Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
3 Integrating Strategies to Address Vector-Borne Disease OVERVIEW Vector-borne diseases, among the general class of emerging infectious dis- eases, entail a host of needs and opportunities that have been characterized in numerous reviews and reports. A core report of the Institute of Medicine, Microbial Threats to Health (2003), recommended several actions related to the prediction, prevention, and control of vector-borne diseases; these are reviewed in this chapterâs first paper by presenter Barry Beaty (a member of the Institute of Medicine committee that produced the Microbial Threats to Health report) and Lars Eisen of Colorado State University. In an additional contribution in Chapter 1, these authors describe how researchers and public health policy makers have responded to specific recommendations, including efforts by the Innovative Vec- tor Control Consortium (IVCC) to develop new pesticides and formulations, as well as novel tools and management approaches, in order to advance vector control in and around the house. In the chapterâs second and third papers, Roger Nasci of the Centers for Disease Control and Prevention (CDC), and Sherrilyn Wainwright, of the U.S. Department of Agricultureâs (USDAâs) Animal and Plant Health Inspection Ser- vice (APHIS), offer their perspectives on issues discussed by the workshop panel on integrating strategies for vector-borne disease surveillance, diagnosis, and response. Topics included the need for, and challenges of, creating multidisci- plinary teams to study and respond to vector-borne disease outbreaks; oppor- tunities to integrate the surveillance and diagnosis of vector-borne disease with outbreak response; funding opportunities; research directions; and the training of vector biologists. 241
242 VECTOR-BORNE DISEASES Based on his experience at CDC, Nasci notes both the successes and chal- lenges of training and fielding multidisciplinary teams for outbreak response and to conduct basic research. Using the ArboNET surveillance network as an example (see also Petersen in Chapter 2), he also explores the creation and expansion of integrated information systems to monitor disease transmission and risk factors and argues for the development of comprehensive, testable predic- tive models based on input from a diversity of scientific fields. APHIS also uses multidisciplinary teams to monitor and detect infectious disease outbreaks in animals and plants, often in collaboration with the U.S. Departments of Health and Human Services and Fish and Wildlife Services, state agencies, affected industries, and diagnostic laboratories. Wainwright notes that these efforts, while largely successful, have on occasion âexposed weaknesses in communication and coordination between human public health and animal health agencies.â Through the Agricultural Research Service (ARS), APHIS is involved in a number of studies of vector-borne disease, many of which are being addressed through a âmultidisciplinary systems approach,â involving other government agencies. The subsequent paper by panelist David Morens of the National Institute of Allergy and Infectious diseases (NIAID) identifies several overarching scientific and logistical obstacles presented by vector-borne disease and compares them with challenges faced by the founders of tropical medicine. âThe question of how to foster generalist training and team approaches to problem-solving, in which team members cross disciplinary lines regarded as being remote from each other . . . is no more impossible than the challenges faced and met successfully in the first 50 years of the 20th century, in which science and public health worked to produce a yellow fever vaccine [and] discovered and developed effective treatments for many vector-borne diseases,â he observes. In order to begin to meet todayâs challenges, Morens explains, scientific and political leaders must recognize the complex problems posed by vector-borne diseases, and a cadre of multidisciplinary scientists and public health workers must be trained to address these problems in innovative and integrative ways. Workshop panelist Adriana Costero, vector biology program officer for NIAIDâs Division of Microbiology and Infectious Diseases, describes the variety of funding mechanisms and projects supported by that agency in her contribution to this chapter. These include grants for basic studies and the initial phases of translational research, training grants, and career awards. As noted in the Summary and Assessment (see section entitled âNeeds and Opportunitiesâ), response to the workshop panel presentations was both deep and wide-ranging. In his manuscript, included in Chapter 1 of this volume, Durland Fish offers a vision of âa new interdisciplinary approach to the understanding of vector-borne diseasesâ firmly grounded in ecologyâa discipline historically central to the control of vector-borne diseases, but now at considerable remove from the biomedical sciences. He argues that the shift in studies of vector biol- ogy away from ecology and toward molecular biology, which began in the 1970s,
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 243 has produced âreductionistic and narrowly focused research agendas [that] have contributed very little to a broader understanding of interactions between vectors and their physical or biological environment.â There is a need to create a balanced, integrated, basic and applied research agenda to address the challenges and opportunites associated with vector-borne disease control efforts. Fish advocates a repositioning of the field of vector biology as a collaboration of environmental sciences and infectious disease epi- demiology, supported by technologies such as remote sensing and geographic information systems. Among infectious diseases, Fish concludes, âvector-borne diseases have the greatest potential for advancing the integration of ecology and environmental science into the mainstream of infectious disease epidemiology.â NEEDS AND OPPORTUNITIES TO CONTROL VECTOR-BORNE DISEASES: RESPONSES TO THE IOM MICROBIAL THREATS TO HEALTH COMMITTEE RECOMMENDATIONS Barry J. Beaty, Ph.D. Colorado State University Lars Eisen, Ph.D.1 Colorado State University Summary Vector-borne diseases (VBDs) remain major threats to human health and well-being, and, as an epidemiological group, inflict a terrible and unacceptable public health burden on humankind. The developed world has been fortunate to have escaped much of the terrible burden that mosquitoes and their arthropod allies inflict on humans in countries endemic for diseases such as malaria and dengue, but the introduction and rapid spread of West Nile virus in the western hemisphere demonstrated that we can no longer be complacent in the face of emerging and resurging VBDs. Unfortunately as the burdens and threats of VBDs have increased, the U.S. and international public health capacity to address them has decreased. The Institute of Medicine (IOM) report entitled Microbial Threats to Health (IOM, 2003) reviewed and identified factors leading to the resurgence and emer- gence of infectious diseases, including VBDs, and made recommendations to address the needs and opportunities for the prediction, prevention, and control of infectious diseases. The factors contributing to resurgence and emergence of â Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences.
244 VECTOR-BORNE DISEASES VBDs and the recommendations made to address these issues will be reviewed here. Much of the information is excerpted directly from the Committee on Emerging Microbial Threats to Health in the 21st Centuryâs 2003 report. This provides a context for the issues, needs, and opportunities in addressing the emergence and resurgence of VBDsâtopics that are directly relevant to many of the chapters in this current report. Despite the seemingly intractable nature of many VBDs, significant prog- ress and new initiatives are underway to address their prediction, prevention, and control. New computer-based tools, novel approaches, and new knowledge being provided in the vector post-genomics era all provide new opportunities and targets for vector control and disease prevention. Rebuilding the human resource capacity to exploit the new tools and information to address VBDs remains a critical need to address. The Extraordinary Burden of Vector-Borne Diseases Resurgence and Emergence of Vector-Borne Diseases In the 20th century, extraordinary advances were made in the diagnosis, treat- ment, and control of many infectious diseases. These successes were not uniform, and, unfortunately, the medical, veterinary, and economic importance of many VBDs has continued and indeed increased. VBDs have proven to be unusually refractory to control or eradication programs. When considered as an epidemio- logical group, VBDs, such as malaria, leishmaniasis, filariasis, onchocerciasis, trypanosomiasis, dengue, West Nile virus (WNV) disease, Lyme disease, and other vector-borne viral, bacterial, and parasitic diseases, put billions of people at risk for infection, infect hundreds of millions of humans annually, and cause millions of deaths and inestimable morbidity each year. Malaria and dengue are most important in this regard. Approximately 40 percent of humankind is at risk for malaria; up to 500 million cases occur annually with 2.7 million deaths. More than 2.5 billion people are at risk for dengue virus infection, and 100 million cases are estimated to occur annually. Ominously, the incidence of life- threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) has increased rapidly throughout the tropics over the past 20 years. The burdens imposed by VBDs can be impediments to social and economic development in the areas of the world least able to afford them. Indeed, VBDs account for 7 of 10 neglected infectious diseases that are considered to disproportionally affect poor and marginalized populations and therefore have been targeted by the World Health Organization (WHO) Special Programme for Research and Training in Tropical Diseases (TDR) for special control programs. It is very frustrating that a number of VBDs were controlled to a certain â See http://www.who.int/tdr/index.html.
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 245 extent in some regions but are now resurgent in these areas. For example, malaria was virtually eradicated from Sri Lanka by the mid-1960s; only 17 cases were recorded in 1963. Over 2 million cases now occur there annually. In India, 50,000 cases were reported in 1961; 35 million are now reported there annually (Gratz, 1999). Epidemic dengue fever and DHF-DSS have emerged as major public health problems in the Americas mirroring what happened in Southeast Asia several decades ago (Beaty, 2000; Gubler, 2002a,b). Other VBDs have emerged in or trafficked to new or previously endemic areas (e.g., Lyme disease, plague, Japanese encephalitis, WNV disease, and Rift Valley fever), resulting in significant morbidity and mortality. Lyme disease is now the most reported VBD of humans in the United States, followed by WNV disease (Gubler, 2002b). The recent resurgence of chikungunya in many parts of the world, including a local outbreak in Italy, is testimony to the ongoing emergence potential of VBDs (Charrel et al., 2007). Agricultural and Economic Impact of Vector-Borne Diseases VBDs also cause significant economic impact in agriculture. Many of the List A diseases of the Office des International Epizooties (OIE), for example, bluetongue and vesicular stomatitis, are VBDs. Worldwide economic losses due to bluetongue are estimated at $3 billion per year, principally due to non-tariff barriers to international trade. Vesicular stomatitis virus epizootics in the western United States in 1995 and 1997 resulted in losses of approximately $50 million. International trade agreements (e.g., General Agreement on Tariffs and Trade [GATT] and North American Free Trade Agreement [NAFTA]) and globalization provide opportunities as well as threats for agriculture. The importation of vectors and pathogens would seem to be the inevitable result of increased movement of animals and products, and increased trade in general (USAHA, 1998). Vector-Borne Diseases and Biodefense Finally, many VBDs (e.g., plague, tularemia, certain equine encephalitis, and VB hemorrhagic fevers) are potential bioterroism agents and some have been weaponized. A natural (or purposeful) introduction of a bioterrorism agent, such as Rift Valley fever virus, would have enormous agricultural and public health consequences (LaBeaud et al., 2007). The emergence of WNV in New York in 1999 and its subsequent spread across the country (Lanciotti et al., 1999; Hayes et al., 2005) clearly demonstrated the vulnerability of the United States to emerg- ing diseases, whether resulting from natural or purposeful events. Such dramatic emergences, the resurgence of diseases such as malaria and dengue, and the failure to control Lyme disease, even with the economic resources available to â See http://www.cdc.gov/ncidod/dvbid.
246 VECTOR-BORNE DISEASES the United States and northern Europe, highlight the deficits in human resources and infrastructure needed to address VBDs, and the critical needs to augment the armamentarium of tools and approaches to predict, prevent, and control VBDs. Factors Contributing to the Resurgence and Emergence of Vector-Borne Diseases The IOM report entitled Microbial Threats to Health (2003) listed a number of factors that have contributed to and exacerbated the emergence of infectious diseases (Table 3-1). In the âconvergenceâ model used in the report, these fac- tors were then placed into larger groupingsâPhysical Environmental Factors, Social, Political, and Economic Factors, Ecological Factors, Genetic and Biologi- cal Factorsâall of which converged with the microbe and human to condition emergence of diseases (IOM, 2003). The emergence of VBDs is clearly conditioned by many if not all of these factors, which have been reviewed elsewhere (Gratz, 1999; Beaty, 2000; Gubler, 2002b). In this paper, the focus will be on selected factors that are particularly rel- evant to the emergence of VBDs (Table 3-2). Brief examples will be discussed to provide insight into the needs, difficulties, and complexities of controlling VBDs. The lack of vaccines and therapeutics for many tropical and orphan diseases, and the economic and public health issues that are associated with the development and deployment of vaccines and therapeutics are described in detail in Microbial Threats to Health (IOM, 2003). This issue will not be discussed further here except to say that enhanced vector control will complement and enhance vaccine deployment for disease control (see paper by Scott in Chapter 2). Clearly, many of the factors listed in Table 3-2 condition the emergence of all TABLE 3-1 Factors in Emergence of Infectious Diseases â¢ Microbial adaptation and change â¢ Human susceptibility to infection â¢ Climate and weather â¢ Changing ecosystems â¢ Economic development and land use â¢ Human demographics and behavior â¢ Technology and industry â¢ International travel and commerce â¢ Breakdown of public health measures â¢ Poverty and social inequality â¢ War and famine â¢ Lack of political will â¢ Intent to harm SOURCE: IOM (2003), pp. 4-7.
