Food and Agriculture
• Project Status: COMPLETE
• Funding Source: HATCH
• Reporting Frequency: Annual
• Accession No.: 0207924
• Project Start Date: Oct 1, 2011
• Project End Date: Apr 14, 2016
• Program Code: [(N/A)]- (N/A)

Recipient Organization
UNIVERSITY OF CALIFORNIA, DAVIS
410 MRAK HALL
DAVIS,CA 95616-8671

Performing Department
Entomology and Nematology

Non Technical Summary
The overall goal of this project is to work closely with public health officials and policy makers in two dengue endemic countries to improve strategies for predicting and preventing the threat of disease. Detailed mathematical models that synthesize information on virus transmission will be used to make well-informed decisions for preemptive disease prevention.The key to early detection and disease prevention is to understand the spatial and temporal dynamics that support risk in a given setting, and then to use that information to target core dependencies in the transmission chain for maximum disease reduction impact. For, example, the earliest days of an epidemic are the most critical. If 100 active cases exist and each spawns 5 new cases with a 2 week generation time, then in a span of 8 weeks, 100 cases rapidly becomes 500, 2500, 12500, and 62500 cases, for a total of 78,100 cases. If the epidemic progression is delayed by even a single 2-week generation time, the potential is reduced to only 15,600 cases, an 80% reduction. Once case numbers are large, it is operationally more difficult to reduce transmission. Monitoring early indicators and targeting appropriate interventions is a more effective approach to averting illness than responding after an epidemic is well underway.As has been done recently for malaria, we will combine simulation modeling with empirical data to frame key elements of early detection and response and then predict the most effective operational methodologies in different settings. Analysis of the spatial-temporal dynamics of dengue outbreaks will facilitate comparative assessments of the timing and spatial configuration of maximally effective interventions. This unique dual-approach of extending empirical data with region-specific simulations will facilitate development of a cost-effective early warning methodology and predict long-term effectiveness of alternative intervention response strategies. Collaboration with Ministry of Health (MoH) surveillance and control programs will provide an ongoing rich exchange of information throughout these assessments.

Animal Health Component

10%

Research Effort Categories

Basic

85%

Applied

10%

Developmental

5%

Classification

Knowledge Area (KA)	Subject of Investigation (SOI)	Field of Science (FOS)	Percent
722	3110	1101	65%
722	3120	3030	10%
722	3110	2080	25%

Knowledge Area
722 - Zoonotic Diseases and Parasites Affecting Humans;

Subject Of Investigation
3120 - Spiders, mites, ticks, and other arthropods; 3110 - Insects;

Field Of Science
1101 - Virology; 2080 - Mathematics and computer sciences; 3030 - Information and communication;

Keywords

mosquito-borne viral disease

dengue virus

spatial and temporal dynamics

predictors of virus transmission

Goals / Objectives
The overall objective of this project is to test the concept that early detection and preemptive intervention of dengue transmission will appreciably reduce cases of severe disease. To do this we will establish innovative, evidence-based, and operationally informative recommendations for identifying local to regional patterns of dengue virus transmission and disease, predicting disease threat, and predicting most cost-effective preemptive surveillance-intervention strategies for averting disease in dengue endemic resource poor countries.

The traditional view of vector control is to track emerging vector populations, control or eliminate them, and thereby control vector-borne pathogen transmission. The problem with this is 3-fold: (a) surveillance methods (i.e., standards of measurement and application in practice) have not been effective in predicting risk, (b) it is difficult and expensive to do this everywhere and all of the time, and (c) if you could do this fairly effectively yet not "perfectly" (disease not eliminated), then the task of disease prevention via vector control alone would simply become increasingly more difficult. Over time the pathogen would continue to circulate, but in general herd immunity would decrease and the potential for an explosive epidemic would increase. Thus to take disease prevention to the next level, key questions are (a) how do you improve the standards of measurement and the application of those standards to better assess risk, (b) how do prioritize and anticipate the space and timing of increased risk in order to effectively target surveillance, and (c) how do you combine the best use of vaccine and vector control resources to provide the most operationally and most cost effective strategies for prevention under varying transmission conditions Answers to these questions will inform a new paradigm in early detection and prevention that is the focus of this project.

Our project will, for the first time, provide a research paradigm for investigating the spatial dynamics of indirect (i.e., human to vector to human) transmission of multiple virus serotypes over a broad scale, heterogeneous setting. We will do this by combining state of the art knowledge of both human and vector dynamics in a broad scale spatially explicit network model of transmission. This will allow problems a, b, and c above, which are associated with vector based prevention approaches, to be more fully defined and investigated. Using model simulations, we will examine the impacts of spatial contact networks and spatial heterogeneity on the geographic dispersion of infection and the relationship between human behavior and vector behavior in local to regional transmission. We expect this to provide new insights regarding early detection and the most effective use of limited vector control resources in different transmission settings.

Project Methods
To assess the effectiveness of specific early predictors of virus transmission and disease, a new generation of quantitative tools is necessary that will simulate virus transmission across a broad range of spatial and temporal scales, environmental and demographic settings, and human activity networks. We will perform country-specific high-resolution simulations of region-wide networks of virus transmission and associated cases of disease over multiple decades in Thailand and Peru, which represent 2 distinct dengue transmission settings. Our model will address the full spectrum of dynamics from individual human and vector contact to broad regional patterns of disease over time. Simulations will provide a toolset for testing hypotheses regarding long-term effectiveness of early predictors of transmission and disease and for comparing regional disease responses to specific human and vector-based intervention strategies and allow for strategic comparisons of otherwise cost-prohibitive systematic assessments of predictors of disease threat; enable comprehensive comparative assessments of existing and planned intervention technologies, alone and in combination, in a preemptive paradigm; and facilitate relative cost-benefit evaluations of preemptive intervention strategies in relation to choice of technology, timing of implementation with respect to early detection, and spatial/demographic configuration in relation to level of disease threat.Obj 1: Develop a stochastic regional network transmission model that will be used to test feasibility and effectiveness of preemptive intervention of virus transmission under varying conditions. Ongoing sharing of data, analyses, strategically designed simulation case studies, and vigorous exchange of ideas among international collaborators are a common thread through all project activities.Obj 2: Apply region-specific (Thailand and Peru) transmission simulations over broad space and time windows to compare and quantify the relative capacity of different risk measures to predict threat of virus transmission and disease under varying conditions. We hope to characterize predictors of transmission and disease that will guide highly effective preemptive surveillance and response by public health officials/policymakers and control managers.Obj 3: Extend the transmission model architecture to include space-time effects and relative unit costs of specific interventions. Perform a simulation-based comprehensive assessment of comparative effectiveness and cost-benefit of preemptive intervention strategies in response to different categories of disease threat (obj 2) under varying conditions.Obj 4: Formulate and share operationally informative and cost-effective recommendations for preemptive surveillance and risk-matched intervention strategies under varying conditions and refine and translate results of analyses in Obj 2/3 into operationally informative data and programmatic recommendations for the dengue prevention community. We will formulate and share operationally informative and cost-effective recommendations and supporting data for preemptive surveillance and risk-matched intervention strategies.

Progress 10/01/11 to 04/14/16

Outputs
Target Audience:Results are directly relevant to mosquito control activities carried out in dengue endemic countries around the world and in California where the mosquito vector of dengue, Aedes aegypti, was discovered during 2014. Because 390 million people are infected with dengue virus each year, there is a huge clientele that is interested in our activities in this project. We aim to influence ministries of health, state and local mosquito control districts, funding agencies, and international bodies like the World Health Organization and the Pan American Health Organization. Results are conveyed to mosquito control personnel, public health, and policy makers in personal meetings, conferences, workshops, courses, commissioned reports, talks at scientific meetings, and in scientific publications. Changes/Problems:I retired from UC Davis in June of 2015, this project and my participation in the AES ended at that time. What opportunities for training and professional development has the project provided?I worked closely with and mentored two post-doctoral scholars, 3 PhD students, 2 Staff Research Associates, and 2 undergraduate researchers regarding dengue prevention research in my laboratory. How have the results been disseminated to communities of interest?In addition to publications and talks at scientific conferences, meetings, universities, and workshops that are publicly available to the vector-borne disease prevention community in general, I work directly with, exchange published and unpublished information with, and provide consultation to the California Mosquito and Vector Control Association, Society for Vector Ecology, American Society of Tropical Medicine and Hygiene, USA Naval Medical Research Unit-6 in Lima, Peru; the Peruvian Ministry of Health; the USA Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand; the Thai Ministry of Public Health; the Institut Pasteur, Paris, France; and the World Health Organization. What do you plan to do during the next reporting period to accomplish the goals?This project ended when I retired from UC Davis in June 2015.

Impacts
What was accomplished under these goals? EPIDEMIOLOGICALLY RELEVANT BIOLOGY: To assess the effectiveness of specific early predictors of disease caused by mosquito-borne viruses, my colleagues and I made the following contributions. We improved understanding of virus transmission dynamics and the clinical spectrum of infection are critical for informing surveillance and control measure by showing that people and mosquitoes from a small portion of houses were responsible for the majority of transmission. We showed that fluctuating daily temperatures have important impacts mosquito life history traits and capacity to transmit virus. Large temperature fluctuations contribute to seasonal reduction in virus transmission. Mosquito infection was delayed under large temperature fluctuations around mean annual temperatures, which helps explain why mosquitoes are less likely to transmit virus during the low than high transmission season. Conversely, large fluctuations at low temperatures reduced the incubation period and increased potential for virus transmission at cooler temperatures. This complexity is important to account for in improved assessments of population dynamics and virus transmission modeling and downstream applications for mosquito surveillance and disease prevention. We assembled a comprehensive database describing adult female movement experiments, which revealed patterns associated with geography as well as mosquito genus, consistent with mosquito biology varying by species-specific life history and ecological context. We showed that when individual human movements overlaped to a high degree within social groups we were able to recreate infection patterns similar to those detected in a dengue-endemic area. We made the first daily estimates for the risk of human dengue virus infection, which indicate that current intervention targets will likely underestimate the level of effort needed to prevent disease. Using contact-clusters in a case-control design, we examined the role of mobility in the invasion and spread of dengue virus. We found that, at an individual level, risk of infection is defined by contact with pathogen across recently visited places conducive to exposure and that movements underlie spatial patterns of incidence, causing marked heterogeneity. At a collective level, transmission is shaped by reciprocal movements of individuals among the same places, such as the homes of family and friends. We concluded that human mobility is a fundamental driver of pathogen transmission and provides a mechanistic basis for predicting and interpreting patterns of infectious diseases within populations. To quantify potential cross-protective effects of infection with different viruses, we estimated disease risk as a function of infection from five years of longitudinal studies at our study site in Iquitos. Our results indicate that pre-existing heterotypic antibodies markedly reduced, but did not eliminate, risk of disease in this study population. Our results improve understanding of how pre-infection history can be associated with dengue disease outcomes and will help guide the development and application of dengue vaccines. We carried out longitudinal cohort and geographic cluster studies in rural Thailand to characterize the clinical spectrum of dengue virus infection. Symptom-based case definitions were unreliable for diagnosis. Mild infections accounted for a major proportion of all DENV infections. These findings are relevant for disease burden assessments, transmission modeling, and determination of vaccine impact. MATHEMATICAL AND SIMULATION MODELING: Mosquito-borne diseases pose some of the greatest challenges in public health, especially in tropical and sub-tropical regions of the world. Efforts to control these diseases are underpinned by a theoretical framework including models, metrics for measuring transmission, and theory of control that identifies key vulnerabilities in the transmission cycle. My colleagues and I did the following to elevate the science of modeling mosquito-bonre disease. We developed novel mathematical approaches that can be used to show how heterogeneity arises from the biology and the landscape on which the processes of mosquito biting and pathogen transmission unfold. We predicted that emerging theory will need to focus attention on the ecological and social context for mosquito blood feeding, the movement of both hosts and mosquitoes, and the relevant spatial scales for measuring transmission and for modeling dynamics and control. We developed and tested a new dynamic framework based on the ecological context of mosquito blood meals and the fine-scale movements of individual mosquitoes and human hosts. We developed a generalizable framework for simulating the locations that an individual visits, the allocation of time across those locations, and population-level variation therein. We carried out a systematic historical review of published mathematical models of mosquito-transmitted diseases revealed the central role in theory and practice of a 40 year old modeling framework. We identified which currently unaddressed topics and alternative approaches that would significantly enhance response and prevention of disease. We compiled a comprehensive bibliography of 325 publications from 1970 through 2010 and concluded that modern theory would benefit from an expansion around the concepts of heterogeneous mosquito biting, poorly mixed mosquito-host encounters, spatial heterogeneity, and temporal variation in the transmission process. We developed simple models with heterogeneity in mosquito egg laying patterns and in the responses of larval populations to crowding in aquatic habitats. Our analysis suggests that, in some contexts, control efforts that account for heterogeneity in production of adult mosquitoes has enormous potential for improved, strategic mosquito control. MAPPING MOSQUITO-BORNE DISEASE: Coupling the insights from infectious disease modeling with the communication strengths of spatial mapping has benefits for assessing risk and prioritizing interventions. My colleagues and I explored the following opportunities for combining these disciplines to improve public health. Using a novel approach, evidence consensus map of disease range that highlights nations with an uncertain dengue status, we produced a map identifying 128 countries for which there is good evidence of dengue occurrence, including 36 countries previously classified as dengue-free by the World Health Organization or Centers for Disease Control. Because the contemporary worldwide distribution of the risk of dengue virus infection and its public health burden are poorly known we undertook an exhaustive assembly of known records of dengue occurrence worldwide and used a formal modeling framework to map the global distribution of dengue virus infection risk. We then paired 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. Using cartographic approaches, we estimate there to be 390 million dengue virus infections per year, of which 96 million manifest apparently. 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. Our 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 guide improvements in disease control strategies using vaccine, drug and vector control methods and in their economic evaluation. We subsequently summarized the global distribution of each DENV type from 1943-2013, presenting our results in a series of global maps.