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 247 TABLE 3-2â Factors Conditioning the Resurgence and Emergence of Vector- Borne Diseases â¢ Population growth and unplanned urbanization â¢ Poverty, social inequalities, and the emergence of the throw-away society â¢ Globalization and trafficking of humans, pathogens, vectors, and genes â¢ rosion of public health infrastructure, including human resource capacity in medical E entomology and vector biology â¢ Lack of new targets and approaches to control vectors and VBDs â¢ oss of pesticides for real and perceived environmental issues, development of pesticide L resistance in vectors, and economic disincentives to new pesticide and formulation development â¢ Lack of robust models and information systems to predict, prevent, and control VBDs SOURCE: Adapted from IOM (2003). infectious diseases, not just VBDs. There is little recourse for Microbial Threats to Health Committee recommendations to address major factors such as popu- lation growth, poverty, unplanned urbanization, and social inequalities. Other behavioral factors such as the throw-away society and the dramatic increases in human, vector, and pathogen trafficking in this era of globalization complicate greatly the control of VBDs. Nonetheless, each of these is a major driver for the resurgence of VBDs and will be briefly discussed herein to illustrate the problems involved with controlling these important diseases. Explosive population growth is a major determinant of the emergence and resurgence of VBDs. Dramatic increases in urbanization are frequently associ- ated with little or no civic planning, and sanitation may be limited or nonexistent (Gratz, 1999; Gubler, 2002a; IOM, 2003). The lack of wastewater and refuse removal provides plentiful breeding sites for mosquitoes. Many newly urbanized areas do not have piped water, and stored water provides plentiful breeding sites for Aedes and Culex vectors. Even when piped water is available, it may be so only sporadically or unreliably. Thus, residents still store water, and paradoxically there may be more water, breeding sites, and mosquitoes than before piped water was available. Population growth and other socioeconomic factors also frequently result in humans migrating into undeveloped areas. There they impinge upon sylvatic or jungle cycles of VBDs and/or perturb the natural environment, making it more conducive to vectors and to pathogen transmission, potentially leading to the emergence of new diseases (Monath, 2001). Poverty, social inequalities, and behavioral issues not only condition emer- gence of VBDs but also exacerbate their prevention and control. There are too many of these factors to enumerate; only a few will be discussed to provide insights into the problems. Clearly, the most important VBDs in tropical regions are diseases of poor people. One recent epidemiological and entomological
248 VECTOR-BORNE DISEASES investigation of dengue in âsisterâ cities in Mexico and Texas illustrates this very well (Reiter et al., 2003). In the U.S. city, Ae. aegypti immatures were relatively abundant in the peridomestic environment, but there was very little dengue. In contrast, the Mexican city was characterized by lower abundances of Ae. aegypti immatures but higher numbers of dengue cases. The investigators attributed this to numerous factors, one of the most important being the quality of housing (window screens and air conditioners were common in the U.S. city). Poverty is directly linked to the dramatic growth in human populations, unplanned urban- ization, and movement of humans, all of which can condition VBDs (Gubler, 2002b; IOM, 2003). Globalization and rapid dissemination of pathogens and vectors has con- tributed greatly to the resurgence and emergence of VBDs. The global economy, which is predicated upon commerce and rapid and efficient transport of goods and people, provides unprecedented capability for emergence and rapid dissemination of pathogens and their vectors throughout the world (IOM, 2003). The recent emergence of WNV in the New World (Roehrig et al., 2002) is testimony to the ability of VBDs to traffic rapidly into new areas. The many reports of airport and railroad malaria also illustrate the continual trafficking of pathogens (Lounibos, 2002). Fortunately, in most cases the components necessary for establishment of a transmission cycle are not present, and the pathogen does not become estab- lished. Obviously, when WNV was introduced into New York, all of the necessary ingredients for establishment and spread were present, and it will be many years before the epidemiologic consequences of this emergence in the New World are determined (Roehrig et al., 2002; Hayes et al., 2005). Vectors themselves can also traffic to and become established in new areas. One of the most notable examples was the dissemination of Ae. aegypti through- out the world (Tabachnick et al., 1985). The ancestral form of Ae. aegypti is found in central Africa and is a sylvatic mosquito. After domestication and adaptation to humans and human environments, Ae. aegypti apparently disseminated to coastal areas of Africa, and was then transported throughout the world in sailing ships. Presumably both Ae. aegypti and yellow fever virus (YFV) were introduced into the New World on slave ships. Aedes albopictus, the Asian tiger mosquito, and Ae. japonicus presumably entered the United States via shipping (Moore, 1999; Fonseca et al., 2001). Aedes spp. eggs can easily be transported in tires, contain- ers, and so on to new areas and hatch upon exposure to water in new settings. Adult mosquitoes can be spread much more quickly throughout the world in air- planes (Lounibos, 2002). Indeed, mosquitoes have become the ultimate frequent fliers, spreading themselves and their genes and perhaps pathogens throughout the world. Such transport has been postulated as the mechanism for the rapid dissemination of an esterase mutation conferring pesticide resistance to organo- phosphates through Culex pipiens populations throughout the world (Raymond et al., 1998). Unfortunately, U.S. public health programs to disinfect aircraft were
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 249 disbanded as a cost-saving measure in the 1960s; such a program could conceiv- ably have prevented the introduction of WNV into the western hemisphere. Human behavioral changes and societal trends can also potentially exac- erbate VBDs. Certainly, the advent of the âthrow-away societyâ has had major implications in terms of breeding sites for vector mosquitoes. Even in the poor- est of societies, breeding sites are now ubiquitous because of the proliferation of bottles, cans, old tires, and so on in the environment, which then provide a pleth- ora of breeding sites for container-breeding mosquitoes and which dramatically complicate source reduction and larviciding control programs (IOM, 2003). The Committee on Emerging Microbial Threats to Health in the 21st Century Recommendations to Address Vector-Borne Diseases The Committee report proposed a number of actions to national agencies to address major needs in emerging diseases (IOM, 2003), many of which were directly applicable to VBDs. The Committee recommended that (1) the human resource capacity in medical entomology, vector biology, and zoonoses (from academia to public health practitioner) be rebuilt, expanded, and sustained; (2) the armamentarium for vector control be enhanced and expanded, by developing (a) new and improved environmentally sound pesticides, (b) novel strategies to prolong the use of existing pesticides by mitigating the evolution of resistance, (c) new biopesticides and biocontrol agents to augment chemical pesticides, (d) safe, efficacious repellants and attractants, and (e) by investigating novel strategies to interrupt vector-borne pathogen transmission to humans; and (3) that appropriate federal and state agencies expand their efforts to exploit geographic information systems (GIS) and robust models to predict and prevent VBDs. Human Resource Capacity The Recommendation: The Centers for Disease Control and Prevention (CDC), Department of Defense (DoD), National Institutes of Health (NIH), and U.S. Department of Agriculture (USDA) should work with academia, private orga- nizations, and foundations to support efforts at rebuilding the human resource capacity at both academic centers and public health agencies in the relevant sciencesâsuch as medical entomology, vector and reservoir biology and ecology, and zoonosesânecessary to control vector-borne and zoonotic diseases. Backgroundâ Erosion in the human resource capacity to address VBDs is linked to the erosion of overall public health infrastructure for VBDs. Surveillance and control programs for VBDs are expensive. These programs are especially vulner- able to reductions or elimination when budget shortfalls occur and when VBD activity is incorrectly perceived to be controlled. Both of these issues have led to decreased support for and deterioration of public health surveillance and control
250 VECTOR-BORNE DISEASES capacity throughout the world. For example, the sporadic and epidemic nature of many VBDs resulted in the closure of state programs and in the demise of university training programs in medical entomology and vector biology (NRC, 1983). In the developing world, where resources are much more limited, the consequences of such reductions can be even more dramatic. For example, in the 1950s and 1960s the Pan American Health Organization (PAHO) and participat- ing western hemisphere countries established a remarkably effective program to control Ae. aegypti to preclude the emergence of sylvatic YFV into urban popula- tions (Gratz, 1999; Monath, 2001; Gubler, 2002a). Overall, the program was quite effective, but success led to demise of the programs, and the resources to support these efforts were shifted to other priorities. Now Ae. aegypti is resurgent and essentially hyperabundant throughout much of tropical and subtropical America. Concomitantly all four dengue virus serotypes including American/Asian geno- types are cocirculating in Latin America (Beaty, 2000; Gubler, 2002a). High mosquito abundance and intensive virus transmission have resulted in a state of dengue hyperendemnicity, resulting in the emergence of DHF-DSS as a major public health problem in the Americas. In addition, YFV has recently caused epidemics in South America and Africa (Monath, 2001; Gubler, 2002b). With Ae. aegypti resurgent in metropolitan areas in the Americas, it seems to be only a question of when urban yellow fever will reemerge or chikungunya (Charrel et al., 2007) will emerge in these areas with disastrous consequences. Concomitant with the erosion of VBD control infrastructure has been the dramatic decline in medical entomology/vector biology expertise. Indeed, it was difficult to identify local medical entomologists, vector biologists, and arbovi- rologists to respond to the WNV emergency in the initially affected states. There has been a reduction in the numbers of medical entomologists, vector biologists, and vector control personnel. This unfortunate trend and its public health implica- tions were first described in a U.S. National Academy of Sciences report (NRC, 1983). The emergence of WNV and the paucity of human resources available to address that emergency were ample testimony to the prescience of the authors of that report. The critical needs in this area have also been addressed in other publications and books (e.g., Spielman, 1994). However, these reports did little to change attitudes in academic departments across the nation. Medical entomology positions were invariably lost when occupants retired or left and when entomol- ogy departments combined with plant pathology and related departments. Responsesâ With the emergence of Lyme disease, human granulocytic anaplas- mosis, human monocytic erlichiosis, and WNV disease in the United States and the resurgence of VBDs throughout the world (Gratz, 1999; Gubler, 2002b), orga- nizations such as the NIH, the World Health Organization Special Programme for Research and Training in Tropical Diseases (WHO-TDR), and a number of foundations began to promote research in vector biology. With increased funding and program development opportunities, there has been an increase in the number
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 251 of scientists entering the field, many of whom are now assuming faculty positions in universities. Indeed, there has been a renaissance in vector biology, which is providing not only new knowledge and targets for vector control but also a new generation of vector biologists capable of applying modern molecular and quan- titative approaches to control VBDs. Hopefully, as the scientific excitement in and public health importance of the field is recognized, and the opportunities for program development in vector biology increase, student demand will increase and previously lost positions will be regained in entomology departments. This will provide a renewed stream of students to replenish the depleted ranks of medi- cal entomologists at all levels. Trainingâ Training of a new generation of vector biologists/medical entomologists capable of applying modern molecular and information technology approaches to prevent and control emerging and resurging VBDs is critical. A number of agencies, including WHO-TDR, PAHO, NIH, CDC, and private foundations, recognized this situation and initiated training programs for vector biologists and medical entomologists in the United States and other countries. Frequently, however, such programs only address urgent needs. For example, the emergence of WNV resulted in a major effort by CDC to train individuals in mosquito iden- tification, arbovirology, and mosquito control. WHO provides workshops devoted to specific important issues concerning vectors and VBDs in disease-endemic areas. Such programs, however, typically do not provide personnel with in-depth training in molecular, biological, epidemiological, and information technology techniques or permit trainees to exploit these techniques effectively in real-world situations. Efficient training strategies are necessary to address the human resource needs in all areas of VBDs, from identification and processing of vectors to gene identification and characterization, and to development of GIS and other informa- tion technology-based approaches for control of vectors and VBDs. Web-based training programs, courses, and texts would seem to be a robust enough venue to address critical short-term needs. However, alternate approaches are neces- sary to provide quickly a new generation of VBD specialists and leaders. The Biology of Disease Vectors course was notable in this regard. This intensive 2- week course, which was supported by the MacArthur Foundation, WHO-TDR, and other agencies, was developed to catalyze the use of modern molecular and quantitative approaches into medical entomology and vector biology. The course also provided exceptional learning and networking opportunities for vector biolo- gists. Many of the students emerged as leaders, trainers, and program initiators in their respective countries. Internationally recognized faculty provided invaluable networking and career opportunities. Similar courses should be offered to provide a new generation of leaders in critical and emerging disciplines. For example, the renaissance of vector biology/medical entomology at NIH and the new vector biology study section
252 VECTOR-BORNE DISEASES has been very laboratory associated; field-oriented and control programs have not kept pace. Training programs and research focusing on the biological, behav- ioral, entomological, and environmental determinants of pathogen emergence and persistence, and that incorporate the most modern and robust molecular and information technology tools, are desperately needed. These would be powerful incentives to translate the explosion of new information concerning vectors into field-relevant tools and management strategies, and to train vector biologists capable of incorporating the new methodologies into daily vector and disease control operations. Indeed, the cadre of molecular vector biologists trained in the laboratories contributing to the renaissance of vector biology would be excellent candidates for such a course. There have been some very notable successes in programs to promote field- oriented VBD research. CDC has established major extramural efforts to partner with state and university scientists to address important vector-borne and rodent- borne diseases such as Lyme disease, WNV disease, and hantavirus pulmonary syndrome. This leverages CDC monies and talents to address emerging disease issues, provides support for applied epidemiological research and training in dis- ease endemic sites, and greatly enhances communication and partnering between CDC and state and local institutions. In addition, CDC launched a Fellowship Training Program (FTP) in Vector-Borne Infectious Diseases in direct response to the introduction of WNV into the United States. The purpose of the FTP was to provide training in arbovirology, microbiology, entomology, and epidemiology relating to VBDs. The goal was to improve the ability of the U.S. public health system to respond to the problem of VBDs by increasing the number of special- ists with demonstrated skills in the public health aspects of VBDs and to provide them with the essential, pertinent field and research skills. Programs such as the NIH International Collaborations in Infectious Disease Research (ICIDR) and Tropical Medicine Research Units also provide excellent training and research opportunities in field-oriented vector biology and control programs. The NIH ICIDR grants with the companion ABC Fogarty Center training programs are well conceived in this regard and emphasize epidemiological research and train- ing in disease-endemic areas in the context of NIH-funded research programs. Scientists not only are trained in cutting-edge scientific methodology but also apply new discoveries and approaches in disease-endemic countries. These types of programs need to be continued and expanded upon in the future, especially to transfer scientific and technical know-how to the developing world where improved vector and disease control is a matter of life and death. Unfortunately, funding for the CDC FTP in Vector-Borne Infectious Diseases has been terminated after one funding cycle, despite the productivity and popularity of this program, which was such a well-conceived approach to address human resource needs in field-oriented vector biology and VBD control.
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 253 Training opportunities in disease-endemic countriesâ Long-term presence of sustainable laboratories in selected disease-endemic countries is critical (IOM, 2003). Such laboratories are invaluable for research, training, and surveillance for tropical and emerging diseases and for training vector biologists. Historically, the U.S. Naval Medical Research Unit, U.S. Army, and WHO laboratories have provided outstanding opportunities for trainees to obtain experience in tropical disease research. Such programs also initiate long-term interactions with col- laborators in tropical regions and yield long-term benefits by establishing public health infrastructure, training and research opportunities, and listening posts in areas of the world where many pathogens emerge. Innovative approaches for rebuilding and sustaining medical entomology/ vector biologyâ Some very innovative approaches to augment proposals to address national and international needs in medical entomology/vector biology and to sustain the expertise were proposed by the Committee (IOM, 2003). Some of these are listed in Table 3-3. For example, CDC could establish a medical entomology/vector biology program to complement the existing Epidemic Intel- ligence Service (EIS) program, and the officers emerging from the new program could provide support to national and international jurisdictions requesting ento- mological expertise. The USDA and DoD should establish a similar program devoted to vectors of animal diseases. Such programs would bring great visibility and prestige to the field. In addition, Regional Centers of Excellence (RCEs) in medical entomology/vector biology should be established, which would pro- vide service, training, and research in medical entomology/vector biology at the regional level, thereby replacing many of the programs lost at the state and local levels. Such an effort would also bring visibility to the field, would provide positions for medical entomologists, and would provide training opportunities for VBD specialists. These RCEs would preferably be incorporated into larger Interdisciplinary and Zoonotic Infectious Disease Centers (IOM, 2003), which TABLE 3-3â Innovative Approaches to Restoring Human Resource Capacity in Vector-Borne Diseases â¢ stablish a medical entomology/vector biology program to complement the existing CDC EIS E program â¢ stablish RCEs in medical entomology/vector biology, preferably incorporated into larger E interdisciplinary comprehensive infectious disease centers â¢ ew training initiatives (e.g., Biology of Disease Vectors course) for targeted areas for N training new leaders and advancing the field scientifically â¢ argeted RFAs for field-oriented research using modern molecular and quantitative tools and T approaches â¢ ong-term sustainable laboratories in disease-endemic countries for training, research, and L surveillance of VBDs SOURCE: Adapted from IOM (2003).
254 VECTOR-BORNE DISEASES would be sustainable and would be invaluable resources to the regions, states, nation, and the world in issues involving vector-borne and other emerging dis- eases and bioterrorism. Summaryâ The efforts and programs outlined and proposed would bring visibil- ity and prestige to medical entomology/vector biology, would educate public and professional groups concerning the importance of vectors and VBDs, and would provide incentives for discipline development and sustainability. These actions would undoubtedly increase student demand and would be of great value in increasing the number of faculty positions and programs in medical entomology/ vector biology in the United States. Increase the Armamentarium for Vector Control The Recommendation: DoD and NIH should develop new and expand upon cur- rent research efforts to enhance the armamentarium for vector control. The devel- opment of safe and effective pesticides and repellents, as well as novel strategies for prolonging the use of existing pesticides by mitigating the evolution of resis- tance, is paramount in the absence of vaccines to prevent most VBDs. In addition, newer methods of vector controlâsuch as biopesticides and biocontrol agents to augment chemical pesticides, and novel strategies for interrupting vector-borne pathogen transmissionâshould be developed and evaluated for effectiveness. Backgroundâ There is a critical need to increase the armamentarium for vec- tor control both in terms of new pesticides and formulations, and new targets and approaches for control. Complicating control of VBDs has been a lack of knowledge of fundamental genetic, biological, and environmental determinants of vector pesticide resistance, vectorial capacity, and vector competence. Indeed, the vector has frequently been viewed as a black box, with little knowledge of the molecular bases of pesticide resistance or pathogen transmission. Similarly, there was a paucity of information concerning critical components of vector biology such as vector immunity, development, diapause, longevity, and so forth, all of which could lead to novel targets and interventions. For the foreseeable future, traditional approaches based on pesticides to reduce vector populations or to repel vectors will remain the first line of defense against emerging and resurging VBDs. Development of new pesticides and for- mulations is critical because of emerging resistance to existing pesticides in vector populations and removal of other pesticides from the armamentarium of vector control (Hemingway et al., 2002, 2006). Societal aversion to the use of pesticides, because of perceived environmental and health effects, is of great concern. This has led to resistance to pesticide application even in the face of ongoing epidemics, such as WNV disease epidemics in New York and Colorado, and the removal of pesticides from control programs. In this regard, the discovery
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 255 and subsequent use of DDT to control VBDs was a major achievement in public health (Attaran et al., 2000). However, indiscriminant DDT usage associated with agricultural practices led to detrimental effects in nontarget organisms, and DDT was banned even for public health use in indoor residual spraying (IRS) programs. New pesticides have proven to be more expensive, less stable, and less efficacious than DDT. Unfortunately, the widespread termination of DDT usage coincided with a resurgence in malaria, leishmaniasis, dengue, and other diseases that are transmitted principally indoors (Roberts et al., 1997; Gratz, 1999; Attaran et al., 2000). IRS of DDT disrupts the close association between the human host and important anthropophilic and endophilic vectors, such as Ae. aegypti and Anopheles gambiae, thereby reducing transmission and disease. Clearly, develop- ment of environmentally sensitive insecticides and formulations with the efficacy of DDT is a public health imperative. Unfortunately, no new public health pesticides for adult mosquitoes have been developed in more than 30 years (Hemingway et al., 2006). Pyrethroids are the cornerstone of vector control, whether for use in spraying, IRS, or bednets (Hawley et al., 2003). Knockdown resistance (kdr) as well as metabolic resistance to pyrethroids has emerged in An. gambiae populations in Africa. The effect that kdr in Anopheles populations may have on the efficacy of bednets and other control measures of this disease remains to be determined (Guillet et al., 2001; NâGuessan et al., 2007). Numerous studies are now documenting resistance in Ae. aegypti to commonly used pesticides targeting immatures and adults, poten- tially removing these from the armamentarium used by mosquito control officials to control dengue (see Eisen and Beaty in Chapter 2). For example, increasing resistance to temephos, which is widely used for control of Ae. aegypti, is of great concern (e.g., Lima et al., 2003). Resistance in vectors is a major problem and one that will undoubtedly worsen without the development of new, environmentally sensitive resistance-breaking pesticides. Responsesâ The Innovative Vector Control Consortium (IVCC) (Hemingway et al., 2006) was founded to address this and other needs and opportunities identified in the 2003 IOM report. The major objectives of the IVCC are to partner with industry to develop new pesticides and formulations and to develop new tools and approaches to manage vector control programs and mitigate pesticide resistance, focusing upon vector control in and around the house. The IVCC and a number of its projects are reviewed in papers by Coleman and Hemingway, Eisen and Beaty, and Scott in this report. Pesticidesâ The Committee recognized the public health imperative to develop new environmentally sensitive insecticides and formulations with the efficacy of DDT. The IVCC (Hemingway et al., 2006) is addressing this in a very unique and potentially powerful way. The first objective of the IVCC is to develop new insecticides and formulations for vector control. The loss of DDT and the poten-
256 VECTOR-BORNE DISEASES tial loss of pyrethroids for vector control due to emerging resistance would be a public health catastrophe. The most expeditious way to develop new pesticides and formulations is to partner with the agrochemical industry. Unfortunately, as noted previously, no new adulticides have been developed in more than 30 years. This is partially due to perceived limited market size for public health pesticides and the costs and opportunity losses associated with bringing a public health pesticide product to market. The IVCC is partnering with industry to develop and deploy new public health pesticides and/or formulations for vector control. The cost of developing a new insecticide is in the range of $70 million. The IVCC will help address issues involving market failure by removing some of the risk associated with bringing a product forward. Partnering companies will revisit existing pesticide libraries with the intent of repurposing products, participate in the development of resistance-breaking pesticides, and even develop new active ingredients. The IVCC will provide the vector and disease expertise as well as field sites to conduct proof of concept and WHO Pesticide Evaluation Scheme (WHOPES) trials, which would be difficult for industrial partners to do. Indeed, the latter issue is a major disincentive to companies becoming involved in public health pesticide development, which will be alleviated by partnerships with IVCC consortium institutions. Such private-public partnerships seem to be an excellent way to address critical needs in developing new public health pesticides. The Committee recognized the public health needs for continued use of DDT in the face of VBD epidemics. Since domicile treatment with DDT has not been associated with major adverse environmental consequences, this practice should be allowed for vector control in public health emergencies until equally effec- tive and inexpensive substitutes for DDT are developed. Care will be needed to ensure that availability of DDT for public health uses does not result in its use in agricultural applications. DDT controls VBDs, such as dengue and malaria, not only by killing vectors but also by repelling them (Roberts et al., 1997), thereby disrupting the close association between the human host and anthropophilic and endophagic vectors (e.g., An. gambiae and Ae. aegypti) and dramatically reducing opportunities for pathogen transmission. Clearly, development of efficacious and environmentally sensitive alternatives to DDT needs to become a major research objective, and one in which the issues of repellency receive equal attention with killing capacity. The Committee also recommended using pesticides in Integrated Pest Man- agement (IPM) programs, which incorporate established agricultural practices to mitigate the evolution of resistance (e.g., rotation of pesticide usage, inclusion of refugia with no pesticide applications), to provide better stewardship of pesti- cides, thereby extending their useful life. Incorporation of new molecular tools to diagnose pesticide resistance into routine control program activities would result in more effective and efficient pesticide usage. Development of novel strategies to prolong pesticide efficacy, such as negative cross-resistance, should be pos- sible in this era of high-throughput screening (Pittendrigh and Gaffney, 2001).
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 257 Determining the effect of pesticide resistance prevalence on control of VBDs would be of great value for risk assessment. The renaissance in vector biology described below has also provided unprec- edented information concerning pesticide resistance in vectors. Indeed, the publi- cation of the genomes of the two major VBD vectors An. gambiae and Ae. aegypti (Holt et al., 2002; Nene et al., 2007) has provided dramatic insight into the molecular bases of resistance (Hemingway et al., 2002). This information can be exploited for developing new tools and approaches for monitoring and mitigat- ing resistance (e.g., David et al., 2005), and for developing new pesticides for vector control. New biopesticides and biocontrol agents to augment chemical pesticidesâ The Committee also recommended renewed effort in developing a new generation of biocontrol agents, such as viruses and bacteria, which could augment chemical pesticides and be incorporated into IPM approaches for vector control. New for- mulations of Bacillus thuringiensis and B. sphaericus exhibit promise for vector control, even in tropical regions (Fillinger et al., 2003; Frederici, 2005). Baculovi- ruses (Becnel, 2006) or parvoviruses (Carlson et al., 2006) from mosquitoes may be useful for vector control. Other biopesticide agents could now be improved using molecular genetic approaches to make them more effective control agents. For example, viruses can be used to transduce effector molecules to enhance vec- tor knockdown or manipulate vector phenotypes. Innovative interventionsâ As noted earlier, for many years the vector was essen- tially viewed as a black box. Little was known about the molecular bases of vector competence, vector biology, vector immunology, and other vector phenotypes critical to pathogen transmission. Such information is essential for developing new interventions for VBD control. The field of vector biology is currently experiencing a renaissance. Efforts of the MacArthur Foundationâs Network on the Biology of Parasite Vectors, as well as other agencies, institutions, and investigators, to infuse modern molecular and genetic approaches into vector research has led to the emergence of a new field of vector molecular biology and the resultant explosion of information on vectors. The genomes of two of the most important vectors of diseases to humankindâAn. gambiae and Ae. aegyptiâhave now been sequenced (Holt et al., 2002; Nene et al., 2007), and other culicine and tick vector genomes are cur- rently being sequenced. Major advances in vector transformation, genetics, and molecular biology have occurred, including the development of effective trans- formation strategies for culicine and anopheline mosquitoes (Coates et al., 1998; Catteruccia et al., 2000); new tools such as virus-based transducing systems and RNAi for gene expression and characterization in vectors (e.g., Johnson et al., 1999; Levashina et al., 2001); robust population genetic approaches for character- izing gene flow in vector populations (e.g., Lanzaro et al., 1995; Besansky et al.,
258 VECTOR-BORNE DISEASES 1997; Gorrochotegui-Escalante et al., 2000); molecular taxonomic approaches for identifying vectors and cryptic species (e.g., Ballinger-Crabtree et al., 1992; Collins and Paskewitz, 1996); new insight into the vector immune system and the development of the field of vector immunology (Christophides et al., 2002; Bartholomay et al., 2003; Keene et al., 2004; Blandin et al., 2004; Waterhouse et al., 2007); new immunization strategies that incorporate vector salivary protein antigens to reduce pathogen transmission or other antigens for vector killing vaccines (e.g., Titus and Ribiero, 1988; Kamhawi et al., 2000); new insights and understanding of vector olfaction and host seeking (e.g., Fox et al., 2001; Pitts et al., 2004), which provides opportunities for developing new repellents and attractants for vector traps; new understanding of the infection, develop- ment, and transmission of pathogens by vectors (e.g., Dimopoulos et al., 1998; Sanders et al., 2005); new insights into the molecular biology of vectors (e.g., Barillas-Mury et al., 1995; Valenzuela et al., 2003; Hansen et al., 2004); and the molecular manipulation of vectors to make them resistant to pathogen (dengue virus and malaria) transmission (e.g., Ito et al., 2002; Franz et al., 2006; Olson et al., 1996). The accumulation of new knowledge of vector biology has been stunning. Indeed, the field moved from one mosquito gene in 1989 (James et al., 1989) to more than 14,000 genes with the publication of the An. gambiae genome in 2002 (Holt et al., 2002). In silico approaches have revolutionized gene identification and research in vector biology, and the post-genomics era in vector biology offers great promise for identifying new targets and approaches for control of vectors and VBDs. This renaissance in vector biology is reflected by the dramatic increase in vector grants at NIH, the development of a new vector biology study section at NIH, a dramatic increase in the number of publications in leading journals, and a dramatic increase in vector biology presentations and sessions at scientific society meetings. There is now unprecedented accumulation of infor- mation concerning vector biology, population genetics, genomics, immunity, and so forth. The task is to translate this research and knowledge into tools and approaches to combat VBDs. The Committee also recommended continued or expanded research in areas pertinent to VBD control, including the following: New repellents and attractants Repellents remain a first line of defense against emerging or resurging VBDs. Development of new personal and spatial repellents for prevention of VBDs was highly recommended by the committee as a potentially very fruitful area of research. Modern high-throughput and genomic approaches may permit identification of new molecules with repellent activity similar to that of DEET (and DDT), but without adverse effects. Understanding the molecular basis of vector olfaction and host seeking (Hill et al., 2002) may lead to new repellents and attractants to control vectors (Day et al., 2001). Novel immunization strategies for vector-borne diseases Insights into the
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 259 molecular basis of vector-pathogen-host interactions provide new strategies to control VBDs (Willadsen, 2001; Foy et al., 2003). Immunizing hosts to vector- specific determinants of pathogen transmission (e.g., salivary effector proteins that enhance pathogen infection [Titus and Ribeiro, 1988]) could provide broad- spectrum protection against multiple pathogens or strains (Kamhawi et al., 2000; Valenzuela et al., 2003). Other critical determinants of pathogen infec- tion of and transmission by vectors (e.g., vector proteolytic enzymes, which process arbovirus proteins and condition vector infection) could be targeted for transmission-blocking vaccines (Carter, 2001). Immunizing vertebrate hosts to immunologically-privileged vector antigens could kill or impair blood-feeding mosquitoes, a strategy that works for ticks (Willadsen, 2001), and may also be useful against mosquito vectors (e.g., An. gambiae and Ae. aegypti), which feed frequently on humans (Foy et al., 2002). Theoretically, these vectors would feed on other hosts (zooprophylaxis), thereby reducing pathogen transmission. Novel genetic approaches to the control of vector-borne diseases Genetic approaches in which vector populations are manipulated to become incompe- tent vectors also offer the potential to interrupt pathogen transmission. Such approaches would minimize potential environmental issues associated with pes- ticide usage and would not create an ecological vacuum that other vectors could occupy. The vector population could theoretically be genetically immunized to make it nonpermissive to pathogen transmission. The âimmunogensâ could be driven into vector populations by harnessing naturally occurring arthropod sys- tems, such as transposable elements, symbionts (e.g., Wolbachia), or transduc- ing viruses, which would be vector specific (Beaty, 2000). RNAi was recently documented as a robust immune response to arboviruses in vectors (Keene et al., 2004), and was quickly exploited to develop transgenic mosquitoes immunized to prevent dengue infection (Franz et al., 2006). Proof of principle has been provided that vectors can be molecular manipulated to make them refractory to arboviruses and trypansome and malaria parasites (Olson et al., 1996; Beard et al., 2002; Ito et al., 2002; Franz et al., 2006). Considering the amazing amount of recent progress in vector molecular biology, continued research in this area may well provide dramatically new approaches for VBD control. Summaryâ The renaissance in vector biology is providing unprecedented infor- mation concerning the molecular basis of vector biology and critical vector phe- notypes that could be exploited for vector control. Testimony to the growth of the field from the black box of the vector to the renaissance in vector molecular biology is the formation of VectorBase (Lawson et al., 2007)âa critical resource for collecting and making available the explosion of information concerning vectors that has emerged in recent years from investigations of vector molecular biology, genomics, population genetics, and pathogen-vector-host interactions, etc. Undoubtedly, this information can be exploited to develop alternate, novel