Publications

• Type: Journal Articles Status: Published Year Published: 2015 Citation: Brady, O.J., H.C.J Godfray, A.J. Tatem, P.W. Gething, J.M. Cohen, F. E. McKenzie, T.A. Perkins, R.C. Reiner Jr., L.S. Tusting, T.W. Scott, S.W. Lindsay, S.I. Hay, and D.L. Smith. 2015. Adult vector control, mosquito ecology, and malaria transmission. Internat. Hlth. 7:121-129. Messina J.P., O.J. Brady, D.M. Pigott, N. Golding, M.U.G. Kraemer, T.W. Scott, G.R.W Wint, D.L. Smith, and S.I. Hay. 2015. The many projected futures of dengue. Nature Reviews Microbiology. 13: 230-239. Achee, N.L., F. Gould, T.A. Perkins, R.C. Reiner, Jr., A.C. Morrison, S.A. Ritchie, D.J. Gubler, R. Teyssou, and T.W. Scott. 2015. A critical assessment of vector control for dengue prevention. PLoS Neglected Tropical Diseases. 9: e0003655. Wilson, A.L., M. Boelaert, T. Burkot, I. Kleinschmidt, M. Pinder, T.W. Scott, L. Tusting, and S.W. Lindsay. 2015. Evidence-based vector control? Improving the quality of vector control trials. Trends Parasit. 31: 380-390. Brady, O.J., D.L. Smith, T.W. Scott, and S.I. Hay. Dengue disease outbreak definitions are implicitly variable. Epidemics. 11: 92-102. Lambrechts, L., N.M. Ferguson, E. Harris, E.C. Holmes, E.A. McGraw, S.L. ONeill, E.E. Ooi, S.A. Ritchie, P.A. Ryan, T.W. Scott, C.P. Simmons, and S.C. Weaver. 2015. Assessing the epidemiology of Wolbachia for dengue control. 2015. Lancet Infectious Disease. 15: 862-866. Kraemer, M.U.G., M.E. Sinka, K.A. Duda, A. Mylne, F.M. Shearer, C.M. Barker, C.G. Moore, R.G. Carvalho, G.E. Coelho, W. Van Bortel, G. Hendrickx, F. Schaffner, I.R.F Elyazar, H.-J. Teng, O.J. Brady, J.P. Messina, D.M. Pigott, T.W. Scott, D.L. Smith, G.R.W. Wint, N. Golding, and S.I. Hay. 2015. The global distribution of the arbovirus vectors Aedes aegypti and Ae. albopictus. eLife. 4: e08347. Thomas, S.J., J. Aldstadt, R.G. Jarman, D. Tannitisupawong, I.K. Yoon, J. Richardson, A. Ponlawat, S. Iamsirithaworn, T.W. Scott, A.L. Rothman, R.V. Gibbons, L. Lambrechts, and T. Endy. 2015. Improving dengue virus capture rates in humans and vectors in Kamphaeng Phet Province, Thailand, using an enhanced spatiotemporal surveillance strategy. Am. J. Trop. Med. Hyg. 93: 24-32. Campbell, K.M., K. Haldeman, C. Lehnig, C.V. Munayco, E.S. Halsey, A. Laguna, M. Yagui, A.C. Morrison, C.D. Lin, and T.W. Scott. 2015. Weather regulates location, timing, and magnitude of dengue virus transmission between humans and mosquitoes. PLoS Neglected Tropical Diseases. 7: e0003957. Duong, V., L. Lambrechts, R. Paul, S. Ly, S.R. Lay, K. Long, A. Tarantola, T.W. Scott, A. Sakuntabhai, and P. Buchy. 2015. Asymptomatic humans transmit dengue virus to mosquitoes. Proc. Natl. Acad. Sci. USA. 112: 14688-14693. Paz-Soldan, V.A., J.J.C. Lopez, A.C. Morrison, A. Lenhart, J. Elder, M. Sihuincha, T.W. Scott, T. Kochel, E. Halsey, H. Astete, and P.J. McCall. 2015. Dengue knowledge and preventive practices in Iquitos, Peru. Am. J. Trop. Med. Hyg. 93: 1330-1337.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Chaves, L.F., T.W. Scott, A.C. Morrison, and T. Takada. 2014. Hot temperatures can force delayed mosquito outbreaks via sequential changes in Aedes aegypti demographic parameters in autocorrelated environments. Acta Tropica. 129: 15-24. Liebman, K.A., S.T. Stoddard, R.C. Reiner, T.A. Perkins, H. Astede, M. Sihuincha, E.J. Halsey, T.J. Kochel, A.C. Morrison, and T.W. Scott. 2014. Determinants of heterogeneous blood feeding patterns by Aedes aegypti in Iquitos, Peru. PLoS Neglected Tropical Diseases. e2702. Ramsey, J.M., J.G. Bond, M.E. Macotela, L. Facchinelli, L. Valerio, D.M. Brown, T.W. Scott, and A. A. James. 2104. A regulatory structure for working with genetically modified mosquitoes: Lessons from Mexico. PLoS Neglected Tropical Diseases. E2623. Messina, J.P., O.J. Brady, T.W. Scott, C. Zou, D.M. Pigott, K. Duda, S. Bhatt, L. Katzelnick, R.E. Howes, K.E. Battle, C.P. Simmons, and S.I. Hay. 2014. Global spread of dengue virus types: Mapping the 70-year history. Trends Microbiology. 22: 138-146. Smith, D.L., T.A. Perkins, R.C. Reiner Jr., C.M. Barker, T. Niu, L.F. Chaves, A.M. Ellis, D.B. George, A. Le Menach, J. Pulliam, D. Bisanzio, C. Buckee, C. Chiyaka, D.A.T. Cummings, A.J. Garcia, M.L. Gatton, P.W. Gething, D.M. Hartley, G. Johnston, E.Y. Klein, E. Michael, S.W. Lindsay, A.L. Lloyd, D.M. Pigott, W.K. Reisen, N. Ruktanonchai, B. Singh, J. Stoller, A.J. Tatem, U. Kitron, S.I. Hay, and T.W. Scott. 2014. Recasting the transmission dynamics of mosquito-borne pathogens. Trans. Roy. Soc. Trop. Med. Hyg. 108: 185-197. Pongsiri, A., A. Ponlawat, B. Thaisomboonsuk, R.G. Jarman, T.W. Scott, and L. Lambrechts. 2014. Differential susceptibility of two field Aedes aegypti populations to a low infectious dose of dengue virus. PLoS ONE. 9: e92971. Reiner, Jr., R.C., S.T. Stoddard, and T.W. Scott. 2014. Socially-structured human movement shapes dengue transmission despite the diffusive effect of mosquito dispersal. Epidemics. 6: 30-36. Paz-Soldan, V.A., R.C. Reiner, Jr., A.C. Morrison, S.T. Stoddard, U. Kitron, T.W. Scott, J.P. Elder, E. Halsey, T.J. Kochel, H. Astete, and G.M. Vazquez-Prokopec. 2014. Strengths and weaknesses of Global Positioning System (GPS) data-loggers and semi-structured interviews for capturing fine-scale human mobility: Findings from Iquitos, Peru. PLoS Neglected Tropical Diseases. 8: e2888. Reiner, Jr, R.C., S.T. Stoddard, B.M. Forshey, A.A. King, A.M. Ellis, A.L. Lloyd, K.C. Long, C. Rocha, S. Vilcarromero, H. Asete, I. Bazan, A. Lenhart, G.M. Vazquez-Prokopec, V. Paz-Soldan, P.J. McCall, U. Kitron, J. Elder, E. Halsey, A.C. Morrison, T.J. Kochel, and T.W. Scott. 2014. Time-varying, serotype-specific force of infection of dengue virus. Proc. Natl. Acad. Sci. USA. 201314933111. Guerra, C.A., R.C. Reiner, T.A. Perkins, S.W. Lindsay, J. Midega, O.J. Brady, C.M. Barker, W.K. Reisen, L.C. Harrington, W. Takken, U. Kitron, A.L. Lloyd, T.W. Scott, and D.L. Smith. A global assembly of adult female mosquito mark-release-recapture data to inform the control of mosquito-born pathogens. Parasites & Vectors. 7: 276. Stoddard, S.T., H.J. Wearing, R.C. Reiner, Jr., A.C. Morrison, H.Astete, S. Vilcarromero, C. Alvarez, C. Ramal-Asayag, M. Sihuincha, C. Rocha, E.S. Halsey, T.W. Scott, T.J. Kochel, and B.M. Forshey. 2014. Long-term and seasonal dynamics of dengue in Iquitos, Peru. PLoS Neglected Tropical Diseases. 8: e3003. Brady, O.J., N. Golding, D.M. Pigott, M.U.G. Kraemer, R.C. Reiner Jr., T.W. Scott, D.L. Smith, P.W. Gething, and S.I. Hay. 2014. Global temperature constraints on Aedes aegypti and Aedes albopictus persistence and competence for dengue virus transmission. Parasites & Vectors. 7: 338.
• Type: Journal Articles Status: Published Year Published: 2013 Citation: Perkins, T.A., T.W. Scott, A. Le Menach, and D.L. Smith. 2013. Heterogeneity, mixing, and the spatial scales of mosquito-borne pathogen transmission. PLoS Computational Bio. 9: e1003327. Legros, M., C. Xu, A.C. Morrison, T.W. Scott, A.L. Lloyd, and F. Gould. 2013. Modeling the dynamics of a non-limited and a self-limited gene drive system in structured Aedes aegypti populations. PLoS ONE. 8: e83354. Brady, O.J., M.A. Johansson, C.A. Guerra, S. Bhatt, N. Golding, D.M. Pigott, H. Delatte, M.G. Grech, P. Leisnham, R. Maciel-de-Freitas, L.M. Styer, D.L. Smith, T.W. Scott, P.W. Gething and S.I. Hay. 2013. Modelling adult Aedes aegypti and Aedes albopictus survival at different temperatures in laboratory and field settings. Parasites & Vectors. 6:351.