260 VECTOR-BORNE DISEASES strategies for vector control, for disrupting host-vector interactions, and for inter- rupting pathogen transmission. Geographic Information Systems and Robust Models for Predicting and Preventing Vector-Borne Diseases The Recommendation: CDC, DoD, and NIH should work with state and local public health agencies and academia to expand efforts to exploit geographic information systems and robust models for predicting and preventing the emer- gence of VB and zoonotic diseases. Backgroundâ Because biological and environmental factors condition transmis- sion of pathogens from vectors or vertebrate amplification or reservoir hosts to humans, temporal models based on climate data to predict outbreaks of sporadi- cally occurring diseases and GIS-based models to predict spatial risk patterns have great potential for providing predictive capability for vector-borne and zoo- notic diseases. A GIS spatial backbone can also be incorporated into a computer- based decision support system as a tool for analysis and presentation of relevant environmental, entomological, or epidemiological data (e.g., presence of larval habitat for anopheline mosquitoes, areas with especially high vector abundance, or locations of human disease cases). This type of system can revolutionize surveillance, risk assessment, and prevention strategies for vector-borne and zoonotic diseases, manage and mitigate pesticide resistance, and permit focusing of resources and talents on prevention efforts in the areas at greatest risk. Responsesâ In the United States, climate-based models to predict outbreaks of rare but severe vector-borne or zoonotic diseases have been developed for hanta- virus pulmonary syndrome and plague (Glass et al., 2000, 2002; Hjelle and Glass, 2000; Enscore et al., 2002). GIS- and/or remote sensing-based models predicting the presence of vector breeding habitat, acarological or entomological risk of exposure to vectors (vector abundance or density), or risk of pathogen exposure (presence or abundance of infected vectors or vertebrates, presence or incidence of human disease) have been developed for a variety of diseases including han- tavirus pulmonary syndrome, Lyme disease, plague, and WNV disease in the United States, and dengue and malaria in tropical areas (e.g., Kitron et al., 1991; Glass et al., 1995, 2000, 2002; Boone et al., 2000; Hay et al., 2000; Brownstein et al., 2002; Rogers et al., 2002; Peterson et al., 2005; Diuk-Wasser et al., 2006; Eisen et al., 2006, 2007a,b). GIS-based modeling approaches also have been used to study spatial patterns of gene flow in key mosquito vectors such as Ae. aegypti (e.g., Gorrochetegui-Escalante et al., 2000; Bosio et al., 2005; da Costa-Ribeiro et al., 2007) and rodent reservoirs of Sin Nombre virus (Root et al., 2003). Incor- poration of GIS into computer-based decision support systems for management of VBDs is described in the paper by Eisen and Beaty in this report.
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 261 To date, there has been a tendency in the research community to stovepipe GIS-based risk modeling approaches for VBDs to either vector data or epide- miological data. This is highly unfortunate because these two types of data have weaknesses but also complementary strengths. For example, although the location of sampling sites for vector data readily can be georeferenced, human behavior may strongly impact risk of vector and pathogen contact. On the other hand, a human disease case, which unequivocally demonstrates contact with an infected vector, often is accompanied by questionable information regarding the patho- gen exposure site. To overcome these issues, models combining independently derived estimates for vector risk and epidemiological risk are needed (Eisen et al., 2006). In the case of GIS-derived risk models for vector-borne and zoonotic dis- eases based on epidemiological data in the United States, plague and hantavirus pulmonary syndrome models are most reliable because probable sites of patho- gen exposure are determined through comprehensive case investigations carried out by state health agencies or CDC (Eisen et al., 2007a,b). The more common but less severe Lyme disease and WNV disease are far more problematic in this regard because the quality of information from case files regarding probable sites of pathogen exposure is highly variable, which can compromise the output model. Simply put, the tremendous potential for using GIS modeling approaches in spa- tial epidemiology and ecoepidemiology currently is severely compromised for many VBDs based on poor quality of information regarding pathogen exposure site (Eisen and Eisen, 2007). Advances in GIS technology and the ever-increasing use of the Internet as a primary knowledge resource present tremendous but currently largely untapped possibilities for disseminating information regarding spatially explicit risk of exposure to VBDs. Using a web mapping approach, static risk maps can readily be converted to a dynamic web-based information delivery system where select- ing an area of interest provides a close-up view showing risk patterns for labeled spatial units (e.g., counties, zip codes, or census tracts) and the location of major roads, population centers, and other easily recognizable features. This approach will facilitate information transfer regarding VBD risk to both the medical com- munity and the public at large. Indeed, web-based delivery of research information is a sadly neglected field that in the future can help to bridge the gap between the research community, the public health community, and the public. Much information of immediate interest and practical use to public health practitioners and the U.S. public now languishing in scientific journals could be effectively broadcast through web- based information delivery systems developed by academic or public health institutions. Positive examples from the academic side are scarce but include the University of Rhode Island web-based Tick Encounter Resource Center and the â See http://www.tickencounter.org.
262 VECTOR-BORNE DISEASES Iowa State University Medical Entomology Laboratory website for mosquito- and tick-borne disease. Summaryâ There has been an explosion in information technology solutions to prediction, prevention, and control of VBDs in recent years. This includes imple- mentation of computer-based VBD surveillance systems (e.g., CDCâs ArboNET and WHOâs DengueNet), development of decision support systems for VBD management, a plethora of GIS-based models predicting risk of exposure to vectors or VBDs, and movement toward web-based delivery of GIS-based risk maps and other pertinent and evidence-based information related to prevention and control of VBDs. One main task ahead is to adapt the technological solu- tions now being incorporated into routine surveillance and control activities in developed countries for use in resource-poor countries in desperate need of VBD management solutions. Discussion Overall, there is considerable excitement in vector biology and vector control. Progress in understanding the molecular biology of vectors has been extraordi- nary, and indeed the actual vectors of the respective pathogens are now becoming the models for studying these processes. Model organisms, such as Drosophila and Manduca, which have contributed enormously to our understanding of the molecular biology and physiology of arthropods and arthropod vectors, are now being supplanted by epidemiologically-relevant organisms. The major advances in understanding the biology and molecular biology of vectors and vectorâpathogen interactions provides promise for the development of new targets and opportunities for control, whether by new pesticides, repel- lents, or even more innovative approaches, especially in the post-genomics era of vector biology. Decision support systems exploiting advances in information technology and robust models provide exciting opportunities for predicting, pre- venting, and controlling emerging and resurging diseases. The task is now to translate this explosion of information as quickly as possible into field programs for surveillance and control of VBDs and to train a generation of VBD specialists capable of deploying and refining these tools to control these important diseases. Acknowledgments This paper is dedicated to Robert E. Shope, who was a friend, mentor, and role model for us all. Support was provided by the Innovative Vector Control â See http://www.ent.iastate.edu/medent.
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 263 Consortium as part of the Dengue Decision Support System project at Colorado State University and the NIH Emerging Virus Disease Unit (AI-25489). INTEGRATION OF STRATEGIES: SURVEILLANCE, DIAGNOSIS, AND RESPONSE Roger S. Nasci, Ph.D. Centers for Disease Control and Prevention The panel convened as part of this workshop on vector-borne diseases was charged with discussing the following questions: â¢ Are multidisciplinary teams and collaborative responses required to deal with emerging vector-borne diseases? â¢ How can systems be integrated to enhance surveillance, diagnosis, and response? â¢ How can vector-borne disease be linked to a broader public health agenda to increase support? â¢ What research directions should be promoted to enhance prediction and control of vector-borne diseases? â¢ Are we effectively training research and operational professionals for the future? I would like to summarize my comments from the panel discussion regarding each of the preceeding points, describing some of the relevant Centers for Disease Control and Preventionâs (CDCâs) activities and recommendations. Multidisciplinary Teams and Collaborative Responses One of the historical strengths of CDC programs in general, and specifically in vector-borne diseases, is the ability to field multidisciplinary teams to respond to outbreaks and to address basic public health research. CDC subject mat- ter experts in epidemiology, medical entomology, vertebrate ecology, virology, immunology, pathology, diagnostics, human behavior, public communication, and so forth readily work as teams to address specific outbreak events and to formulate comprehensive approaches to further public health programs. In addi- tion, CDC frequently works closely with a variety of government, academic, and â Research Entomologist; Chief of the Arboviral Diseases Branch, Division of Vector-Borne In- fectious Diseases. 3150 Rampart Road, Fort Collins, CO 80521. Phone: (970) 221-6400; E-mail: firstname.lastname@example.org. â The findings and conclusions in this report are those of the author and do not necessarily represent the views of the Centers for Disease Control and Prevention.
264 VECTOR-BORNE DISEASES private agencies and organizations to address specific problems. The complexity of zoonotic, vector-borne diseases demands this multidisciplinary response. The West Nile virus outbreak during 1999 in New York is an excellent example of this broad networking among agencies and has been described in detail in numerous reports (e.g., GAO, 2000). Similar responses and networks are functional inter- nationally as well. The recent (2006-2007) epidemic of Rift Valley fever virus in East Africa and the multiagency international response (CDC, 2007) demon- strated how multidisciplinary teams and collaborative responses are essential to dealing with these events. Though the multidisciplinary teams within CDC generally assemble quickly and respond efficiently, the ad hoc formation of larger collaborations involving many agencies is often accompanied by inefficiencies and complications. The Government Accountability Office (GAO) 2000 report on the 1999 West Nile virus response identifies many of the problems encountered during the initial event, makes recommendations for resolving them, and outlines a number of actions taken by CDC and other agencies to achieve that end. Similarly, the 2006- 2007 Rift Valley fever response by numerous U.S. federal agencies was followed by an effort coordinated by U.S. Department of Agriculture (USDA) to take a priori steps to plan multidisciplinary, multiagency responses (Britch et al., 2007). While large, multiagency emergency responses will always be accompanied by some degree of confusion, communication among the agencies, planning, and network development can significantly decrease these problems and should be actively promoted. Integration of Systems Surveillance systems are the foundations of public health. Surveillance for human disease is well developed in the United States and is a primary function of health programs from the local to the national level. Because vector-borne zoonotic diseases involve nonhuman components (e.g., mosquitoes and birds amplify West Nile virus), monitoring enzootic/epizootic transmission activity may provide early warning of conditions that result in epidemic transmission. An example of a system designed to capture enzootic/epizootic arbovirus trans- mission activity as well as human case data is the ArboNET arbovirus surveil- lance system (CDC, 2004) that was developed and implemented in response to the introduction of West Nile virus into the United States in 1999. This system was expanded to capture information about all mosquito-transmitted arboviral zoonoses in 2004. ArboNET exemplifies the integration of systems because it allows capture of arbovirus prevalence information from numerous agencies (e.g., mosquito-based surveillance from local mosquito control programs, horse deaths from state public health veterinary programs, dead birds from local/state wildlife health agencies), as well as information about human case reports from the traditional health surveillance networks. These data are compiled weekly at
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 265 the state health department level and submitted to the CDC Division of Vector- Borne Infectious Diseases. The data are summarized and disseminated through a variety of avenues; prominent among them is the U.S. Geological Survey (USGS) Disease Maps program, which provides graphic representations of the weekly data summaries. There are likely additional data sources that could be integrated into a more comprehensive ArboNET system. For example, the USDA National Animal Health Monitoring and Surveillance equine arbovirus monitoring pro- gram captures data on arboviruses in horses that are reported independently of the CDC ArboNET system. Currently, it is difficult to determine if these cases duplicate or supplement data provided to ArboNET. The ArboNET arbovirus surveillance system is structured to provide a flex- ible data capture portal at the state health department level that may be modified to capture similar environmental surveillance data for other zoonotic vector-borne diseases. It may also be used to capture and disseminate weather/climate informa- tion that may provide better prediction of regional risk patterns. An example of such a program is the still experimental ArboNET/plague surveillance system. 10 This system, a partnership between the CDC Division of Vector-Borne Infec- tious Diseases and the NASA Science Mission Directorate, Earth-Sun System Division Applied Sciences Program, is designed to evaluate and verify models as early warning tools for plague. There are likely a number of complementary systems and developing models that may be formulated into better, integrated surveillance programs. Linking Vector-Borne Disease to a Broader Public Health Agenda In a previous report, the Institute of Medicine (IOM) did an excellent job describing the global importance of zoonotic diseases (IOM, 2002), producing a comprehensive report that unequivocally linked vector-borne disease to core pub- lic health issues. Similarly demonstrating the link between vector-borne disease and a broad health agenda is the fact that several of the disease agents recognized to be of high health impact and with the potential to impact national security are vector-borne (e.g., plague, tularemia, alphavirus, and flavivirus viral encepha- litides such as Venezuelan equine encephalitis, eastern equine encephalitis, and Japanese encephalitis).11 Increased support for research should logically flow to these programs due to the apparent association of vector-borne diseases with the high-profile, national security health agenda. In fact, the National Institutes of Health (NIH) does provide substantial support for research addressing a variety of vector-borne disease topics (see paper by Adriana Costero in this chapter). Addi- ââSeehttp://diseasemaps.usgs.gov. ââSeehttp://nsu.aphis.usda.gov/nahss_web/faces/arbovirus_summary.jsp. 10â See http://aiwg.gsfc.nasa.gov/esappdocs/projplans/arbonet_plague_ProjectPlan.pdf. 11â See http://www.bt.cdc.gov/agent/agentlist.asp.