Progress 10/01/13 to 09/30/14

Outputs
Target Audience: Results are directly relevant to mosquito control activities carried out in dengue endemic countries around the world and in California where the mosquito vector of dengue, Aedes aegypti, was discovered during 2014. Because 390 million people are infected with dengue virus each year, there is a huge clientele that is interested in our activities in this project. We aim to influence ministries of health, state and local mosquito control districts, funding agencies, and international bodies like the World Health Organization and the Pan American Health Organization. Results are conveyed to mosquito control personnel, public health, and policy makers in personal meetings, conferences, workshops, courses, commissioned reports, talks at scientific meetings, and in scientific publications. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided? I worked closely with and mentored two post-doctoral scholars, 3 PhD students, 2 Staff Research Associates, and 2 undergraduate researchers regarding dengue prevention research in my laboratory. How have the results been disseminated to communities of interest? In addition to publications and talks are scientific conferences, meetings, and workshops that are publicly available to the vector-borne disease prevention community in general, I work directly with, exchange published and unpublished information with, and provide consultation to the USA Naval Medical Research Unit-6 in Lima, Peru; the Peruvian Ministry of Health; the USA Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand; the Thai Ministry of Public Health; the Institut Pasteur, Paris, France; and the World Health Organization. What do you plan to do during the next reporting period to accomplish the goals? During the next reporting period I will (1) carry out new analyses of temporal and spatial dynamics in dengue transmission dynamics and (2) develop new modeling frameworks that account for heterogeneity in the role of humans and mosquitoes in virus transmission. Results from empirical analyses and theoretical modeling exercises will be the basis for predicting dengue transmission and disease dynamics under varying epidemiological and ecological conditions. Knowledge gained from those activities will be applied to improve public health policy and strategic concepts in disease prevention programs at global (World Health Organization), regional (Peru and Thailand), and local (local Peruvian Ministry of Health and Mosquito and Vector Control Association of California).

Impacts
What was accomplished under these goals? Mosquito-borne diseases pose some of the greatest challenges in public health, especially in tropical and sub-tropical regions of the world. Efforts to control these diseases are underpinned by a theoretical framework developed for malaria, including models, metrics for measuring transmission, and theory of control that identifies key vulnerabilities in the transmission cycle. We determined that fine-scale heterogeneity causes transmission dynamics to vary from assumptions of traditional approaches. Novel mathematical approaches can be used to show how heterogeneity arises from the biology and the landscape on which the processes of mosquito biting and pathogen transmission unfold. We predicted that emerging theory will need to focus attention on the ecological and social context for mosquito blood feeding, the movement of both hosts and mosquitoes, and the relevant spatial scales for measuring transmission and for modeling dynamics and control. Most current mathematical models often make the convenient assumption that populations are well mixed; i.e., that each mosquito is equally likely to bite any human host. This assumption conflicts with empirical evidence that transmission is heterogeneous. We developed and tested a new dynamic framework based on the ecological context of mosquito blood meals and the fine-scale movements of individual mosquitoes and human hosts. Our analyses indicate that movement patterns of mosquitoes and humans are an important source of heterogeneity in pathogen transmission, which affects epidemic dynamics and vaccine coverage levels necessary to achieve herd immunity. Existing models of fine-scale human movement either pertain to overly coarse scales, simulate some aspects of movement but not others, or were designed specifically for populations in developed countries. We developed a generalizable framework for simulating the locations that an individual visits, the allocation of time across those locations, and population-level variation therein. We found that location type and distance from home were significant determinants of the locations that individuals visited and the proportions of time that they spent at those locations. Simulated patterns of time allocation matched empirical patterns in a number of ways, suggesting that our framework constitutes a sound basis for simulating fine-scale movement and for investigating factors that influence it. Documenting the type-specific record of dengue spread has important implications for understanding patterns in hyper-endemicity and disease severity as well as vaccine design and deployment strategies. We summarized the global distribution of each DENV type from 1943-2013, presenting our results in a series of global maps. These show the worldwide expansion of the types, of disease hyper-endemicity, and the establishment of an increasingly important infectious disease of global public health significance. We used data from over 400 published Ae. aegypti and Ae. albopictus survival experiments to create survival models for laboratory and field conditions. Survival is a critical component of their ability to transmit dengue virus. Our results support the importance of producing site-specific mosquito survival estimates. Our models can be integrated with dengue modeling efforts to guide and evaluate vector control, map the distribution of disease, and produce early warning systems for dengue epidemics. Mosquito mark-release-recapture (MMRR) experiments are a standard method for estimating such parameters including dispersal, population size and density, survival, blood feeding frequency and blood meal host preferences. We assembled a comprehensive database describing adult female MMRR experiments. The resulting database contained 774 unique adult female MMRR experiments involving 58 vector mosquito species from the three main genera of importance to human health. Crude examination of these data revealed patterns associated with geography as well as mosquito genus, consistent with mosquito biology varying by species-specific life history and ecological context. Our database is a substantial contribution to the compilation of global data that can be used to better inform basic research and public health interventions, to identify and fill knowledge gaps and to enrich theory and evidence-based ecological and epidemiological studies of mosquito vectors, pathogen transmission and disease prevention. We investigated the effect of socially structured movement on DENV transmission using a spatially explicit, agent-based transmission model. When individual movements overlaped to a high degree within social groups we were able to recreate infection patterns similar to those detected in a dengue-endemic area. Our results support the hypothesis that social proximity drives fine-scale heterogeneity in DENV transmission rates. This heterogeneity appeared to be hidden by the diffusive effect of mosquito dispersal in aggregated infection dynamics, which implies it could be present and active in real dengue systems without being easily noticed. Accounting for socially determined, overlapping human movements would substantially improve the efficiency and efficacy of dengue surveillance and disease prevention programs as well as result in more accurate estimates of important epidemiological measure of virus transmission. These models rely on accurate estimates of key transmission parameters such as the force of infection (FoI), which is the percapita risk of a susceptible person being infected. The FoI captures the fundamental dynamics of transmission and is crucial for gauging control efforts, such as identifying vaccination targets. Existing estimates of the dengue FoI are inaccurate because they rely on the unrealistic assumption that risk is constant over time. Dengue models are thus unreliable for designing vaccine deployment strategies. We made the first time-varying (daily), serotype-specific estimates of dengue FoIs using a spline-based fitting procedure. Yearly FoI varied markedly across time and serotypes (0–0.33), as did daily basic reproductive numbers (0.49–4.72). During specific time periods, the FoI fluctuations correlated across serotypes, indicating that different DENV serotypes shared common transmission drivers. Our results indicate that intervention targets based on one-time estimates of the FoI could underestimate the level of effort needed to prevent disease. Our description of dengue virus transmission dynamics provides a basis for understanding the persistence of this rapidly emerging pathogen and improving disease prevention programs.

Publications

• Type: Journal Articles Status: Published Year Published: 2014 Citation: Perkins, T.A., T.W. Scott, A. Le Menach, and D.L. Smith. 2013. Heterogeneity, mixing, and the spatial scales of mosquito-borne pathogen transmission. PLoS Computational Bio. 9: e1003327. Legros, M., C. Xu, A.C. Morrison, T.W. Scott, A.L. Lloyd, and F. Gould. 2013. Modeling the dynamics of a non-limited and a self-limited gene drive system in structured Aedes aegypti populations. PLoS ONE. 8: e83354.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Brady, O.J., M.A. Johansson, C.A. Guerra, S. Bhatt, N. Golding, D.M. Pigott, H. Delatte, M.G. Grech, P. Leisnham, R. Maciel-de-Freitas, L.M. Styer, D.L. Smith, T.W. Scott, P.W. Gething and S.I. Hay. 2013. Modelling adult Aedes aegypti and Aedes albopictus survival at different temperatures in laboratory and field settings. Parasites & Vectors. 6:351.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Chaves, L.F., T.W. Scott, A.C. Morrison, and T. Takada. 2014. Hot temperatures can force delayed mosquito outbreaks via sequential changes in Aedes aegypti demographic parameters in autocorrelated environments. Acta Tropica. 129: 15-24.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Liebman, K.A., S.T. Stoddard, R.C. Reiner, T.A. Perkins, H. Astede, M. Sihuincha, E.J. Halsey, T.J. Kochel, A.C. Morrison, and T.W. Scott. 2014. Determinants of heterogeneous blood feeding patterns by Aedes aegypti in Iquitos, Peru. PLoS Neglected Tropical Diseases. e2702.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Ramsey, J.M., J.G. Bond, M.E. Macotela, L. Facchinelli, L. Valerio, D.M. Brown, T.W. Scott, and A. A. James. 2014. A regulatory structure for working with genetically modified mosquitoes: Lessons from Mexico. PLoS Neglected Tropical Diseases. E2623.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Messina, J.P., O.J. Brady, T.W. Scott, C. Zou, D.M. Pigott, K. Duda, S. Bhatt, L. Katzelnick, R.E. Howes, K.E. Battle, C.P. Simmons, and S.I. Hay. 2014. Global spread of dengue virus types: Mapping the 70-year history. Trends Microbiology. 22: 138-146.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Smith, D.L., T.A. Perkins, R.C. Reiner Jr., C.M. Barker, T. Niu, L.F. Chaves, A.M. Ellis, D.B. George, A. Le Menach, J. Pulliam, D. Bisanzio, C. Buckee, C. Chiyaka, D.A.T. Cummings, A.J. Garcia, M.L. Gatton, P.W. Gething, D.M. Hartley, G. Johnston, E.Y. Klein, E. Michael, S.W. Lindsay, A.L. Lloyd, D.M. Pigott, W.K. Reisen, N. Ruktanonchai, B. Singh, J. Stoller, A.J. Tatem, U. Kitron, S.I. Hay, and T.W. Scott. 2014. Recasting the transmission dynamics of mosquito-borne pathogens. Trans. Roy. Soc. Trop. Med. Hyg. 108: 185-197.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Pongsiri, A., A. Ponlawat, B. Thaisomboonsuk, R.G. Jarman, T.W. Scott, and L. Lambrechts. 2014. Differential susceptibility of two field Aedes aegypti populations to a low infectious dose of dengue virus. PLoS ONE. 9: e92971.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Reiner, Jr., R.C., S.T. Stoddard, and T.W. Scott. 2014. Socially-structured human movement shapes dengue transmission despite the diffusive effect of mosquito dispersal. Epidemics. 6: 30-36. Paz-Soldan, V.A., R.C. Reiner, Jr., A.C. Morrison, S.T. Stoddard, U. Kitron, T.W. Scott, J.P. Elder, E. Halsey, T.J. Kochel, H. Astete, and G.M. Vazquez-Prokopec. 2014. Strengths and weaknesses of Global Positioning System (GPS) data-loggers and semi-structured interviews for capturing fine-scale human mobility: Findings from Iquitos, Peru. PLoS Neglected Tropical Diseases. 8: e2888.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Reiner, Jr, R.C., S.T. Stoddard, B.M. Forshey, A.A. King, A.M. Ellis, A.L. Lloyd, K.C. Long, C. Rocha, S. Vilcarromero, H. Asete, I. Bazan, A. Lenhart, G.M. Vazquez-Prokopec, V. Paz-Soldan, P.J. McCall, U. Kitron, J. Elder, E. Halsey, A.C. Morrison, T.J. Kochel, and T.W. Scott. 2014. Time-varying, serotype-specific force of infection of dengue virus. Proc. Natl. Acad. Sci. USA. 201314933111.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Guerra, C.A., R.C. Reiner, T.A. Perkins, S.W. Lindsay, J. Midega, O.J. Brady, C.M. Barker, W.K. Reisen, L.C. Harrington, W. Takken, U. Kitron, A.L. Lloyd, T.W. Scott, and D.L. Smith. A global assembly of adult female mosquito mark-release-recapture data to inform the control of mosquito-born pathogens. Parasites & Vectors. 7: 276.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Stoddard, S.T., H.J. Wearing, R.C. Reiner, Jr., A.C. Morrison, H.Astete, S. Vilcarromero, C. Alvarez, C. Ramal-Asayag, M. Sihuincha, C. Rocha, E.S. Halsey, T.W. Scott, T.J. Kochel, and B.M. Forshey. 2014. Long-term and seasonal dynamics of dengue in Iquitos, Peru. PLoS Neglected Tropical Diseases. 8: e3003.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Brady, O.J., N. Golding, D.M. Pigott, M.U.G. Kraemer, R.C. Reiner Jr., T.W. Scott, D.L. Smith, P.W. Gething, and S.I. Hay. 2014. Global temperature constraints on Aedes aegypti and Aedes albopictus persistence and competence for dengue virus transmission. Parasites & Vectors. 7: 338.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: LaCon, G., A.C. Morrison, H. Astete, S.T. Stoddard, V. Paz-Soldan, J.P. Elder, E.S. Halsey, T.W. Scott, U. Kitron, and G.M. Vazquez-Prokopec. 2014. Shifting patterns of Aedes aegypti fine scale spatial clustering in Iquitos, Peru. Neglected Tropical Diseases. 8: e3038.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Harrington, L.C., A. Fleisher, D. Ruiz-Moreno, F. Vermeylen, C.V. Wa, R.L. Poulson, J.D. Edman, J.M. Clark, J. Jones, S. Kitthawee, and T.W. Scott. 2014. Heterogeneous feeding patterns of the dengue vector, Aedes aegypti, on individual human hosts in rural Thailand. PLoS Neglected Tropical Diseases. 8: e3048.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Wilson, A.L., R. Dhiman, U. Kitron, T.W. Scott, H. van den Berg, and S.W. Lindsay. 2014. Benefit of insecticide-treated nets, curtains and screening on vector borne diseases, excluding malaria: A systematic review and meta-analysis. PLoS Neglected Tropical Diseases. 8: e3228.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Thomas, S.J., J. Aldstadt, R.G. Jarman, D. Tannitisupawong, I.K. Yoon, J. Richardson, A. Ponlawat, S. Iamsirithaworn, T.W. Scott, A.L. Rothman, R.V. Gibbons, L. Lambrechts, and T. Endy. Improving dengue virus capture rates in humans and vectors in Kamphaeng Phet Province, Thailand, using an enhanced spatiotemporal surveillance strategy. Am. J. Trop. Med. Hyg.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Buddhari, D., J. Aldstadt, T.P. Endy, A. Srikiatkhachorn, B. Thaisomboonsuk, C. Klungthong, A. Nisalak, B. Khuntirat, R.G. Jarman, S. Fernandez, S.J. Thomas, T.W. Scott, A.L. Rothman, I-K. Yoon. 2014. Dengue virus neutralizing antibody levels associated with protection from infection in Thai cluster studies. PLoS Neglected Tropical Diseases. 8: e3230.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Perkins, T.A., A.J. Garcia, V. Paz-Soldan, S.T. Stoddard, R.C. Reiner, Jr., G. Vazquez-Prokopec, D. Bisanzio, A.C. Morrison, E.S. Halsey, T.J. Kochel, D.L. Smith, U. Kitron, T.W. Scott, and A.J. Tatem. Theory and data for simulating fine-scale human movement in an urban environment. J. Roy. Soc. Interface. 11: 20140642.
• Type: Journal Articles Status: Submitted Year Published: 2014 Citation: Brady, O.J., J.P. Messina, T.W. Scott, and S.I. Hay. 2014. Mapping the epidemiology of dengue. In: Dengue and Dengue Hemorrhagic Fever, eds. D.J., E.E. Ooi, and J. Farrar. CABI Publishing. Perkins, T.A., R.C. Reiner, Jr., I. Rodriguez-Barraquer, D.L. Smith, T.W. Scott, and D.A.T. Cummings. 2014. A review of transmission models of dengue: A quantitative and qualitative analysis of model features. In: Dengue and Dengue Hemorrhagic Fever, eds. D.J. Gubler, E.E. Ooi, and J. Farrar. CABI Publishing.
• Type: Journal Articles Status: Submitted Year Published: 2014 Citation: Messina J.P., O.J. Brady, D.M. Pigott, N. Golding, M.U.G. Kraemer, T.W. Scott, G.R.W Wint, D.L. Smith, and S.I. Hay. The many projected futures of dengue. Nature Reviews Microbiology.
• Type: Journal Articles Status: Submitted Year Published: 2014 Citation: Lambrechts, L., N.M. Ferguson, E. Harris, E.C. Holmes, E.A. McGraw, S.L. ONeill, E.E. Ooi, S.A. Ritchie, P.A. Ryan, T.W. Scott, C.P. Simmons, and S.C. Weaver. Pragmatically assessing the efficacy of Wolbachia deployments for dengue control. Lancet Infectious Disease.
• Type: Journal Articles Status: Submitted Year Published: 2014 Citation: Brady, O.J., D.L. Smith, T.W. Scott, and S.I. Hay. Dengue disease outbreak definitions are implicitly variable. Nature Communications.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Achee, N.L., F. Gould, T.A. Perkins, R.C. Reiner, Jr., A.C. Morrison, S. Ritchie, D.J. Gubler, R. Teyssou, and T.W. Scott. A critical assessment of vector control for dengue prevention. PLoS Neglected Tropical Diseases.
• Type: Journal Articles Status: Submitted Year Published: 2014 Citation: Forshey, B.M., R.C. Reiner, Jr., S.M. Olkowski, A.C. Morrison, A. Espinoza, K.C. Long, S. Vilcarromerro, H.J. Wearing, E.S. Halsey, T.J. Kochel, T.W. Scott, S.T. Stoddard. Homologous re-infection by dengue virus type 2 in Peru. Lancet Infectious Disease.
• Type: Journal Articles Status: Submitted Year Published: 2014 Citation: Duong, V., L. Lambrechts, R. Paul, S. Ly, S.R. Lay, K. Long, A. Tarantola, T.W. Scott, and A. Sakuntabhai. Evidence for human to mosquito transmission of dengue viruses in the absence of clinical symptoms. Proc. Natl. Acad. Sci. USA.