266 VECTOR-BORNE DISEASES tional needed support may be obtained by explicitly publicizing the importance of these diseases to a broader audience, and by developing targeted requests for proposals by the nationâs research funding agencies. Research Directions to Enhance Prediction and Control of Vector-Borne Diseases There is a large number of critical research directions related to vector-borne diseases, many of which have been previously described in earlier reports by this Forum (IOM, 2002). Much of the discussion about research directions in the current Forum centered on climate change and the impact global warming may have on vector-borne zoonotic diseases. This issue has been the subject of numer- ous speculative publications, as well as a number of publications describing the influence of climate and weather on transmission dynamics. The complexity of the topic and the difficulty in deriving simple answers is reviewed admirably by Sutherst (2004). In this article, Sutherst states the following: Adaptation (to the impact of climate change) must be based on a sound under- standing of the causes of changed transmission patterns in each situation, in other words on an understanding of the whole vector-pathogen-host-environ- ment system. This calls for a systems approach with comprehensive and testable predictive models to remove the subjectivity from qualitative judgments. Only through application of âsystems analysisâ research, combining input from a diversity of fields like epidemiology, vector biology, quantitative ecol- ogy, spatial modeling, and meteorology/climatology will we be able to develop a knowledge base leading to predictive models and operational decision support systems for use in public health. A second research direction that should be pursued is related to the develop- ment of public health pesticides (PHPs). For most vector-borne diseases there are no vaccines or effective medical therapies. As a result, vector control is the primary strategy for disease prevention and pesticides are integral to pest man- agement programs designed to manage vector populations. Pesticides to control mosquitoes target larvae with a variety of modes of action (e.g., insect growth regulators, oils, microbial-produced insecticides like Bacillus thuringiensis israelensis or B. sphaericus). However, the alternatives available to control adult mosquitoes, which often is required for rapid control during disease outbreaks and emergencies, are limited to two modes of action represented by the pyrethroids and organophosphates. Unfortunately, development of resistance and growing concerns about human exposure and environmental safety restrict how and where these pesticides can be used. There is an urgent need not only to maintain the PHPs currently registered for vector control, but also to develop new pesticides with novel modes of action to increase safety and to allow us to better manage vector resistance. This is a global concern recognized by the World Health Orga-
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 267 nization (WHO) Global Collaboration for Development of Pesticides for Public Health, which recognized the serious public health risk incurred because of the reduction in available PHPs. This body noted that the development of alternative pesticide products and technologies is a high priority for the WHO (2004). The United Nations also called upon the international community to support invest- ment in new insecticides and delivery modes as part of the Roll Back Malaria plan (United Nations General Assembly, 2005). Effective Training of Research and Operational Professionals for the Future The recent introduction of West Nile virus into the United States has resulted in an unprecedented demand for expertise in mosquito surveillance and control operations throughout much of the country. Not only are there not enough trained medical entomologists to fill these new positions, but there are very few academic institutions still capable of providing such training (Fish, 2001). This quote succinctly summarizes the situation regarding operational scien- tists in the United States, and I suspect it is representative of the global situation. Fish goes on to describe prior reports highlighting this problem going back to 1983. The topic of ensuring an adequate public health entomology workforce is discussed in the broader context of education and training needs in the IOM report Ensuring an Infectious Disease Workforce: Education and Training Needs for the 21st Century (IOM, 2006). In my position at the CDC, I interact regularly with public health entomologists in health departments at the state and local lev- els. While it is laudable that many of these jurisdictions have chosen to add such staff to deal with the problems stemming from the West Nile virus introduction, in my experience many of the positions are being filled by entomologists lacking public health training or experience. Many are highly skilled, professional ento- mologists, but many come from fields like insect ecology, forest entomology, or crop entomology and are responding to changes in the current job market. In prior years, the NIH supported topical training grants (e.g., parasitol- ogy and vector biology) to partially address these needs in the public health community. Currently, training grants are rare and most training is done under the auspices of NIHâs Research Project Grant Program (R01). In 2002, CDCâs Division of Vector-Borne Infectious Diseases solicited proposals from universi- ties to develop multidisciplinary masters and doctoral programs in public health entomology in an effort to improve the ability of the U.S. public health system to effectively respond to the problem of vector-borne infectious diseases and to increase the number of specialists with demonstrated field- and laboratory-based skills. Tuition, stipend, and research support were provided for 5 years in four university programs. However, this training grant program is not being continued beyond the initial 5-year cycle due to shifts in public health funding priorities.
268 VECTOR-BORNE DISEASES It is apparent that more training programs must be developed at the nationâs uni- versities to meet the growing needs of public health entomology and the global health community. Acknowledgments Numerous colleagues in the Division of Vector-Borne Infectious Diseases and the Public Health Pesticide Consortium contributed to the programs described above and provided comment in the development of this discussion. SURVEILLANCE, DIAGNOSIS, AND RESPONSE: INTEGRATION OF STRATEGIES12 Sherrilyn Wainwright, D.V.M., M.P.H.13 U.S. Department of Agriculture During the Forum on Microbial Threats âVector-Borne Diseasesâ workshop, a panel of experts convened to discuss the following questions pertaining to vector-borne disease surveillance, diagnosis, and response strategies: â¢ Are multidisciplinary teams and collaborative responses required to deal with emerging vector-borne diseases? â¢ How can systems be integrated to enhance surveillance, diagnosis, and response? â¢ How can vector-borne disease be linked to a broader public health agenda to increase support? â¢ What research directions should be promoted to enhance prediction and control of vector-borne diseases? â¢ Are we effectively training research and operational professionals for the future? I would like to summarize my comments from the panel discussion regarding each of these points and describe some of the relevant Animal and Plant Health Inspection Service (APHIS) activities related to the aforementioned topics. 12â The findings and conclusions in this report are those of the author and do not necessarily repre- sent the views of the U.S. Department of Agriculture, Animal and Plant Health Insepction Service, Veterinary Services, Centers for Epidemiology and Animal Health (CEAH). 13â Animal and Plant Health Inspection Service (APHIS), Center for Epidemiology and Animal Health, Center for Animal Disease and Information Analysis, Risk Analysis Team, 2150 Cen- tre Ave., Building B, 2W75, Fort Collins, CO 80526. Phone: (970) 494-7318; E-mail: Sherrilyn. H.Wainwright@aphis.usda.gov.
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 269 Multidisciplinary Teams and Collaborative Responses The U.S. Department of Agriculture (USDA) APHIS, Veterinary Services (VS) plays a leading role in animal health outbreak responses by using multi- disciplinary teams to expand current national and international monitoring and surveillance programs, support early detection of threats to animal and plant resources, including wildlife disease threats, and coordinate with congress and other government agencies.14 The Food and Agriculture Incident Annex (July 2006) describes how the USDA and HHS (the âcoordinating agenciesâ) should respond to incidents involving the U.S. food and agriculture system, with the help of several other federal agencies (DHS, 2006). The Annex lists the following objectives of a coordinated federal response: â¢ Detect the event through the reporting of illness, disease/pest surveillance, routine testing, consumer complaints, and/or environmental monitoring â¢ Establish the primary coordinating agency â¢ Determine the source of the incident or outbreak â¢ Control and contain the distribution of the affected source â¢ Identify and protect the population at risk â¢ Assess the public health, food, agriculture, and law enforcement implications â¢ Assess the extent of residual biological, chemical, or radiological con- tamination and decontaminate and dispose as necessary A collaborative effort between USDA APHIS VS, HHS, Agriculture Research Service (ARS), U.S. Fish and Wildlife Services, state agencies, affected animal industries, and diagnostic laboratories is essential in the response to a vector- borne disease outbreak. APHIS has worked successfully with these agencies on national and international vector-borne disease outbreak responses, such as in the case of responses to West Nile virus (GAO, 2000) and vesicular stomatitis virus. However, West Nile virus outbreaks have exposed weaknesses in communication and coordination between human public health and animal health agencies, as described in a Government Accountability Office (GAO) 2000 report: Links between public and animal health agencies are becoming more important. Many emerging diseases, including West Nile, affect both animals and humans. So do many viruses or other disease-causing agents that might be used in bioter- rorist attacks. The length of time it took to connect the bird and human outbreaks of the West Nile virus signal a need for better coordination among public and animal health agencies. 14â Department of Homeland Security (DHS), Health and Human Services (HHS), Environmental Protection Agency (EPA), and Department of the Interior (DoI).
270 VECTOR-BORNE DISEASES APHIS has addressed vector-borne disease VBD challenges through ini- tiatives such as the creation of a new biological threat awareness capacity, the development of mitigation strategies for critical production and processing node vulnerabilities, and the enhancement, integration, and protection of its science and technology infrastructure. Within APHIS, multiple scientific and technical disciplines are represented.15 Working together, they coordinate with the other agencies and manage commu- nications to address the multiple issues associated with a zoonotic vector-borne disease outbreak response. APHISâs operational program units mobilized to participate in multidisci- plinary teams include Animal Care, Biotechnology Regulatory Services, Inter- national Services and Trade Support Team, Plant Protection and Quarantine, Wildlife Services, and Veterinary Services. Each team contributes its vast expe- rience, knowledge, and expertise to collaborative responses. For example, in 2003 the Centers for Disease Control and Prevention (CDC) collaborated with the Food and Drug Administration (FDA) and APHIS in response to the multi- state outbreak of monkeypox (CDC, 2003). In this case, APHISâs Animal Care program assisted FDA in obtaining information from pet store distributors of prairie dogs and African rodents, including Gambian giant rats and dormice. The investigation concluded that prairie dogs were likely infected by Gambian giant rats and dormice at an Illinois animal distributor in April and May 2003. At least 35 human cases of monkeypox were linked to contact with prairie dogs from this distributor. APHISâs Wildlife Services also assisted by trapping and testing prairie dogs, Gambian giant rats, and dormice for surveillance and control. Internationally, the multidisciplinary responses and collaborations have also functioned well. In May 2000, a joint CDC-USDA APHIS team investigated a Q-fever and Brucellosis outbreak in Bosnia and Herzegovina (Nicholson et al., 2003). The team included human and animal health epidemiologists and labora- torians who worked closely with in-country counterparts and ultimately assisted in capacity building for Bosnia and Herzegovina. There is a real need for proactive, rather than reactive, planning for outbreak responses involving multiagency collaborations. Multidisciplinary teams should prepare in advance to minimize inefficiencies and complications. Actions identi- fied by the GAO (2000) report to resolve such issues have been initiated by a number of agencies, including USDA APHIS and CDC, though more work is needed for essential communication, coordination for planning, operations, logis- tics, administration, and diagnostics for an effective outbreak response. 15â Including veterinarians, epidemiologists, entomologists, virologists, pathologists, laboratory di- agnosticians, geographic information specialists, information technologists, economists, diagnostic laboratories, and legislative and public affairs specialists.
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 271 Integration of Systems Integration of information management surveillance, laboratory, emergency, and other systems is essential for the efficiency of a multidisciplinary mul- tiagency outbreak response. The exchange of information, especially during a zoonotic vector-borne disease response, is vitally important. Within APHIS, the National Surveillance Unit (NSU) coordinates animal health surveillance activi- ties in the United States through evaluation, design, analysis, prioritization, and integration (USDA, 2007a). The National Animal Health Surveillance System (NAHSS) combines animal health monitoring and surveillance activities into a comprehensive, coordinated system. The NSU coordinates, implements, and dis- tributes information about the NAHSS (USDA, 2007a). The Center for Emerging Issues (CEI) was created in the early 1990s to work on emerging animal health problems. Today, CEI also explores surveillance approaches and examines open source information for signs of international animal health events using advanced information technology tools (USDA, 2007b). Adding to this surveillance net- work are reports from APHIS International Services (IS). Nationally, APHIS VS has developed the Veterinary Services Process Streamlining System to capture the interstate movement and transportation of animals, both imports and exports, that when combined with other surveillance systems will assist in identifying the potential transmission of diseases. Much of the detailed information gathered for the aforementioned information systems is collected and electronically entered and transmitted to centralized databases by trained field USDA APHIS VS and state veterinary medical officers located in every state throughout the United States. APHIS is currently integrating state and the National Veterinary Services Laboratory resources into a nationwide laboratory network, the National Animal Health Laboratory Network (NAHLN), for veterinary and plant health; standard- izing diagnostic protocols and procedures; and working in concert with HHS, CDC, and the Department of Justice (DoJ) to develop and implement processes and procedures for monitoring and tracking the possession and use of select agents and toxins. The NAHLN is a state and federal partnership currently con- sisting of 58 laboratories in 45 states (USDA, 2007c). It is critical to evaluate the accuracy and compatibility of the multiple, com- plicated, and varied reporting systems, to identify any duplication or gaps, as well as to gather and analyze appropriate information for an effective, coordinated multiagency, multidisciplinary outbreak response. The integration of multiagency, multidisciplinary surveillance systems is essential because the epidemiology of vector-borne diseases involves not only human and animal hosts, but also vectors (i.e., mosquitoes, ticks, etc.) and often wild animal hosts. The outbreak of West Nile virus is an example of the need to integrate the varied animal, human, and entomological surveillance and labora- tory systems. By monitoring an outbreak and anticipating the potential transmis-
272 VECTOR-BORNE DISEASES sion variables that could indicate favorable outbreak conditions, multiagency prevention and intervention measures can be set up in advance. For example, the U.S. Geological Survey (USGS), CDC, and DoI created Disease Maps16 to document wild bird testing and results for West Nile virus. Together with APHIS Wildlife Services, these systems also monitor wild birds for highly pathogenic avian influenza (HPAI). The National Animal Health Monitoring and Surveillance (NAHMS) system reports all equine arbovirus cases to CDC ArboNET.17 Addi- tionally, the USDA APHIS VS, Centers for Epidemiology and Animal Health (CEAH), CEI, Spatial Epidemiology Team (SET), utilizing geographic informa- tion systems (GIS) supports VSâs spatial analysis needs in animal disease surveil- lance, incident management, and epidemiological analysis. The SET provides this support to many customers in VS.18 Linking Vector-Borne Disease to a Broader Public Health Agenda A number of reports have linked vector-borne disease to the broader public health agenda, including the IOM (2002) report on the global importance of zoonotic diseases. Effective historical and ongoing links between vector-borne disease and the broader public health agenda have involved public health, animal health, and entomology experts, such as in the cases of equine encephalitides, West Nile virus, and Rift Valley fever. HHS, CDC, DHS, and APHIS have identi- fied many agents and diseases that could be used for bioterrorism, many of which are zoonotic. A number of these agents are on the Select Agents list. 19 Research Directions to Enhance Prediction and Control of Vector-Borne Diseases ARS, the research arm of APHIS, has extensive expertise in the area of vector-borne diseases. It is currently working on a number of research projects to enhance prediction and control of vector-borne diseases and has worked with other agencies to coordinate a multidisciplinary method. Current vector-borne disease research projects include the following: 16â See http://diseasemaps.usgs.gov. 17â See http://nsu.aphis.usda.gov/nahss_web/faces/arbovirus_summary.jsp. 18â These customers include the following: CEAH, National Animal Health Policy and Program, Emergency Management, National Veterinary Services Laboratory, VS area offices, VS regional of- fices, VS deputy administratorâs office; and customers outside Veterinary Services, including the GIS user community, ARS, CDC, Food Safety Inspection Service, state departments of animal agriculture, colleges and universities, International Services, Wildlife Services, Plant Protection and Quarantine, Animal Care, Planning and Program Development, and the World Organization for Animal Health (OIE) (USDA, 2007d). 19â See http://www.bt.cdc.gov/agent/agentlist.asp.
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 273 â¢ âUse of Geographic Information System (GIS) methods to understand spatial patterns of mosquito vectors of West Nile virus,â to predict areas and conditions of high and low risk for WNV â¢ âEvaluation of operator safe diagnostic reagents for Rift Valley fever virus,â to develop diagnostic reagents and vaccines for Rift Valley fever that can be safely produced and distributed in North America â¢ âGenetic studies of Rift Valley fever virus vectors in Kenya,â to study the genetics of known Rift Valley fever virus (RVFV) vectors in Kenya â¢ âRemotely sensed satellite climate and environmental data to detect ele- vated populations of mosquito vectors of emerging arboviruses in the U.S.,â to develop an early warning system to detect elevated populations of potential vectors of RVF and other mosquito-borne emerging virus threat in the United States, providing decision support for agricultural and public health officials to implement improved agricultural and medical planning for potential containment and control operations â¢ âVector competence of North American mosquitoes for Rift Valley fever,â to assess and determine epidemiological and entomological factors to facilitate/ develop effective RVFV control measures â¢ âCountermeasures to control and eradicate RVF,â through diagnostics Addressing questions through a multidisciplinary systems approach, includ- ing predictive modeling, is an essential component of the research that is needed. Research related to prevention and control measures, as well as effective vaccines for viral diseases in both humans and animals, is also needed. Effective Training of Research and Operational Professionals for the Future There is a recognized demand for trained and skilled vector-borne disease experts, especially entomologists; however, the available financial and human resources are currently limited. Academic training programs need to increase capac- ity for field veterinary and entomology emergency response programs, as well as laboratory, policy, and emergency response management programs. Training grants from the National Institutes of Health provide some opportunities to address these needs; but they are not on the scale needed to fill the gaps. The efforts of the multi- disciplicary agencies with vested and mutual interests to mount effective emergency responses to incursions of vector-borne diseases of public and animal health signifi- cance, potentially threatening U.S. national security, can jointly promote the need to provide incentives and financial support for interdisciplinary studies towards the development of experts to work in the area of vector-borne diseases at the national level through funding sources, including NIH and DHS.
274 VECTOR-BORNE DISEASES CONFRONTING VECTOR-BORNE DISEASES IN AN AGE OF ECOLOGIC CHANGE David M. Morens, M.D.20 National Institutes of Health Introduction The human-inhabited world has been changing dramatically since before recorded time. Such change has inevitably created new microbial opportunities to exploit ecosystem dynamism, including the ability to find, infect, and adapt to human hosts. In manâs hunter-gatherer days, from about 2 million years ago until about 10,000 years ago, infectious diseases were substantially limited to those caused by colonizing skin and gut organisms because person-to-person spread was unsustainable beyond small roving kinship groups. Crop domestication and animal husbandry (revolutions occurring about 10,000 years ago) led to geographic stability, the establishment of populous cities, and in consequence the first era of disease emergence, in which animal organisms switched and adapted to human populations, being sustained by now- unimpeded human-to-human transmission. It was in this era that many of the worldâs great epidemic diseases emerged as zoonoses, including tuberculosis, smallpox, measles, and possibly some of the human arboviruses. This era of newly emerging diseases was eventually followed by disease reemergences as existing but localized diseases spread geographically with expanding trade and travel (e.g., the movement of plague from China to Europe in the 14th century; syphilis from the New World to Europe in 1493; and smallpox back from Europe to the Americas in 1520). It was in this same reemergence era that exploration and the slave trade spread African mosquitoes around the world, along with some of the diseases they carried (e.g., Aedes aegypti carrying yellow fever, dengue, and chikungunya). The idea that once having emerged, such vector-borne diseases would settle down and become endemic background problems has, in the past 50 years, been shattered by tens of millions of deaths from increasingly drug-resistant falciparum malaria, by a 30-fold increase in the incidence of dengue associated with the emergence and global spread of dengue hemorrhagic fever, and by the emergences and reemergences of many other important vector-borne diseases, such as Lyme disease, West Nile virus disease, Rift Valley fever, and others (Gubler, 1998). There are now hundreds of vector-borne diseases associated with hundreds of vectors and intermediate hosts. Each of them is a product of interrelated determinants operating within complex and dynamic ecosystems that are poorly 20â National Institute of Allergy and Infectious Diseases, Building 31, Room 7A-10, 31 Center Drive, Bethesda, MD 20892. Phone: (301) 496-7453; E-mail: email@example.com.
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 275 understood. It is also clear that many changes of modern life, such as population growth, urbanization, climate changes, and environmental perturbation, are creat- ing new opportunities for the global expansion of vector-borne diseases (Gubler, 1998; Watson et al., 2005). They are clearly on the move and all evidence sug- gests that we are not well prepared to deal with them. The Scope of the Problem Vector-borne diseases have killed more humans in the past three centuries than all other diseases combined (Gubler, 1998). After a brief respite (a half- century; roughly from 1900 to 1950), in which public health and scientific advances either stopped or slowed down the relentless advance of these diseases, many are now aggressively reemerging by expanding into new geographic terri- tory (e.g., dengue, West Nile virus, and Japanese encephalitis), becoming resistant to drugs or insecticides (e.g., malaria), developing genetic mutations that favor spread (e.g., Venezuelan equine encephalitis [Anischenko et al., 2006]), or adapt- ing to new vector hosts (e.g., West Nile virus). New vector-borne diseases are also emerging (e.g., Lyme disease and dengue hemorrhagic fever). At the same time, the decay of public health infrastructure in developed countries, and the inability to create and sustain them in developing ones, leaves us largely helpless at a time of belated recognition that vector-borne diseases have straddled the two worlds (developed and developing) to such an extent that solu- tions can no longer be compartmentalized or reduced to localized responses. Moreover, earth and the human environments within it are also rapidly changing. Largely rural only a century ago, the world is now becoming decidedly urban and periurban. Within the next century, most humans will live in large cities surrounded by periurban environments directly connected to ecosystems harbor- ing nonurban pathogens (e.g., tick-borne encephalitis virus), and directly inter- connected to each other by international air routes; even now, it is possible for a microorganism in any place to reach almost any other place in the world within 1-2 days. While it has long been the notion that vector-borne diseases are largely rural, there has been an increasing tendency for many of the major vector-borne causes of morbidity and mortality to be urban and periurban. For example, yellow fever, dengue, and chikungunya are largely urban diseases; the first emergence of West Nile virus in the western hemisphere occurred in New York City; and the resurgence of tick-borne encephalitis in the former Soviet Union has been fueled by the building of dachas in periurban fringes of large cities, placing millions of urbanites in direct contact with rural microorganisms (Morens et al., 2004). Determinants of vector-borne diseases include not only urbanization and periurbanization, but also population growth, travel and transportation, deforesta- tion, and environmental perturbation, the existence of multiple vector hosts, or intermediate or alternative reservoir hosts, climate change (e.g., El NiÃ±o/Southern Oscillation, global warming, expanding vector mosquito distributions), govern-
276 VECTOR-BORNE DISEASES mental policy and public funding patterns, professional training and support, and many others (Benedict et al., 2007; Gubler, 1998; Morens et al., 2004; Watson et al., 2005). Ironically, some of these same determinants have led to the emer- gence of non-vector-borne tropical diseases (e.g., HIV/AIDS) that now compete for limited funds that might otherwise go to maintaining general public health infrastructure and vector-borne disease control. Balancing somewhat these critical determinants of vector-borne disease emergence, we are also experiencing an explosion in scientific knowledge that promises new approaches and tools to fight them, including genomics and pro- teomics. In the past decade, for example, the genes of all three âplayersâ in the global tragedy of falciparum malaria have been fully sequencedâthe parasite, the vector Anopheles gambiae, and the human hostâand that information is now beginning to be exploited in search of new disease-fighting tools. Thus, there is hope that with an additional emphasis on translational and applied research, seemingly insurmountable problems of vector-borne diseases can be met with new solutions. But this can only happen if we look beyond the old approaches that have emphasized limited responses and fatalistic outlooks. That responding to vector- borne diseases is now recognized as not only difficult but also a challenge mired in complexities suggests a need to escape the constraint of âbiomedical modelsâ to place them in a larger ecological context. This obviously requires inter- and multidisciplinary approaches. But who can take these approaches? Who has the training, experience, and perspective, and how do they acquire it? How do we initiate and support the necessary interactions? If complex problems require complex solutions, what are they, and how do we put the pieces together? While these questions are not easily answered, and little consensus has yet formed around them, the many experts who have begun to address them seem to agree on a few fundamental deficiencies that inhibit our ability to implement any solution to the vector-borne disease problem: â¢ Deterioration of public health infrastructure â¢ Lack of adequate funding â¢ Lack of adequate training and training models â¢ Overspecialization in the biomedical sciences driven by the explosions of technology and basic science information â¢ Bureaucratization While many other deficiencies can be cited, these five are among the most fundamental. There is a general consensus that fixing them is an essential pre- requisite to further progress.
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 277 Deterioration of Public Health Infrastructure In the early 20th century, when epidemiology was strongly allied with micro- biology, local health departments were well funded to deal with some of the most important infectious diseases (e.g., tuberculosis, water-borne and milk-borne dis- eases, and epidemic childhood diseases, such as measles and poliomyelitis). But the phenomenal rise in developed countries of institutionalized hospital-based curative medicine, coupled with the development first of passive immunotherapy (diphtheria antitoxin in 1890), followed by vaccines in the 1920s and antibiotics in the 1940s, led to a gradual and then a rapidly accelerating decline in public health infrastructure. When the AIDS pandemic was noticed in the early 1980s, tuberculosis control programs were so deeply eroded in the United States that none were able to respond adequately to the AIDS-related tuberculosis resur- gence. When West Nile virus was imported into the United States in 1999, it was learned that some states had abandoned their vector control capacities entirely. Some states had no vector control personnel at all. That basic public health infrastructure needs to be strengthened in the United States and in many other developed countries is almost universally agreed. That it has not happened is difficult to attribute to any one cause but may reflect a combination of the difficulty in securing and sustaining long-term commitment to substantial funding, competing priorities, and a psychological reluctance to spend money on things that have not happened yet but might happen in the future. In some countries, such as the United States, there is an ingrained prefer- ence for fire-fighting approaches to problem solving, rather than fire-prevention approaches. All of these deficiencies are magnified by problems like vector-borne diseases, which require integrated multidisciplinary approaches. It is enough of a problem to face insufficient personnel to staff unmanned and deteriorated facili- ties; it is quite another to be faced with creating new models for and mechanisms to train and support diverse professionals and to bring them together into working teams. Infrastructure deterioration is of course a problem specific to the developed world. The challenge for the developing world, where the burden of morbidity and mortality from vector-borne diseases is much higher, is substantially greater because there has generally been little vector control infrastructure to begin with, and no funding to support it even if created. In much of the world the infrastruc- ture gap cannot be filled by nongovernmental organizations (NGOs) or by monies from donor nations. It will probably require sustained economic development over many decades, if not longer. Thus both the developed and the developing world are destined, for the foreseeable future, to rely on the resources and exper- tise of developed nations to control vector-borne diseases.