Progress 01/01/13 to 09/30/13

Outputs
Target Audience: Results are directly relevant to mosquito control activities carried out in dengue endemic countries around the world. Because 390 million people are infected with dengue virus each year, there is a huge clientele that is interested in our activities in this project. We aim to influence ministries of health, local mosquito control districts, funding agencies, and international bodies like the World Health Organization and the Pan American Health Organization. Results are conveyed to mosquito control personnel and policy makers in personal meetings, workshops, courses, commissioned reports, talks at scientific meetings, and in scientific publications. Changes/Problems: No major changes are planned for the next reporting period. What opportunities for training and professional development has the project provided? I work closely with and mentor personnel in my laboratory. Two post-doctoral scholars, 2 PhD students, 2 Staff Research Associates, and 2 undergraduate researchers participate in dengue prevention research in my laboratory. How have the results been disseminated to communities of interest? In addition to publications and talks are scientific meetings and workshops that are publicly available to the vector-borne disease prevention community in general, I work directly with, exchange published and unpublished information with, and provide consultation to the USA Naval Medical Research Unit-6 in Lima, Peru; the Peruvian Ministry of Health; the USA Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand; the Thai Ministry of Public Health; and the Institut Pasteur, Paris, France. What do you plan to do during the next reporting period to accomplish the goals? During the next reporting period I will (1) carry out new analyses of temporal and spatial dynamics in dengue transmission dynamics and (2) develop new modeling frameworks that account for heterogeneity in the role of humans and mosquitoes in virus transmission. Results from empirical analyses and theoretical modeling exercises will be the basis for predicting dengue transmission and disease dynamics under varying epidemiological and ecological conditions. Knowledge gained from those activities will be applied to improve public health policy and strategic concepts in disease prevention programs.

Impacts
What was accomplished under these goals? To assess how theory for mathematical models of mosquito-borne pathogen transmission has changed to confront evolving public health challenges, we compiled a comprehensive bibliography of 325 publications from 1970 through 2010. Although our analysis illustrated a growing acknowledgment of geographic and epidemiological complexities in modeling transmission, there was little innovation in model assumptions and structure during the past 40 years. We concluded that modern theory would benefit from an expansion around the concepts of heterogeneous mosquito biting, poorly mixed mosquito-host encounters, spatial heterogeneity, and temporal variation in the transmission process. An important question for mosquito population dynamics, mosquito-borne pathogen transmission and vector control is how mosquito populations are regulated. We developed simple models with heterogeneity in egg laying patterns and in the responses of larval populations to crowding in aquatic habitats. We use the models to evaluate how such heterogeneity affects mosquito population regulation and the effects of larval source management. Our analysis suggests that, in some contexts, LSM that accounts for heterogeneity in production of adult mosquitoes has enormous potential for mosquito-borne disease prevention through strategic and repeated application of modern larvicides. Based on detailed analyses of comprehensive datasets we showed how small seasonal changes in temperature and humidity regulate onset, peak, and decline of epidemics, likely by directly influencing mosquito life cycles, competence, and mosquito-human contact in specific ways. We reported that larger epidemics begin earlier and develop faster in a local transmission season, a phenomenon likely driven by the local level of human immunity, and that large epidemics can likely be identified early allowing preventative measures to be strategically targeted and therefore most effective. This information is important for developing dynamic estimations of risk of dengue disease that can inform intervention planning and the use of limited prevention resources. Prevention of infectious diseases remains challenging because the drivers of transmission dynamics are poorly understood. Human movement is potentially key because it underlies contact, but how mobility patterns shape pathogen spread is unclear. Using contact-clusters in a case-control design, we examined the role of mobility in the invasion and spread of dengue virus. We found that, at an individual level, risk of infection is defined by contact with pathogen across recently visited places conducive to exposure and that movements underlie spatial patterns of incidence, causing marked heterogeneity. At a collective level, transmission is shaped by reciprocal movements of individuals among the same places, such as the homes of family and friends. We concluded that human mobility is a fundamental driver of pathogen transmission and provides a mechanistic basis for predicting and interpreting patterns of infectious diseases within populations. Because the contemporary worldwide distribution of the risk of dengue virus infection and its public health burden are poorly known we undertook an exhaustive assembly of known records of dengue occurrence worldwide and used a formal modeling framework to map the global distribution of dengue virus infection risk. We then paired 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. Using cartographic approaches, we estimate there to be 390 million dengue virus infections per year, of which 96 million manifest apparently. 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. Our 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 guide improvements in disease control strategies using vaccine, drug and vector control methods and in their economic evaluation. Antibodies induced by infection with any one of four dengue virus serotypes may influence the clinical outcome of subsequent heterologous infections. To quantify potential cross-protective effects, we estimated disease risk as a function of infection from five years of longitudinal studies at our study site in Iquitos. Our results indicate that pre-existing heterotypic antibodies markedly reduced, but did not eliminate, risk of disease in this study population. These results improve understanding of how pre-infection history can be associated with dengue disease outcomes and will help guide the development and application of dengue vaccines. The tourniquet test is a physical examination maneuver often performed on patients suspected of having severe dengue infections. It has been incorporated into dengue diagnostic guidelines and is used in clinical studies. We performed tourniquet tests and dengue laboratory assays on 13,548 subjects with febrile disease. Our results demonstrated that the tourniquet test was more sensitive in identifying dengue disease in women and those of younger age and that sensitivity increased the later a subject presented to a medical clinical for care, which will help with the clinical care of suspected dengue patients. We carried out longitudinal cohort and geographic cluster studies in rural Thailand to characterize the clinical spectrum of dengue virus infection. Among infected study participants only 19% were asymptomatic; 81% were symptomatic, but only 65.9% reported fever. Symptom-based case definitions were unreliable for diagnosis. Mild infections accounted for a major proportion of all DENV infections. These findings are relevant for disease burden assessments, transmission modeling, and determination of vaccine impact.