278 VECTOR-BORNE DISEASES Lack of Adequate Funding Establishing and supporting public health infrastructures is expensive, but it is only a part of the funding challenge. In recent decades, philanthropic sources like the Bill and Melinda Gates Foundation have stepped up to provide substantial new monies for disease control in developing countries, but these foundations must work through existing structures rather than build new ones. Infrastructure and funding problems are therefore codependent. Moreover, the orientation of these philanthropic programs is necessarily toward support of existing approaches (e.g., bringing vaccines to populations with a high burden of vaccine-preventable diseases), rather than supporting basic or translational research to develop new tools, or even to purchase and maintain expensive equipment or train cadres of technical personnel. Much the same can be said of national programs such as the U.S. Presidentâs Emergency Plan for AIDS Relief (PEPFAR) program. The successes of such programs in developing countries are threatened by the same forces that impede local efforts and traditional research partnerships with wealthy nations, such as lack of trained personnel, lack of roads, bridges, and cold chains, climate and weather challenges, and so on. Researchers and field workers in developing countries repeatedly claim that funders do not understand these basic realities. This observer recalls an incident that occurred almost 30 years ago in which, after several days of travel, he caught up with a tropical disease research colleague in a remote African village. âThe last thing I need is another epidemiologist,â she observed, not entirely in jest. âWhat I really need is a Revco repairman, a diesel generator, and someone to fix the broken axle on the Land Rover.â No amount of philanthropy or scientific ardor can bring all of the benefits of the developed to the developing world. Moreover, direct support from wealthy nations, however motivated by humanitarian concerns, is unlikely to have any substantial impact because there is limited coordination between wealthy donor nations and because the funds are typically inadequate to address problems so large, so complex, and so deeply rooted. Models for funding national and international vector control were never fully established and are now largely forgotten or no longer relevant. Aedes aegypti and malaria eradication programs are remembered only by senior experts, most of them retired. To the average citizen, DDT is more likely to evoke cartoon images of poison labels and dead eagles than of effective pesticides that could potentially save millions of human lives. In addition, there is a long history of donor nations picking up ambitious projects to benefit the developing world only to drop them once problems or unexpected resistanceâsometimes from vec- tors, other times from interest groupsâarise. On the other hand, there is little history of such benevolence expressed in long-term commitment to solving a problem no matter what level of effort is required. While the situation has been slowly improving, large-scale funding from wealthy donor nations has clearly
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 279 suffered from a variety of ills that include inadequate resources, lack of coordi- nation between donors, lack of commitment to solving problems that have been addressed, and lack of long-range vision. Lack of Adequate Training and Training Models The past 50 years have seen revolutions in medical, biomedical, and public health training, which have pulled apart many of the shared values and approaches that once formed the basis of natural interdisciplinary alliances. Throughout the 1930s epidemiology and microbiology were closely allied fields within biomedi- cine. When the United States began its experiment with schools of public health in the 1920s, they were located within medical schools because of the obvious importance of the medical arts and basic biomedical sciences, but were also established with the conscious intent to forge interdisciplinary partnerships with the social sciences (Fee and Acheson, 1991). Whether or not this was an idea doomed to failure from the beginning, as many Europeans seem to believe, it has worked poorly with respect to the par- ticular question of vector-borne diseases. Few schools of public health are found outside the United States; of the 33 American schools, most are now free-standing (i.e., not within, and in general not closely allied with, medical schools). Indeed, it is customary to view the two as being in competition. Infectious disease epi- demiology, so recently the bedrock of most schools of public health, has been marginalized in all but a few. Public health laboratory programs, long required for accreditation, have been dropped. Most graduates of public health masters pro- grams have had no infectious disease experience beyond an epidemiology survey course; in most schools, students desiring solid infectious disease epidemiology training have difficulty acquiring it. Even epidemiology departments have been largely abandoned to the study of chronic and behavioral disorders, fueled by the âmassagingâ of large data sets with sophisticated computer programs rather than âhands-onâ or âreal-worldâ experiences. American-born physicians have also become something of an endan- gered species within public health schools, most of which have become focused on social sciences, as well as health services administration and health educa- tion. Even maternal and child health programs have often tilted toward program administration. With the exception of a few excellent schools, prominent among them the London School of Hygiene and Tropical Medicine, and the Johns Hop- kins School of Public Health, public health schools seem incapable of making substantial contributions to the creation of a professional and scientific workforce engaged in interdisciplinary approaches to vector-borne diseases in their current configurations. Beyond schools of public health, the picture remains grim. Nearly a century after the âFlexner reportâ (1910), American medical schools have been gradu- ally squeezing out the basic sciences in favor of courses in ethics, intercultural
280 VECTOR-BORNE DISEASES sensitivity, doctorâpatient relationships, and so forth. In some schools anatomy is now an elective. In others, resident physicians, whose counterparts three decades ago would have been delivering babies and assisting at major surgeries, now stand waiting at the bedside to have procedure cards signed for drawing 10 cc of blood from an arm vein. Medical education is expensive, and the public wants doctors with whom they can empathize. At the same time, the biomedical sci- ences have become increasingly complex and technical, and thus less accessible to medical students and medical graduates with generalist educations that include only survey courses in the basic sciences. Some medical schools (e.g., Duke) have experimented with aggressive programs that emphasize scientific training (OâConnor et al., 2007), but most of these, however excellent, are not oriented toward tropical medicine, epidemiology, or vector-borne diseases. Two approaches that have worked extremely well, as judged by the qual- ity and output of scientific work and the record of professional development of vector-borne disease and tropical medicine researchers, have been those of the U.S. Department of Defense (DoD) and the U.S. Centers for Disease Control and Prevention (CDC). The DoD has long maintained sophisticated overseas labs in partnership with scientists from host countries (e.g., the Armed Forces Research Institute of Medical Science [AFRIMS] in Bangkok, Thailand; and the Naval Medical Research Unit No. 3 [NAMRU-3] in Masr-el-Gedida, Egypt). These and a number of other overseas laboratories have been leaders in interdisciplinary and international tropical medicine research. They have also trained several genera- tions of leaders in tropical medicine/vector-borne diseases, including researchers based in preventive medicine, microbiology, entomology, and other allied fields. Unfortunately, however, these programs are âone of a kind,â may be difficult to duplicate outside the military environment, and are expensive to operate. In recent years, the military emphasis on the âwarfighterâ mission, as well as the outside contracting of many medical services, has led to concerns that continued existence of the overseas research programs may be imperiled. The CDC has for decades been involved in national and international vector- borne disease research and investigation. In recent years, these activities have been sustained even though strained by losses of key scientists. A different chal- lenge has been a greater emphasis for young Atlanta-based scientists on program management, with fewer opportunities to do hands-on work, including overseas field work, in part a result of the growing expertise of state health departments and foreign ministries of health who are less dependent on the once unique out- break investigative skills of the CDC. While historically successful in supporting solid research and training a cadre of leaders, the ability of relevant CDC pro- grams to expand seems limited; like the DoD programs, the CDC vector-borne and international programs may be âone of a kind,â resistant to duplication, and easily saturated.
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 281 Overspecialization in the Biomedical Sciences Driven by Explosions of Technology The increasing schism between generalist training for physicians and spe- cialist training for biomedical scientists in doctoral programs is being widened by an explosion of technology and basic science information that is increasingly backlogged and untranslated into medical advances, creating the dual problems of insufficient progress and interdisciplinary alienation that further impedes such progress. A similar phenomenon occurred in England 125 years ago when the new and highly technical field of microbiology, which required microscopes, expensive laboratory equipment, and much nontraditional study, was largely passed over by the British medical profession, to its great detriment (Worboys, 2000). The other side of the coin is that graduates of doctoral programs in fields like microbiology or entomology have often become so narrowly focused that they lack any practical orientation toward diseases associated with the microbes or vectors they have studied. Several decades ago, for example, graduates of micro- biology programs would generally have been well grounded in bacteriology, virology, parasitology, immunology, and pathology. Nowadays, in the genomics era, the traditional distinction between bacteriology, parasitology, and virology has become almost anachronistic. It is probably possible to obtain a Ph.D. degree in molecular biology studying one molecule, or even one gene, but having had little or no exposure to a disease or to an interdisciplinary problem, let alone any experience working with colleagues or students from different disciplines, or in international settings. Bureaucratization We live in an increasingly bureaucratized world, in which governments and other authoritative entities believe that order and progress is best served by increasing layers of oversight. For researchers in tropical and vector-borne diseases, the impediments to accomplishing the most basic tasks have become so great that it is apparently driving prospective students and junior faculty out of the field. The flow of biological materials, the life blood of vector-borne dis- ease research, is now impeded, and often times stopped entirely, by air transport regulations (International Air Transport Association [IATA] and Air Transport Association [ATA]), the USDA, and âselect agentâ rules associated with the U.S. Patriot Act, which also restricts foreign scientists from working on U.S.-funded research even in their own countries, where the diseases, vectors, and microbial agents are widely prevalent. In other cases, nations experiencing disease outbreaks have refused to let biological specimens outside their borders for fear of losing patent rights or, more ominously, to blackmail developed nations who they believe will use the
282 VECTOR-BORNE DISEASES materials to develop vaccines they will not be able to purchase because of cost or unavailability. At the same time, clinical studies conducted by Western research- ers have been greatly impeded by regulations and paperwork, often surrounding issues of informed consent and recordkeeping practices, and despite pleas from the nations where the studies are being conducted that they meet all of their own ethical and documentary requirements. Looking Backward in Time Although it would be easy to lose heart at the challenges noted earlier and at the lack of easy or obvious solutions, it may be worthwhile to look back at an earlier time in which the challenges were even greater, but were met with foresight, commitment, and considerable success. Tropical medicine as an idea and discipline arose during the colonial era when European powers began send- ing their citizens abroad to administer new colony-nations. Realizing that they were among the most important and deadly challenges, these nations turned their scientific attention to tropical diseases. While it is popular today to character- ize these efforts as exploitative, since colonialism itself was exploitative, the historical records suggests otherwise; in any case, advances that benefited one group benefited others. For example, the efforts of Gorgas to eliminate yellow fever from Havana saved mostly the local poor, while overseas tropical disease research by Kitasato, Koch, Yersin, and others led to advances against diseases that predominantly affected native peoples (e.g., cholera and plague). Advances within the first three decades of the microbiology era (beginning in 1876) led to subsequent decades of startling successes in tropical medicine in general, and in vector-borne diseases in particular. By the first few years of the 20th century, the agents of malaria and dengue had been discovered, and the transmission of yellow fever worked out. By 1899, the London School of Hygiene and Tropical Medicine had been set up, followed by an explosion of public health and tropical disease research in the United States. The U.S. Public Health Service Hygienic Laboratory was set up under the leadership of a physician trained in tropical medicine (under both Koch and Pasteur); eventually it became the U.S. National Institutes of Health. Internationally, agencies like the Pan-American Health Organization (PAHO) and the Office International dâHygiÃ¨ne Publique (OIHP) grew out of the sanitary movements of the 19th century to develop programs based on the breakthroughs from microbiology and tropical medicine. After World War I, the League of Nations Health Office initiated its own tropical disease programs. In the 1940s, the CDC evolved out of a war-related malaria control program. In the middle years of the 20th century, as NIH and CDC grew in the United States, the Rockefeller Foundation, long active in tropical diseases, moved for- ward to establish a number of overseas research centers (e.g., in Bahia, Entebbe, and Trinidad). It was the influential work of these centers that largely created the
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 283 field of arbovirology. Most of the major arboviruses were discovered, character- ized, studied, and placed in the Arbovirus Catalog during this era. It is surpris- ing and painful to reflect that most of our knowledge of tropical medicine, and most of the tropical medicine pharmacopeia still in use, derives from the body of scientific work undertaken in the first five decades of the 20th century (Hotez, 2004), now relegated to seldom-read history books and increasingly distanced from modern science and practicing scientists. It would probably be a mistake to try to recreate these golden days of tropical medicine by returning to the formulae that worked then. The problem of vector-borne diseases is a complex one that goes beyond simple âbug and drugâ solutions. One expert has opined that we need a North American tropical disease training and research center (Hotez, 2004), but however timely and powerful the idea, one senses it would not be sufficient to meet a challenge so broad, so deep, and so complicated. While there seem to be no easy or obvious solutions, a first step must be rec- ognition of the problem in all its challenges and complexities by policy makers, government scientists, and academic leaders. A next step is surely to find new and innovative ways to train and co-train key scientists and public health work- ers taken from a variety of disciplinesâmedicine, nursing, biomedical sciences, entomology, veterinary sciences, ecological sciences, wildlife management, and many othersâin interdisciplinary approaches to these complex problems, and then to provide them job opportunities to apply their new skills in interdisciplin- ary settings. There are few if any models for how to achieve thisâperhaps the closest are the DoD and CDC modelsâand there is also a need for models that work in academic settings where advanced training has become increasingly compartmentalized and narrowly focused, rather than multidisciplinary. A greater emphasis on applied research in overseas settings is required, and an attempt to solve bureaucratic and regulatory impediments to such work is crucial. The vector-borne disease problem will not go away nor will it simplify itself. We can expect accelerating problems and a substantial start-up time for any new solution destined to work. Among the greatest challenges to innovation is nostalgia for old approaches that once worked but are now outdated. In an era in which scientific and technical advances drive narrowly focused research and training, the question of how to foster generalist training and team approaches to problem solving, in which team members cross disciplinary lines regarded as being remote from each other, is a difficult challenge. But it is no more impos- sible than the challenges faced and met successfully in the first half of the 20th century, in which science and public health worked to produce a yellow fever vaccine, discovered and developed effective treatments for many vector-borne diseases, and rolled back some of the deadliest among them in the direction of, if not quite up to, eradication.
284 VECTOR-BORNE DISEASES THE VECTOR BIOLOGY PROGRAM AT THE NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES Adriana Costero, Ph.D.21 National Institute of Allergy and Infectious Diseases Introduction The Division of Microbiology and Infectious Diseases (DMID), part of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), supports a wide variety of vector biology research projects mainly through its Vector Biology Program, but also through other programs within the Division. Projects range from basic research to studies on the ecology and epidemiology of vector-borne diseases of human importance. The overall purpose of the Vector Biology Program is to advance our under- standing of vectors of pathogens responsible for human disease by supporting research projects on a wide scope of topics and vectors. A variety of funding mechanisms exist that support different facets of the research process, from basic studies of vector biochemistry and physiology to the initial phases of translational research in the form of proof-of-concept or target validation studies. DMID is also committed to providing career development opportunities to new investigators through training grants and career awards. In addition, confer- ence grants are available to provide financial support to students, postdocs, and new investigators attending and participating in scientific meetings. Vector Biology Portfolio The Vector Biology portfolio comprises approximately 140 grants and coop- erative agreements for fiscal year 2007. Most of these are studies on mosquitoes; the remainder deal with snails, ticks, sandflies, triatomine bugs, tsetse flies, lice, and scabies mites. Many grants encompass different aspects of research related to vector con- trol. These include target identification; development of improved larvicides; understanding of insecticide resistance mechanisms; development of improved traps for mosquitoes, ticks, and triatomine bugs; and studies on effectiveness of bednets in preventing malaria transmission. Numerous projects are looking at the ecology and epidemiology of vector-borne diseases, including biochemistry, control, genetics, genomics, immunology, interaction, modeling, pathogenesis, physiology, surveillance, proteomics, transgenics, and vaccines. Research on a variety of vectors and their associated pathogens is supported by different funding mechanisms. Grant applications in the Vector Biology port- folio come in mostly as unsolicited grants, and occasionally in response to NIAID 21â Vector Biology Program Officer, Division of Microbiology and Infectious Diseases.