Publications

• Type: Journal Articles Status: Published Year Published: 2013 Citation: Stoddard, S.T., B.M. Forshey, A.C. Morrison, H. Astete Vega, V. Paz Soldan, G.M. Vazquez-Prokopec, S. Vilcarromero, M. Sihuincha, T.J. Kochel, U. Kitron, J.P. Elder, and T.W. Scott. 2013. House-to-house human movement drives dengue virus transmission. Proc. Natl. Acad. Sci. USA. 110: 994-999.
• Type: Journal Articles Status: Published Year Published: 2013 Citation: Rabaa, M.A., C. Klungthong, I.K. Yoon, E.C. Holmes, P. Chinnawirotpisan, B. Thaisomboonsuk, A. Srikiatkhachorn, A.L. Rothman, D. Tannitisupawong, J. Aldstadt, A. Nisalak, M.P. Mammen Jr., S. Thammapalo, R.V. Gibbons, T. Endy, T. Fansiri, T.W. Scott, and R.G. Jarman. 2013. Frequent in-migration and highly focal transmission of dengue viruses among children in Kamphaeng Phet, Thailand. PLoS Neglected Tropical Diseases. 7: e1990.
• Type: Journal Articles Status: Published Year Published: 2013 Citation: Facchinelli, L., L. Valerio, J.M. Ramsey, F. Gould, R. Katz, G. Bond, M.A. Robert, A.L. Lloyd, A.A. James, L. Alphey, and T.W. Scott. 2013. Field cage studies and progressive evaluation of genetically-engineered mosquitoes. PLoS Neglected Tropical Diseases. 7: e2001.
• Type: Journal Articles Status: Published Year Published: 2013 Citation: Reiner, Jr., R.C., T.A. Perkins, C.M. Barker, T. Niu, L.F. Chaves, A.M. Ellis, D.B. George, A. Le Menach, J. Pulliam, D. Bisanzio, C. Buckee, C. Chiyaka, D.A.T. Cummings, A.J. Garcia, M.L. Gatton, P.W. Gething, D.M. Hartley, G. Johnston, E.Y. Klein, E. Michael, S.W. Linsday, A.L. Lloyd, D.M. Pigott, W.K. Reisen, N. Ruktanonchai, B. Singh, A.J. Tatem, U. Kitron, S.I. Hay, T.W. Scott, and D.L. Smith. 2013. A systematic review of mathematical models of mosquito-borne pathogen transmission: 1970-2010. J. Roy. Soc. Interface. 10: 20120921.
• Type: Journal Articles Status: Published Year Published: 2013 Citation: Carrington, L.B., S.N. Seifert, L. Lambrechts, and T.W. Scott. 2013. Large diurnal temperature fluctuations negatively influence Aedes aegypti (Diptera: Culicidae) life-history traits. J. Med. Entomol. 50: 43-51.
• Type: Journal Articles Status: Published Year Published: 2013 Citation: Carrington, L.B., M.V. Armijos, L. Lambrechts, C.M. Barker, and T.W. Scott. 2013. Effects of fluctuating daily temperatures at critical thermal extremes on Aedes aegypti life-history traits. PLoS ONE. 8: e58824.
• Type: Journal Articles Status: Published Year Published: 2013 Citation: Vazquez-Prokopec, G.M., D. Bisanzio, S.T. Stoddard, V. Paz-Soldan, A.C. Morrison, J.P. Elder, J. Ramirez-Paredes, T. Kochel, E. Halsey, T.W. Scott, and U. Kitron. 2013. Using GPS Technology to Quantify Human Mobility, Dynamic Contacts and Infectious Disease Dynamics in a Resource-Poor Urban Environment. PLoS ONE. 8: e58802.
• Type: Journal Articles Status: Published Year Published: 2013 Citation: Carrington, L.B., S.N. Seifert, M.V. Armijos, L. Lambrechts, and T.W. Scott. 2013. Reduction of Aedes aegypti vector competence for dengue virus under large temperature fluctuations. Am. J. Trop. Med. Hyg. 88: 689-697.
• Type: Journal Articles Status: Published Year Published: 2013 Citation: Bhatt, S., P.W. Gething, O.J. Brady, J.P. Messina, A.W. Farlow, C.L. Moyes, J.M. Drake, J.S. Brownstein, A.G. Hoen, O. Sankoh, M.F. Myers, D.B. George, T. Jaenisch, G.R.W. Wint, C.P. Simmons, T.W. Scott, J.J. Farrar, and S.I. Hay. 2013. The global distribution and burden of dengue. Nature. 496: 504-507.
• Type: Journal Articles Status: Published Year Published: 2013 Citation: Carrington, L.B., M.V. Armijos, L. Lambrechts, and Thomas W. Scott. 2013. Fluctuations at low mean temperatures accelerate dengue virus transmission by Aedes aegypti. PLoS Neglected Tropical Diseases. 7: e2190.
• Type: Journal Articles Status: Published Year Published: 2013 Citation: Facchinelli, L., L. Valerio, J.M. Ramsey, F. Gould, R. Katz, G. Bond, M.A. Robert, A.L. Lloyd, A.A. James, L. Alphey, and T.W. Scott. 2013. Field cage studies and progressive evaluation of genetically-engineered mosquitoes. PLoS Neglected Tropical
• Type: Journal Articles Status: Published Year Published: 2013 Citation: Walsh, R.K., C.L. Aguilar, L. Facchinelli, L. Valerio, J.M. Ramsey, T.W. Scott, and F. Gould. 2013. Regulation of Aedes aegypti population dynamics in field systems: Quantifying direct and delayed density dependence. Am. J. Trop. Med. Hyg. 89: 68-77.
• Type: Journal Articles Status: Published Year Published: 2013 Citation: Sun, P., J. Garc�a, G. Comach, M.T. Vahey, Z. Wang, B.M. Forshey, A.C. Morrison, G. Sierra, I. Bazan, C. Rocha, S. Vilcarromero, P. Blair, T.W. Scott, D.E. Camacho, C.F. Ockenhouse, E. Halsey, and T.J. Kochel. 2013. Sequential waves of gene expression in patients with clinically defined dengue illnesses reveal subtle disease phases and predict disease severity. PLoS Neglected Tropical Diseases. 7: e2298.
• Type: Journal Articles Status: Published Year Published: 2013 Citation: Halsey, E.S., S. Vilcarromero1, B.M. Forshey, C. Rocha, I. Bazan, S.T. Stoddard, T.J. Kochel, M. Casapia, T.W. Scott, and A.C. Morrison. 2013. Performance of the tourniquet test for diagnosing dengue in Peru. Am. J. Trop. Med. Hyg. 89: 99-104.
• Type: Journal Articles Status: Published Year Published: 2013 Citation: Smith, D.L., T.A. Perkins, L. Tusting, T.W. Scott, and S.W. Lindsay. 2013. Mosquito population regulation and larval source management in heterogeneous environments. PLoS ONE. 8: e71247. Olkowski, S., B.M. Forshey, A.C. Morrison, C. Rocha, S. Vilcarromero, E.S. Halsey, T.J. Kochel, T.W. Scott, and S.T. Stoddard. 2013. Reduced risk of disease during postsecondary dengue virus infections. J. Infect. Dis. 208: 1026-1033.
• Type: Journal Articles Status: Published Year Published: 2013 Citation: Campbell, K.M., C.D. Lin, S. Iamsirithaworn, and T.W. Scott. 2013. The complex relationship between weather and dengue virus transmission in Thailand. Am. J. Trop. Med. Hyg. 89: 1066-1080.
• Type: Journal Articles Status: Published Year Published: 2013 Citation: Yoon, I-K., A. Srikiatkhachorn, L. Hermann, D. Buddhari, T.W. Scott, R.G. Jarman, J. Aldstadt, A. Nisalak, S. Thammapalo, P. Bhoomiboonchoo, M.P. Mammen, S. Green, R.V. Gibbons, T. Endy, and A.L. Rothman. 2013. Characteristics of mild dengue infection in Thai children. Am. J. Trop. Med. Hyg. 89: 1081-1087.

Progress 01/01/12 to 12/31/12

Outputs
OUTPUTS: To assess the effectiveness of specific early predictors of disease caused by mosquito-borne viruses, I am developing a new generation of mathematical models and carrying out statistical analyses that will examine virus transmission across a broad range of spatial and temporal scales, environmental and demographic settings, and networks of human activity. During 2012 I studied the role of mathematical models in understanding disease transmission dynamics and predicting the most effective disease prevention strategies, spatial and temporal patterns in virus transmission, mosquito egg laying behavior and its relationship to disease prevention strategies, and the affects of natural daily temperature fluctuations on the life history of mosquitoes and virus infection in mosquitoes. Information was disseminated during personal meetings with local, national, and international public health and vector control officials, workshops and courses in disease endemic countries, professional scientific meetings, and publication of results in scientific journals. PARTICIPANTS: Drs. Amy Morrison and Steven Stoddard are Project Scientists in my laboratory. We work closely together on dengue prevention in a long-term study in Iquitos, Peru. Iquitos is a dengue endemic city of about 400,000 people in the Amazon Basin of northeastern Peru.

I work closely with the Naval Medical Research Unit-6 in Lima, Peru; the Peruvian Ministry of Health; the Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand; the Thai Ministry of Public Health; and the Institut Pasteur, Paris, France.

Five post-doctoral scholars, 2 PhD students, 2 Staff Research Associate, and two undergraduate researchers contribute to dengue prevention research in my laboratory. TARGET AUDIENCES: Results are directly relevant to mosquito control activities carried out dengue endemic countries around the world. Because 2.5 billion people are at risk of dengue infection each year, there is a huge clientele that is interested in our activities in this project. We aim to influence ministries of health, local mosquito control districts, funding agencies, and international bodies like the World Health Organization and the Pan American Health Organization. Results are conveyed to mosquito control personnel and policy makers in personal meetings, workshops, courses, commissioned reports, talks at scientific meetings, and in scientific publications. PROJECT MODIFICATIONS: Not relevant to this project.

Impacts
Local virus transmission between infected humans and mosquitoes was examined. Human and mosquito infections were positively associated at the level of individual houses and neighboring residences. At a given point in time, people and mosquitoes from a small portion of houses were responsible for the majority of transmission. Virus transmission risk was highest near infected children. Children with mild febrile infections, but who remained active, are now recognized as important sources of mosquito infection and virus transmission. These insights improve understanding of virus transmission dynamics and the clinical spectrum of infection that are critical for informing surveillance and control measures.

A series of studies were carried out on the impact of fluctuating daily temperatures on mosquito life history traits and capacity to transmit virus. There was a negative impact of large temperature fluctuations on mosquito biology indicating that large temperature fluctuations contribute to seasonal reduction in virus transmission. Mosquito infection was delayed under large temperature fluctuations around mean annual temperatures, which helps explain why mosquitoes are less likely to transmit virus during the low than high transmission season. Conversely, large fluctuations at low temperatures reduced the incubation period and increased potential for virus transmission at cooler temperatures. This complexity is important to account for in improved assessments of population dynamics and virus transmission modeling and downstream applications for mosquito surveillance and disease prevention.

A systematic historical review of published mathematical models of mosquito-transmitted diseases revealed the central role in theory and practice of a 40 year old modeling framework. Although this approach has played a central role in development of research on mosquito-borne pathogen transmission and the development of strategies for mosquito-borne disease prevention, there are currently unaddressed topics and alternative approaches that would significantly enhance response and prevention of disease. My colleagues and I identified those topics and began building the missing components to improve mosquito-borne disease models that will be used to address pressing public health needs.

Using a novel approach, using an evidence consensus map of disease range that highlights nations with an uncertain dengue status, my colleagues and I are bringing together all available information on dengue occurrence. A map was produced identifying 128 countries for which there is good evidence of dengue occurrence, including 36 countries previously classified as dengue-free by the World Health Organization or Centers for Disease Control. A subsequent effort resulted in an exhaustive assembly of all known records of dengue occurrence worldwide and used a formal modeling framework to map the global distribution of virus infection risk, which will help guide improvements in disease control strategies using vaccine, drug and vector control methods and in their economic evaluation.

Publications

• Scott, T.W. and W. Takken. 2012. Feeding strategies of anthropophilic mosquitoes result in increased risk of pathogen transmission. Trends Parasit. 28: 114-121.
• Chaves, L.F., A.C. Morrison, U.D. Kitron, and T.W. Scott. 2012. Non-linear impacts of climatic variability on the density-dependent regulation of an insect vector of disease. Global Change Bio. 18: 457-468.
• Wong, J., Y.Y. Chu, S.T. Stoddard, Y. Lee, A.C. Morrison, and T.W. Scott. 2012. Microsatellite-based parentage analysis of Aedes aegypti (Diptera: Culicidae) using non-lethal DNA sampling. J. Med. Entomol. 49: 85-93.
• Brasier, A.R., H. Ju, J. Garcia, H.M. Spratt, S.S. Victor, B.M. Forshey, E.S. Halsey, G. Comach, G. Sierra, P.J. Blair, C. Rocha, A.C. Morrison, T.W. Scott, I. Bazan, T.J. Kochel, and the Venezuelan Dengue Fever Working Group. 2012. A three-component biomarker panel for prediction of dengue hemorrhagic fever. Am. J. Trop. Med. Hyg. 86: 341-348.
• Liebman, K.A., S.T. Stoddard, A.C. Morrison, C. Rocha, S. Minnick, M. Sihuincha, K.L. Russell, J.G. Olson, P.J. Blair, D.M. Watts, T. Kochel, and T.W. Scott. 2012. Spatial dimensions of dengue virus transmission across interepidemic and epidemic periods in Iquitos, Peru (1999 - 2003). PLoS Neglected Tropical Diseases. 6: e1472.
• Brasier , A.R., J. Garcia , J.E. Wiktorowicz , H.M. Spratt, G. Comach, H. Ju , A. Recinos III, K. Soman, B.M. Forshey, E.S. Halsey, P.J. Blair, C. Rocha, I. Bazan, S.S. Victor, Z. Wu, S. Stafford, D. Watts, A.C. Morrison, T.W. Scott, T.J. Kochel, and the Venezuelan Dengue Fever Working Group. 2012. Discovery proteomics and nonparametric modeling pipeline in the development of a candidate biomarker panel for dengue hemorrhagic fever. Clinical Translational Sci. J. 5: 8-20.
• Helinski, M.E.H., L. Valerio, L. Facchinelli, T.W. Scott, J. Ramsey, and L.C. Harrington. 2012. Evidence of polyandry in a natural population of Aedes aegypti under semi-field conditions. Am. J. Trop. Med. Hyg. 86: 635-641.
• Valerio, L., L. Facchinelli, J.M. Ramsey, J.G. Bond, and T.W. Scott. 2012. Dispersal of male Aedes aegypti in a coastal village in southern Mexico. Am. J. Trop. Med. Hyg. 86: 665-676.
• Smith, D.L., K.E. Battle, S.I. Hay, C. Barker, T.W. Scott, and F.E. McKenzie. 2012. Ross, Macdonald and a theory for the dynamics and control of mosquito-transmitted pathogens. PLoS Pathogens. 8: e1002588.
• Wong, J., A.C. Morrison, S.T. Stoddard, H. Astete, Y.Y. Chu, I. Baseer, and T.W. Scott. 2012. Linking oviposition site choice to offspring fitness in Aedes aegypti: Consequences for targeted larval control of dengue vectors. PLoS Neglected Tropical Diseases. 6: e1632.
• Lambrechts, L., E. Quillery, V. Noel, J.H. Richardson, R.G. Jarman, T.W. Scott, and C. Chevillon. 2013. Genotype-by-genotype interaction between the mosquito antiviral gene Dicer-2 and dengue virus. Proc. Roy. Soc B. 280: 2012.2437.
• Yoon, I-K., A.L. Rothman, D. Tannitisupawong, A. Srikiatkhachorn, R.G. Jarman, J. Aldstadt, A. Nisalak, M.P. Mammen, S. Thammapalo, S. Green, D.H. Libraty, R.V. Gibbons, A. Getis, T. Endy, J.W. Jones, C.J.M. Koenraadt, A.C. Morrison, T. Fansiri, C. Pimgate, and T.W. Scott. 2012. Under-recognized mildly symptomatic viremic dengue virus infections in rural Thai schools and villages. J. Infect. Dis. 206: 389-398.
• Yoon, I.-K., A. Getis, J. Aldstadt, A.L. Rothman, D. Tannitisupawong, C.J.M. Koenraadt, T. Fansiri, J.W. Jones, A.C. Morrison, R.G. Jarman, A. Nisalak, M.P. Mammen Jr., S. Thammapalo, A. Srikiatkhachorn, S. Green, D.H. Libraty, R.V. Gibbons, T.Endy, C. Pimgate, and T.W. Scott. 2012. Fine scale spatiotemporal clustering of dengue virus transmission in children and Aedes aegypti in rural Thai villages. PLoS Neglected Tropical Diseases. 6: e1730.
• Brady, O.J., P.W. Gething, S. Bhatt, J.P. Messina, C.L. Moyes, A. Farlow, T.W. Scott, and S.I. Hay. 2012. Refining the global spatial limits of dengue transmission in 2012 by evidence-based consensus. PLoS Neglected Tropical Diseases. 6: e1760.
• Aldstadt, J., I-K. Yoon, D. Tannitisupawong, R.G. Jarman, S.J. Thomas, R.V. Gibbons, A. Uppapong, S. Iamsirithaworn, A.L. Rothman, T.W. Scott, and T. Endy. 2012. Space-time analysis of hospitalized dengue patients in rural Thailand reveals important temporal intervals in the pattern of dengue virus transmission. Trop. Med. Internat. Hlth. 17: 1076-1085.
• Robert, M.A., M. Legros, L. Facchinelli, L. Valerio, J.M. Ramsey, T.W. Scott, F. Gould, and A.L. Lloyd. 2012. Mathematical models as aids for design and interpretation of experiments: The case of transgenic mosquitoes. J. Med. Entomol. 49: 1177-1188.
• Legros, M., C. Xu, T.W. Scott, A.C. Morrison, A.L. Lloyd, and F. Gould. 2012. Assessing the feasibility of controlling Aedes aegypti with transgenic methods: A model-based evaluation. PLoS ONE. 7: e522335.

Progress 01/01/11 to 12/31/11

Outputs
OUTPUTS: To assess the effectiveness of specific early predictors of mosquito-borne virus transmission and disease, a new generation of quantitative tools is being developed that will simulate virus transmission across a broad range of spatial and temporal scales, environmental and demographic settings, and human activity networks. During 2011 we developed new means for studying mosquito vector reproductive behavior, development of larval mosquitoes, the affects of natural daily temperature fluctuations on virus infection in mosquitoes, the role of mosquitoes in the evolution of new viruses, evaluation of detailed computer simulation models for studying mosquito population and virus transmission dynamics, and development of novel means for assessing innovative strategies for prevention of mosquito-borne disease. Information was disseminated during personal meetings with local and national public health and vector control officials, workshops and courses in disease endemic countries, professional scientific meetings, and publication of results in scientific journals. PARTICIPANTS: Drs. Amy Morrison and Steven Stoddard are Project Scientists in my laboratory. We work closely together on dengue prevention in a long-term study in Iquitos, Peru. Iquitos is a dengue endemic city of about 400,000 people in the Amazon Basin of northeastern Peru. Seven post-doctoral scholars, 2 PhD students, 2 Staff Research Associate, and several undergraduate researchers contribute to dengue prevention research in my laboratory. TARGET AUDIENCES: Results are directly relevant to mosquito control activities carried out dengue endemic countries around the world. Because 2.5 billion people are at risk of dengue infection each year, there is a huge clientele that is interested in our activities in this project. We aim to influence ministries of health, local mosquito control districts, funding agencies, and international bodies like the World Health Organization and the Pan American Health Organization. Results are conveyed to mosquito control personnel and policy makers in personal meetings, workshops, courses, commissioned reports, talks at scientific meetings, and in scientific publications. PROJECT MODIFICATIONS: Not relevant to this project.

Impacts
I was involved in three core activities this past year. Implementing successful mosquito control programs requires understanding what factors regulate population abundance, as well as anticipating how mosquitoes may adapt to control measures. My colleagues and I tested whether the mosquito Aedes aegypti actively choose the containers in which they lay their eggs and determined what cues are most relevant to that process. Egg-laying females were most attracted to sites containing other immature Ae. aegypti, rather than to sites containing the most food. In a different, complimentary study my colleagues and I determined that containers holding immature mosquitoes in areas of high development site density are most likely to be produce adult mosquitoes. Accounting for and taking advantage of these natural mosquito tendencies will lead to more effective strategies for dengue prevention. In two studies of mosquito vector competence for dengue virus, my colleagues and I determined that daily temperature fluctuation drive seasonal dynamics of virus transmission and region-wide replacement of one virus genotype by another was associated with enhanced capacity of virus to infect and be transmitted by local mosquitoes. Our results reveal the importance of short-term temperature variations on virus transmission dynamics and show that virus adaptation to local mosquitoes drives virus lineage replacement events. Two studies were carried out to test the validity of complex simulation models for mosquito-borne virus transmission dynamics. Our results show that the models studied provide a faithful description of Ae. aegypti populations, through a process of location-specific customization that is contingent on the amount of data available from field collections. We explored specific components of the models, such as the description of food dynamics, and assessed the challenges that these limitations bring to model evaluation.

Publications

• Wong, J., H. Astete, A.C. Morrison, and T.W. Scott. 2011. Sampling considerations for designing Aedes aegypti (Diptera: Culicidae) oviposition studies in Iquitos, Peru: Substrate preference, diurnal periodicity, and gonotrophic cycle length, J. Med. Entomol.48: 45-52.
• Aldstadt, J., C.J.M. Koenraadt, T. Fansiri, U. Kijchalao, J. Richardson, J.W. Jones, and T.W. Scott. 2011. Ecological modeling of Aedes aegypti (L.) pupal production in rural Kamphaeng Phet, Thailand. PLoS Neglected Tropical Diseases. 5: e940.
• Wong, J., S.T. Stoddard, H. Astete, A.C. Morrison, and T.W. Scott. 2011. Oviposition site selection by the dengue vector Aedes aegypti and implications for dengue control. PLoS Neglected Tropical Diseases. 5: e1015.
• Chaves, L.F., A.C. Morrison, U.D. Kitron, and T.W. Scott. 2011. Non-linear impacts of climatic variability on the density-dependent regulation of an insect vector of disease. Global Change Bio.
• Lambrechts, L., K.P. Paaijmans, L.D. Kramer, M.B. Thomas, and T.W. Scott. 2011. Impact of daily temperature fluctuations on dengue virus transmission by Aedes aegypti. Proc. Natl. Acad. Sci. USA. 108: 7460-7465.
• Lambrechts, L., Fansiri, T., Pongsiri, A., Thaisomboonsuk, B., Klungthong, C., Richardson, J.H., Ponlawat, A., Jarman, R.J., and Scott T.W. 2011. Dengue-1 virus clade replacement in Thailand associated with enhanced mosquito transmission. J. Virology. 86: 1853-1861.
• Legros, M., K. Magori, A. Morrison, C. Xu, T.W. Scott, A.L. Lloyd, and F. Gould. 2011. Evaluation of location-specific predictions by a detailed simulation model of Aedes aegypti populations. PLoS ONE. 6: e22701.
• Ellis, A.M., A. Garcia, D.A. Focks, A.C. Morrison, and T.W. Scott. 2011. Parameterization and sensitivity analysis of a complex simulation model for mosquito population dynamics, dengue transmission, and their control. Am. J. Trop. Med. Hyg. 85: 257-264.
• Facchinelli, L., L. Valerio, J.G. Bond, M.R. Wise de Valdez, L.C. Harrigton, J.M. Ramsey, M. Casas-Martinez and, T.W. Scott. 2011. Development of a semi-field system for contained field trials with Aedes aegypti in Southern Mexico. Am. J. Trop. Med. Hyg. 85: 248-256.

Progress 01/01/10 to 12/31/10

Outputs
OUTPUTS: I was involved in three core activities this past year.

Recent advances in empirical, methodological, and theoretical aspects of mosquito vector biology are an impetus for re-examining critical research needs aimed at improving human health. Unfortunately, successful vector control programs are too often the exception, or when they do occur they are difficult to sustain. Although vector control remains an essential component in the battle against mosquito-borne disease, persistence of vector-borne pathogens and resilience of their mosquito vectors continue to motivate the search for novel solutions. In response to this challenge my colleagues and I developed a new vision for the future of vector-borne disease research that will address these important issues.

The dramatic global expansion of the mosquito Aedes albopictus in the last three decades has increased public health concern because it is a potential vector of numerous arthropod-borne viruses (arboviruses), including the most prevalent arboviral pathogen of humans, dengue virus. Ae. aegypti is considered the primary dengue virus vector and has repeatedly been incriminated as a driving force in dengue's worldwide emergence. What remains unresolved is the extent to which Ae. albopictus contributes to dengue virus transmission and whether an improved understanding of its vector status would enhance dengue surveillance and prevention. To assess the relative public health importance of Ae. albopictus for dengue, we carried out two complementary analyses. We reviewed its role in past dengue epidemics and compared its dengue virus vector competence with that of Ae. aegypti.

Comprehensive, longitudinal field studies that monitor both disease and vector populations for dengue viruses are urgently needed as a pre-requisite for developing locally adaptable prevention programs or to appropriately test and license new vaccines. My colleagues and I reported results from such a study spanning 5 years in the Amazonian city of Iquitos, Peru where dengue virus infection was monitored serologically among 2,400 people in a neighborhood-based cohort and through school-based absenteeism surveillance for active febrile illness among a subset of this cohort. PARTICIPANTS: Drs. Amy Morrison and Steve Stoddard are Project Scientists in my laboratory. We work closely together on dengue prevention in a long-term study in Iquitos, Peru. Iquitos is a dengue endemic city of about 400,000 people in the Amazon Basin of northeastern Peru. Five post-doctoral scholars, 2 PhD students, 1 Staff Research Associate, and several undergraduate researchers contribute to dengue prevention research in my laboratory. TARGET AUDIENCES: Results are directly relevant to mosquito control activities carried out dengue endemic countries around the world. Because 2.5 billion people are at risk of dengue infection each year, there is a huge clientele that is interested in our activities in this project. We aim to influence ministries of health, local mosquito control districts, funding agencies, and international bodies like the World Health Organization and the Pan American Health Organization. Results are conveyed to mosquito control personnel and policy makers in personal meetings, commissioned reports, talks at scientific meetings, and in scientific publications. PROJECT MODIFICATIONS: Not relevant to this project.

Impacts
Regarding the agenda for vector-borne disease research my colleagues and I recommend a vision that is broader and more holistic than the past, looking at new, multiple, and integrated methods for combating disease. We suggested that success will require that vector biologists more effectively engage with clinicians, epidemiologists, and other natural and social scientists. The future requires breaking down silos, thinking about using combinations of tools for disease control, and attacking multiple diseases.

Regarding mosquito vectors of dengue virus, our observations from natural experiments indicate that, despite seemingly favorable conditions, places where Ae. albopictus predominates over Ae. aegypti have never experienced a typical explosive dengue epidemic with severe cases of the disease. Results from a meta-analysis of experimental laboratory studies reveal that although Ae. albopictus is overall more susceptible to dengue virus midgut infection, rates of virus dissemination from the midgut to other tissues are significantly lower in Ae. albopictus than in Ae. aegypti. For both indices of vector competence, a few generations of mosquito colonization appear to result in a relative increase of Ae. albopictus susceptibility, which may have been a confounding factor in the literature. Our results lead to the conclusion that Ae. albopictus plays a relatively minor role compared to Ae. aegypti in DENV transmission, at least in part due to differences in host preferences and reduced vector competence. Recent examples of rapid arboviral adaptation to alternative mosquito vectors, however, call for cautious extrapolation of our conclusion. Vector status is a dynamic process that in the future could change in epidemiologically important ways.

In our dengue epidemiologic study, at baseline, 80% of the study population had dengue virus antibodies, the prevalence for which increased with age, and significant geographic variation was detected with neighborhood-specific age-adjusted rates ranging from 67.1 to 89.9%. During the first 15 months, when 2 dengue viruses were co-circulating, population-based incidence rates ranged from 2-3 infections/100 person-years. The introduction of a new dengue virus during the last half of 2001 was characterized by 3 distinct periods: amplification over at least 5-6 months, replacement of previously circulating serotypes, and epidemic transmission when incidence peaked at 89 infections/100 p-years. Neighborhood-specific baseline seroprevalence rates were not predictive of geographic incidence patterns prior to introduction of the new virus, but were closely mirrored during the invasion of the novel virus. Transmission varied geographically, with peak incidence occurring at different times among the 8 geographic zones in the 16 km2 of the city. The lag from novel virus introduction to epidemic transmission and knowledge of spatially explicit areas of elevated risk will be important for designing more effective application of limited resources for dengue prevention.

Publications

• Luckhart, S., S.W. Lindsay, A.A. James, and T.W. Scott. 2010. Reframing critical needs in vector biology and management of vector-borne disease. PLoS Neglected Tropical Diseases. 4: e566.
  Paz-Soldan, V.A., S.T. Stoddard, G. Vasquez-Prokopec, A.C. Morrison, J.P. Elder, U. Kitron, T.J. Kochel, B. Forshey, T.W. Scott. 2010. Assessing and maximizing the acceptability of GPS device use for studying the role of human movement in dengue virus transmission in Iquitos, Peru. Am. J. Trop. Med. Hyg. 82: 723-730.
  Lambrechts, L., T.W. Scott, and D.J. Gubler. 2010. Consequences of the expanding global distribution of Aedes albopictus for dengue virus transmission. PLoS Neglected Tropical Diseases. 4: e646.
  Lavery, J.V., P.O. Tinadana, T.W. Scott, L.C. Harrington, J.M. Ramsey-Willoquet, Claudia Ytuarte-Nunez, and A.A. James. 2010. Towards a framework for community engagement in global health research. Trends in Parasitology. 26: 279-283.
  Morrison, A.C., S.L. Minnick, C. Rocha, B.M. Forshey, S. Stoddard, A. Getis, D.A. Focks, K.L. Russell, J.G. Olson, P.J. Blair, D.M. Watts, M. Sihuincha, T.W. Scott, and T.J. Kochel. 2010. Epidemiology of dengue virus in Iquitos, Peru 1999 to 2005: Interepidemic and epidemic patterns of transmission. PLoS Neglected Tropical Diseases. 4: e670.
  

Progress 01/01/09 to 12/31/09

Outputs
OUTPUTS: Human movement is a key behavioral factor in many vector-borne disease systems because it influences exposure to insect vectors and thus the transmission of pathogens. Human movement transcends spatial and temporal scales with different influences on disease dynamics. My colleagues and I developed a conceptual model and a global positioning system device that can be used to evaluate the importance of variation in exposure due to individual human movements for pathogen transmission, focusing on dengue virus. I participated in an empirical study compared the efficacy of distinct community-based (door to door) and school absenteeism-based febrile surveillance strategies in detecting active human infections with dengue virus. I helped develop a new computer modeling tool of Ae. aegypti (the mosquito vector of dengue virus) population dynamics and genetics. The model operates at the scale of individual water-filled containers for immature mosquitoes and individual properties (houses) for adults. The model allowed us to predict the genetic structure of a mosquito population and to examine the effects of adult mosquito dispersal and container movement between properties. I contributed to a conceptual framework for improving dengue virus surveillance and prevention. PARTICIPANTS: Dr Amy Morrison is an Associate Project Scientist in my laboratory. We work closely together on dengue prevention in a long-term study in Iquitos, Peru. Iquitos is a dengue endemic city of about 400,000 people in the Amazon Basin of northeastern Peru. Five post-docs and 2 PhD students work on dengue prevention research in my laboratory. TARGET AUDIENCES: Results are directly relevant to mosquito control activities carried out dengue endemic countries around the world. Because 2.5 billion people are at risk of dengue infection each year, there is a huge clientele that is interested in our activities in this project. We aim to influence ministries of health, local mosquito control districts, funding agencies, and international bodies like the World Health Organization and the Pan American Health Organization. Results are conveyed to mosquito control personnel and policy makers in personal meetings, commissioned reports, talks at scientific meetings, and in scientific publications. PROJECT MODIFICATIONS: Not relevant to this project.

Impacts
We developed a conceptual model and GPS tool to determine the importance of variation in exposure due to individual human movements for a mosquito transmitted virus. We show that the relevance of human movement at a particular scale depends on vector behavior by showing how vector biting behavior combined with fine-scale movements of individual humans engaged in their regular daily routine can influence virus transmission. We explain why understanding human 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. We demonstrate the feasibility of a novel, commercially available GPS data-logger for long-term tracking of humans and show the potential of these units to quantify mobility patterns in relationship with dengue virus transmission risk. Cost, battery life, size, programmability, and ease of wear are unprecedented from previously tested units, proving the usefulness of GPS-dataloggers for linking movement of individuals and transmission risk of dengue virus and other infectious agents, particularly in resource-poor settings. We demonstrate that a community-based door-to-door surveillance for mosquito-borne human disease is a more efficient and sensitive design for detecting active human dengue cases than programs based on school absenteeism. Our computer simulation model is a new tool for predicting the most effective surveillance and prevention strategies. We demonstrate that the incorporating stochastic processes and level of spatial detail into the model have major impacts on mosquito population dynamics, which can impact predictions for control measures. Our capacity to describe population genetics confers the ability to model the outcome of genetic control methods. Our new model, therefore, is an important tool to new tool for assessing the outcome of vector control measures. Our new dengue control paradigm accounts for the spatial scale at which risk should be assessed and interventions are applied, is proactive rather than reactive, focuses on the home which is the primary site of human exposure to bites from infected mosquitoes, and describes a novel integrated strategy for disease prevention that combines vector control with vaccine delivery.

Publications

• Rocha, C., A.C. Morrison, B.M. Forshey, P.J. Blair, J.G. Olson, J.D. Stancil, M. Sihuincha, T.W. Scott, and T.J. Kochel. 2009. Comparison of two active surveillance programs for the detection of clinical dengue cases in Iquitos, Peru. Am. J. Trop. Med., 80: 656 to 660.
• Stoddard, S.T., A.C. Morrison, G.M. Vasquez-Prokopec, U. Kitron, V. Paz-Soldan, B.M. Forshey, T.J. Kochel, J. Elder, and T.W. Scott. 2009. The role of human movement in the transmission of vector-borne pathogens. PLoS Neglected Tropical Diseases. 3:e481.
• Vazquez-Prokopec, G.M., S.T. Stoddard, V. Paz-Soldan, A.C. Morrison, J.P. Elder, T.W. Scott, and U. Kitron. 2009. Usefulness of commercially available GPS data-loggers for tracking human movement and exposure to dengue virus. Internat. J. Hlth. Geographics. 8: 68.Magori, K.. M.
• Legros, M.E. Puente, D.A. Focks, T.W. Scott, A.L. Lloyd, and F. Gould. 2009. Skeeter Buster: A stochastic, spatially-explicit modeling tool for studying Aedes aegypti population replacement and population suppression strategies. PLoS Neglected Tropical Diseases. 3: e508.
• Scott, T.W. and A.C. Morrison. 2010. Vector dynamics and transmission of dengue virus: Implications for dengue surveillance and prevention strategies. In: Dengue Virus. A.L. Rothman, ed., Current Topics in Microbiology and Immunology 338, Springer‐Verlag Berlin Heidelberg. pp: 115 to 128.
• Eisen, L., B. J. Beaty, A.C. Morrison, and T.W. Scott. 2009. Proactive vector control strategies and improved monitoring and evaluation practices for dengue prevention. J. Med. Entomol. 46: 1245 to 1255.

Progress 01/01/08 to 12/31/08

Outputs
OUTPUTS: Five outputs were directly related to the objective of develop best practices for mosquito vector control to prevent dengue. I organized a meeting of mosquito experts to critically examine why mosquito control has so seldom been successful in eliminating disease and to recommend measures to increase the opportunities for success in the future. With my colleague Amy Morrison I developed the conceptual foundation for research that will substantially improved dengue prevention. I lead a group effort in delineating the ecological challenges to using genetic strategies with mosquitoes to prevent dengue. I was a key participant in the development of ethical, social, and cultural considerations for choosing a field site where research would be done with genetically modified mosquitoes in a long-term program designed to prevent dengue. I helped develop guidelines for safe laboratory research with genetically modified mosquitoes. Six outputs were related to the objective of developing new systems for assessing entomological risk of dengue transmission. I carried out detailed studies on dengue epidemiology that define the over what time an spatial area surveillance and control should be carried out. I participated in the development of a new trap for mosquito surveillance and conducted studies on ways to assess mosquitoes abundance, survival, and egg laying behavior. All of which can be used in surveillance programs to assess risk of human infection and to determine how well mosquito control programs have worked. I participated in a program to develop new genetic markers that can be used to study the role of misquotes in dengue virus transmission. PARTICIPANTS: Dr Amy Morrison is an Associate Project Scientist in my laboratory. We work closely together on dengue prevention a long-term study in Iquitos, Peru; a dengue endemic city of about 300,000 people in the Amazon region of northeastern Peru. Five post-docs and 2 PhD students work on dengue prevention research in my laboratory. TARGET AUDIENCES: Results are directly relevant to mosquito control activities carried out dengue endemic countries around the world. Because 2.5 billion people are at risk of dengue infection each year, there is a huge clientele that is interested in our activities in this project. We aim to influence ministries of health, local mosquito control districts, funding agencies, and international bodies like the World Health Organization and the Pan American Health Organization. Results are conveyed to mosquito control personnel and policy makers in personal meetings, commissioned reports, talks at scientific meetings, and in scientific publications. PROJECT MODIFICATIONS: Not relevant to this project.

Impacts
My colleagues and I provided guidance for research and development activities that would have the biggest impact on prevention of dengue. We proposed program design and management improvements (i.e., sustainability issues, proper goals, and surveillance and assessment strategies), new tools (i.e., novel methods for control of immature and adult mosquitoes, adult mosquito monitoring tools, and quantitative assessment tools), long-term study design features (highlighted their benefits and potential for new insights), and developed prioritized research agendas for traditional and more forward thinking vector control strategies (i.e., insecticide development, resistance testing, and genetic strategies for dengue prevention). Our empirical research revealed new insights into dengue transmission and mosquito vector ecology. We showed that dengue transmission can be extremely focal, within a radius of 100m, which suggests that active dengue case detection prompting local spraying could contain recent virus introductions and reduce the longitudinal risk of virus spread within rural areas. Our results should prompt future studies to explore how host immune and behavioral aspects may impact dengue transmission and prevention strategies. The methodology we developed for this study could serve as a useful research tool for investigation of other temporally and spatially clustered infectious diseases. We showed that survey methods to determine the density of mosquitoes were not bias by seasonal or interannual affects and, therefore, they can be used to assess risk of dengue transmission to humans. We determined that physical attributes of where mosquitoes lay their eggs, such as size, light-dark contrasts, and specular reflectance from water surfaces, play a significant role in site selection, which can be used to design new surveillance and mosquito control strategies. We determined for the first time in field studies that mosquitoes senesce, which means that age-dependent processes in mosquito biology and ecology can no longer be ignored. This makes understanding the role of these process much more complicated, even if our appreciation of the complexity of the system is more accurate. We developed and field evaluated a new trap for adult mosquito vectors of dengue virus. This species is very difficult to collect as adults, so the novel trap is an important breakthrough for improving surveillance programs. For genetic control strategies, studies of the genetic structure of dengue mosquitoes vector populations, and research on mosquito behavior we develop new genetic markers that provide greater resolution than was previously possible.

Publications

• Scott, T.W., L.C. Harrington, B.G.J. Knols, and W. Takken. 2008. Applications of mosquito ecology for successful insect transgenesis-based disease prevention programs. In: Transgenesis and the Management of Vector-Borne Disease. Ed: Serap Aksoy. Landes Bioscience and Springer Science+Business Media. pp:151-168.
• Harrington, L.C., F.Vermeylen, J.J. Jones, S. Kitthawee, R. Sithiprasasna, J.D. Edman, and T.W. Scott. 2008. Age-dependent survival of the dengue vector, Aedes aegypti (Diptera: Culicidae), demonstrated by simultaneous release-recapture of different age cohorts. J. Med. Entomol. 45:307-313.
• Morrison, A.C., E. Zielinski-Gutierrez, T.W. Scott, and R. Rosenberg. 2008. Defining the challenges and proposing new solutions for Aedes aegypti-borne disease prevention. PLoS Medicine. 5:362-366.
• Scott, T.W. and A.C. Morrison. 2008. Longitudinal field studies will guide a paradigm shift in dengue prevention. In: Vector-borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections. Washington, DC: The National Academies Press. pp.132-149.
• Faccinelli, L., C.J.M. Koenraadt, C. Fanello, U. Kijchalao, L. Valerio, J.W. Jones, T.W. Scott, and A. della Torre. 2008. Evaluation of a novel sticky trap collecting Aedes (Stegomyia) adults in a dengue-endemic area in Thailand. Am. J. Trop. Med. Hyg. 78:904-909.
• Koenraadt, C.J.M., J. Alsadt, U. Kijchalao, R. Sithiprasasna, A. Getis, J.W. Jones, and T.W. Scott. 2008. Spatial and temporal patterns in pupal and adult production of the dengue vector Aedes aegypti L. in Kamphaeng Phet. 2008. Thailand. Am. J. Trop. Med. Hyg. 79:230-238.
• Lavery, J.V., L.C. Harrington, and T.W. Scott. 2008. Ethical, social and cultural considerations for site selection for research with genetically modified mosquitoes. Am. J. Trop. Med. Hyg. 79:312-318.
• Wong, J., F. Tripet, J.L. Rasgon, G.C. Lamzaro, and T.W. Scott. 2008. SSCP analysis of scnDNA for genetic profiling of Aedes aegypti. Am. J. Trop. Med. Hyg. 79:511-517.
• Mammen, M.P.,Jr, C. Pimgate, C.J.M. Koenraadt, A.L. Rothman, J. Aldstadt, A.Nisalak, R.G. Jarman, J.W. Jones, A. Srikiatkhachorn, C.A. Ypil-Butac, A. Getis, S. Thammapalo, A.C. Morrison, D.H. Libraty, S. Green, and T.W. Scott. 2008. Spatial and temporal focality of dengue virus transmission in Thai villages revealed by cluster investigations. PLoS Medicine. 5:1-11.
• Benedict, M., P. DAbbs, S. Dobson, M. Gottlieb, L. Harrington, S. Higgs, A. James, S. James, B. Knols, J. Lavery, S. ONeill, T. Scott, W. Takken, and Y. Toure. 2008. Guidance for Contained Field Trials of Vector Mosquitoes Engineered to Contain a Gene Drive System: Recommendations of a Scientific Working Group. Vector-borne and Zoonotic Dis. 8:127-166.
• Harrington, L.C., A. Ponlawat, J.D. Edman, T.W. Scott, and F. Vermeylen. 2008. Influence of container size, location and time of day on oviposition patterns of the dengue vector, Aedes aegypti, in Thailand. Vector-borne and Zoonotic Dis. 8:1-9.

Progress 01/01/07 to 12/31/07

Outputs
Material on two initiatives was published this year. The first concerned evaluation of the susceptibility to infection and capacity to transmit West Nile virus in seven populations of mosquito vectors that were collected in a north-south transect of California. Results revealed extensive geographic variation in vector competence for West Nile virus in the Culex pipiens species complex across California. This new information will help mosquito abatement personnel direct their control efforts toward mosquito populations that have the greatest potential to transmit West Nile virus to humans, domestic animals, and wildlife. The second initiative concerned two research projects on epidemiologic patterns of West Nile virus transmission in Davis, CA. A study of vaccinated and unvaccinated horses maintained at the UC Davis Center for Equine Health revealed that non-vaccinated horses are a sensitive indicator of West Nile virus transmission activity. Risk of horse infection is associated with the abundance of key mosquito vector species, which served to transmit virus to songbirds, infect horses, and increase the risk of human infection. A second study examined variation in patterns of West Nile virus transmission in Davis, CA. Abundance and infection status of mosquito vectors were compared to virus infected dead birds. Different species of mosquito vectors were found to be located in different, predictable habitats. One species was most abundant near agriculture surrounding the city, whereas the other clustered within residential areas and greenbelt systems in the old portion of the city. West Nile virus-infected dead birds and West Nile virus-positive mosquito vectors overlapped in areas with high incidences of confirmed human cases. The research group concluded that spatial analyses of West Nile virus surveillance data may be an effective method to identify areas with an increased risk for human infection and to target control efforts to reduce the incidence of human disease.

Impacts
Results from activities during 2007 are directly relevant to improved arbovirus surveillance and mosquito control for prevention of arbovirus transmission. Publications on mosquito vector competence, risk of horse infection, and spatial associations between mosquito vectors, infected birds, and risk of human infection contribute to the development of novel surveillance, mosquito control, and disease prevention programs.

Publications

• Nielson, C.F., W.K. Reisen M.V. Armijos, and T.W. Scott. 2008. High subclinical West Nile virus incidence among non-vaccinated horses in northern California associated with low vector abundance and infection. J. Amer. Soc. Trop. Med. Hyg. 78: 45-52
• Nielson, C.F., M.V. Armijos, S. Wheeler, T.E. Carpenter, W. Boyce, K. Kelly, D. Brown, T.W. Scott, and W.K. Reisen. 2008. Risk factors associated with human infection during the 2006 West Nile virus outbreak in Davis, a residential community in northern California. J. Amer. Soc. Trop. Med. Hyg. 78: 53-62.
• Vaidyanathan, R. and T.W. Scott. 2007. Geographic variation in vector competence for West Nile virus in the Culex pipiens (Diptera: Culicidae) complex in California. Vector-borne and Zoonotic Dis. 7: 193-198.

Progress 01/01/06 to 12/31/06

Outputs
Material on four initiatives was published this year. The first concerned interactions between mosquito vectors and West Nile virus in California. Our results indicate that (1) there is geographic and temporal variation in the competence for mosquitoes to transmit virus and (2) programmed cell death is a mosquito refractory mechanism. Elucidation of these processes helps to further refine our understanding of which mosquito species should be targeted for control by mosquito abatement districts. The second initiative evaluated recover of a natural mosquito population after it had been exposed to insecticide. Specifically, we determined following insecticide treatment of dengue vectors in Thailand how well are mosquitoes killed, and how quick do their populations recover and from where? We found that during the first two days after spraying immigration from untreated areas extended approximately 15 m into the sprayed area. After seven days this effect extended up to 50 m. Thus, re-invasion occurred but was relatively slow. Our third initiative focused on development of new molecular tools for studying important mosquito vectors. We evaluated genetic variation at 17 microsatellite loci identified in the A. aegypti genome. Our results greatly increase the number of highly variable markers available for the study of the genetics and the population structure of the most important vector of dengue virus world-wide. Our fourth initiative brought large-scale laboratory life table techniques (n>100,000) to bear on the question of age-dependent mortality in the mosquito vector of dengue virus, Aedes aegypti. We definitively demonstrated that mortality of the mosquito that transmits dengue is age-dependent. Departure from the age-independent mortality paradigm encourages research on overlooked complexities in mosquito biology, the need for innovative methods to investigate mosquito population dynamics, and the need to study age-dependent changes for an accurate understanding of mosquito biology and pathogen transmission.

Impacts
Results from my activities during 2006-2007 are directly relevant to improved arbovirus surveillance and mosquito control for prevention of arbovirus transmission. Publications on mosquito-virus interactions, mosquito response to insecticide treatment, genetic markers for studying mosquito population biology, and mosquito aging contribute to the development of novel mosquito control and disease prevention programs.

Publications

• Vaidyanathan, R. and T.W. Scott. 2006. Apoptosis in mosquito midgut epithelia associated with West Nile virus infection. Apoptosis. 11(9): 1643-1651.
• Vaidyanathan, R. and T. W. Scott. 2006. Seasonal variation in susceptibility to West Nile virus infection in Culex pipiens pipiens (L.) (Diptera: Culicidae) from San Joaquin County, California J. Vector Ecol. 31: 423-425.
• Koenraadt, C.J.M., J. Aldstadt, U. Kijchalao, A. Kengluecha, J. W. Jones, and T.W. Scott. 2007. Spatial and Temporal Patterns in the Recovery of Aedes aegypti (Diptera: Culicidae) Populations after Insecticide Treatment. J. Med. Entomol. 44: 65-71.
• Styer, L.M., J.R. Carey, J-L. Wang, and T.W. Scott. 2007. Mosquitoes do senesce: Departure from the paradigm of constant mortality. Am. J. Trop. Med. Hyg. 76: 111-117.
• Slotman, M.A., N.B. Kelly, L.C. Harrington, S. Kitthawee, J.W. Jones, T.W. Scott, A. Caccone, and J.R. Powell. 2007. Polymorphic microsatellite markers for studies of Aedes aegypti (Diptera: Culicidae), the vector of dengue and yellow fever. Molec. Ecol. Notes. 7: 168-171.