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 285 solicitations (requests for applications [RFAs] or program announcements [PAs]). The cornerstone of NIH-funded extramural programs is the peer-review process, carried out by study sections stationed at the Center for Scientific Review. Several study sections review grants for the Vector Biology Program, but most applica- tions go through peer review in the Vector Biology Study Section. This reflects the support for well-established investigators as well as for highly innovative/high-risk projects that may move the field forward. DMID also supports small research projects to generate hypotheses and data, as well as support for undergraduate-prevalent institutions, which are primarily designed for training new investigators. Cooperative agreements have facilitated transla- tion of basic science into products, and small business grants (SBIRs/STTRs) have allowed for the development of short-term vector control technologies and approaches. Conference grants support new investigators in their participation in scientific meetings. The great majority of grants in the portfolio are supported by the Research Grant (R01) mechanism. This mechanism supports research with strong prelimi- nary data and hypotheses. R01 grants can be as short as 3 years or as long as 5 years. This mechanism is the cornerstone of scientific research at NIH and sup- ports a high percentage of investigators in the United States and abroad. The second most represented mechanism in the Vector Biology portfolio is the Exploratory/Developmental Research Grant mechanism (R21). The purpose of this funding mechanism is to support research that is considered high risk/ high pay-off. Preliminary data are not required for submission of an application, and projects are supported for 2 years with a moderate level of funding. This mechanism enables investigators with highly innovative ideas or approaches to determine if their approach may be feasible and allows for the generation of preliminary data that can later be included in an R01. The Small Research Grant mechanism (R03) is also represented in the port- folio. This mechanism typically supports 2-year projects with a small budget. Research projects supported as R03s are designed to generate preliminary data and/or hypotheses that can later be tested in an R01 application. NIH Academic Research Enhancement Award (AREA) grants are also rep- resented and are valuable in providing funding to investigators in undergraduate- prevalent institutions, allowing them to perform 3-year projects and train the next generation of investigators. This funding mechanism is very valuable in allowing investigators in small institutions to contribute to the scientific knowledge being generated about vectors. As a result of the NIAIDâs Partnerships initiative, several cooperative agree- ments have been funded that address translational aspects of vector management strategies. These projects have resulted in new insights and potential products for improved control of vector-borne diseases. Several mechanisms are available for postdocs and new investigators (F32, F33, K22) to enable them to start designing and writing small-grant applications.
286 VECTOR-BORNE DISEASES Career funding mechanisms Ph.D. Student Postdoc Independent investigator K22 K02 F33 R37 F31 F32 K99 Basic research Research spectrum Translational research R03 R21 R01 P01s U01 SBIR/STTR R15 Research funding mechanisms FIGURE 3-1â Available funding mechanisms for research. These mechanisms involve a new investigator and a mentor/institution where the 3-1 transition from student to independent investigator can be made, providing an invaluable experience for those transitioning into independent careers. Small business grants (SBIRs, STTRs) are also represented in the portfolio and represent short-term investments into technologies and devices that may develop into vector control strategies. This mechanism encourages small busi- nesses to become involved in research on novel mechanisms to better control and/or prevent vector-borne diseases. The Vector Biology portfolio is well rounded in terms of the mechanisms represented and the type of research being supported, ranging from basic to translational. Figure 3-1 demonstrates different funding mechanisms available during these research phases. Numerous projects headed by U.S. investigators contain foreign components. Some DMID initiatives, such as the International Research in Infectious Diseases (IRID) Program, and the Tropical Medicine Research Centers (TMRCs) are designed for investigators in foreign institutions. This is very important to the program as many vector-borne diseases occur in tropical and subtropical areas of the world and not in the United States. Foreign investigators are encouraged to take advantage of these initiatives whenever possible to fund their research projects.
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 287 Challenges The Vector Biology Program at NIAID is vibrant and strong, with research on many aspects of the field and a wide variety of organisms. The Program uses a broad range of funding mechanisms that support new as well as more experi- enced investigators. The Program encourages interdisciplinary projects and col- laboration among field- and lab-based investigators in order to help to elucidate the complex interactions among vectors, their hosts, the pathogens they transmit, and the ecological environment in which these interactions take place. Only by understanding these complex networks of interactions can we achieve sound, comprehensive, and sustainable vector management and disease prevention. The training and retention of new investigators must continue to be a prior- ity; not only as part of the regular research mechanisms (R15, R01, etc.) but also through training grants such as the Ruth L. Kirschstein National Research Service Awards (NRSAs) (F32, F33), the Career Development Awards (K22), and the Institutional Research Training grants (T32). In addition, Conference Grants (R13) can help fund participation of students and new investigators in scientific meetings. Communication and collaboration among federal agencies involved in vector research will enable the resources of all agencies to be used more effectively in supporting the research community. Conclusion The vector biology field is at an exciting juncture. With great potential for novel vector management strategies underway and exciting cutting-edge research being performed, there is great promise ahead. Our challenge is to work together as a group, with open communication channels, to achieve the promise of the future to improve peopleâs health. REFERENCES Anischenko, M., R. A. Bowen, S. Paessler, L. Austgen, I. P. Greene, and S. C. Weaver. 2006. Venezu- elan encephalitis emergence mediated by a phylogenetically predicted viral mutation. Proceed- ings of the National Academy of Sciences 103(13):4994-4999. Attaran, A., D. R. Roberts, C. F. Curtis, and W. L. Kilama. 2000. Balancing risks on the backs of the poor. Nature Medicine 6(7):729-731. Ballinger-Crabtree, M. E., W. C. Black IV, and B. R. Miller. 1992. Use of genetic polymorphisms detected by the random-amplified polymorphic DNA polymerase chain reaction (RAPD-PCR) for differentiation and identification of Aedes aegypti subspecies and populations. American Journal of Tropical Medicine and Hygiene 47(6):893-901. Barillas-Mury, C. V., F. G. Noriega, and M. A. Wells. 1995. Early trypsin activity is part of the signal transduction system that activates transcription of the late trypsin gene in the midgut of the mosquito, Aedes aegypti. Insect Biochemistry and Molecular Biology 25(2):241-246.
288 VECTOR-BORNE DISEASES Bartholomay, L. C., H. A. Farid, R. M. Ramzy, and B. M. Christensen. 2003. Culex pipiens pipiens: characterization of immune peptides and the influence of immune activation on development of Wuchereria bancrofti. Molecular and Biochemical Parasitology 130(1):43-50. Beard, C. B., C. Cordon-Rosales, and R. V. Durvasula. 2002. Bacterial symbionts of the Triatominae and their potential use in control of Chagas disease transmission. Annual Review of Entomol- ogy 47:123-141. Beaty, B. J. 2000. Genetic manipulation of vectors: a potential novel approach for control of vector- borne diseases. Proceedings of the National Academy of Sciences 97(19):10295-10297. Becnel, J. J. 2006. Prospects for the mosquito baculovirus CuniNPV as a tool for mosquito control. Journal of the American Mosquito Control Association 22(3):523-526. Benedict, M. Q., R. S. Levine, W. A. Hawley, and L. P. Lounibos. 2007. Spread of the tiger: global risk of invasion by the mosquito Aedes albopictus. Vector-Borne and Zoonotic Diseases 7(1):76-85. Besansky, N. J., T. Lehmann, G. T. Fahey, D. Fontenille, L. E. Braack, W. A. Hawley, and F. H. Collins. 1997. Patterns of mitochondrial variation within and between African malaria vectors, Anoph- eles gambiae and An. arabiensis, suggest extensive gene flow. Genetics 147(4):1817-1828. Blandin, S., S. H. Shiao, L. F. Moita, C. J. Janse, A. P. Waters, F. C. Kafatos, and E. A. Levashina. 2004. Complement-like protein TEP1 is a determinant of vectorial capacity in the malaria vector Anopheles gambiae. Cell 116(5):661-670. Boone, J. D., K. C. McGwire, E. W. Otteson, R. S. DeBaca, E. A. Kuhn, P. Villard, P. F. Brussard, and S. C. St. Jeor. 2000. Remote sensing and geographic information systems: charting Sin Nombre virus infections in deer mice. Emerging Infectious Diseases 6(3):248-258. Bosio, C. F., L. C. Harrington, J. W. Jones, R. Sithiprasasna, D. E. Norris, and T. W. Scott. 2005. Genetic structure of Aedes aegypti populations in Thailand using mitochondrial DNA. American Journal of Tropical Medicine and Hygiene 72(4):434-442. Britch, S. C., K. J. Linthicum, and the Rift Valley Fever Working Group. 2007. Developing a research agenda and a comprehensive national prevention and response plan for Rift Valley fever in the United States. Emerging Infectious Diseases 13(8):e1, http://0-www.cdc.gov.mill1.sjlibrary. org:80/EID/content/13/8/e1.htm (accessed September 6, 2007). Brownstein, J. S., H. Rosen, D. Purdy, J. R. Miller, M. Merlino, F. Mostashari, and D. Fish. 2002. Spatial analysis of West Nile virus: rapid risk assessment of an introduced vector-borne zoono- sis. Vector-Borne and Zoonotic Diseases 2(3):157-164. Carlson, J., E. Suchman, and L. Buchatsky. 2006. Densoviruses for control and genetic manipulation of mosquitoes. Advances in Virus Research 68:361-392. Carter, R. 2001. Transmission blocking malaria vaccines. Vaccine 19(17-19):2309-2314. Catteruccia, F., T. Nolan, T. G. Loukeris, C. Blass, C. Savakis, F. C. Kafatos, and A. Crisanti. 2000. Stable germline transformation of the malaria mosquito Anopheles stephensi. Nature 405(6789):959-962. CDC (Centers for Disease Prevention and Control). 2003. Update: multistate outbreak of monkeypoxâ Illinois, Indiana, Kansas, Missouri, Ohio, and Wisconsin, 2003. Morbidity and Mortality Weekly Report 52(27):642-646. CDC. 2004. Notice to readers: change in source for arboviral disease data reported to the National No- tifiable Diseases Surveillance System. Morbidity and Mortality Weekly Report 53(22):487-488, http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5322a9.htm (accessed September 6, 2007). CDC. 2007. Rift Valley fever outbreakâKenya, November 2006âJanuary 2007. Morbidity and Mor- tality Weekly Report 56(04):73-76, http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5604a3. htm?s_cid=mm5604a3_e (accessed September 6, 2007). Charrel, R. N., X. de Lamballerie, and D. Raoult. 2007. Chikungunya outbreaksâthe globalization of vector-borne diseases. New England Journal of Medicine 356(8):769-771.
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 289 Christophides, G. K., E. Zdobnov, C. Barillas-Mury, E. Birney, S. Blandin, C. Blass, P. T. Brey, F. H. Collins, A. Danielli, G. Dimopoulos, C. Hetru, N. T. Hoa, J. A. Hoffmann, S. M. Kanzok, I. Letunic, E. A. Levashina, T. G. Loukeris, G. Lycett, S. Meister, K. Michel, L. F. Moita, H. M. Muller, M. A. Osta, S. M. Paskewitz, J. M. Reichhart, A. Rzhetsky, L. Troxler, K. D. Vernick, D. Vlachou, J. Volz, C. von Mering, J. Xu, L. Zheng, P. Bork, and F. C. Kafatos. 2002. Immu- nity-related genes and gene families in Anopheles gambiae. Science 298(5591):159-165. Coates, C. J., N. Jasinskiene, L. Miyashiro, and A. A. James. 1998. Mariner transposition and trans- formation of the yellow fever mosquito, Aedes aegypti. Proceedings of the National Academy of Sciences 95(7):3748-3751. Coleman, M., and J. Hemingway. 2008. The implications of entomological monitoring and evaluation for arthropod vector borne disease control programs. In Vector-borne diseases: understanding the environmental, human health, and ecological connections. Washington, DC: The National Academies Press. Collins, F. H., and S. M. Paskewitz. 1996. A review of the use of ribosomal DNA (rDNA) to differenti- ate among cryptic Anopheles species. Insect Molecular Biology 5(1):1-9. da Costa-Ribeiro, M. C. V., R. Lourenco-de-Oliveira, and A.-B. Failloux. ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ 2007. Low gene flow of Aedes aegypti between dengue-endemic and dengue-free areas in southeastern and southern Brazil. American Journal of Tropical Medicine and Hygiene 77(2):303-309. David, J. P., C. Strode, J. Vontas, D. Nikou, A. Vaughan, P. M. Pignatelli, C. Louis, J. Hemingway, and H. Ranson. 2005. The Anopheles gambiae detoxification chip: a highly specific microarray to study metabolic-based insecticide resistance in malaria vectors. Proceedings of the National Academy of Sciences 102(11):4080-4084. Day, J. F., C. G. Duxbury, S. Glasscock, and J. E. Paganessi. 2001. Removal trapping for control of coastal biting midge populations. Technical Bulletin of the Florida Mosquito Control Associa- tion 3:15-16. DHS (Department of Homeland Security). 2006. Food and agriculture incident index, http://www.dhs. gov/xlibrary/assets/nrp_foodagincidentannex.pdf (accessed September 26, 2007). Dimopoulos, G., D. Seeley, A. Wolf, and F. C. Kafatos. 1998. Malaria infection of the mosquito Anopheles gambiae activates immune-responsive genes during critical transition stages of the parasite life cycle. The EMBO Journal 17(21):6115-6123. Diuk-Wasser, M. A., H. E. Brown, T. G. Andreadis, and D. Fish. 2006. Modeling the spatial distribu- tion of mosquito vectors for West Nile virus in Connecticut, USA. Vector-Borne and Zoonotic Diseases 6(3):283-295. Eisen, L., and B. J. Beaty. 2008. Innovative decision support and vector control approaches to control dengue. In Vector-borne diseases: understanding the environmental, human health, and ecologi- cal connections. Washington, DC: The National Academies Press. Eisen, L., and R. J. Eisen. ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ 2007. Need for improved methods to collect and present spatial epidemio- logic data for vectorborne diseases. Emerging Infectious Diseases 13(12):1816-1820. Eisen, R. J., R. S. Lane, C. L. Fritz, and L. Eisen. 2006. Spatial patterns of Lyme disease risk in California based on disease incidence data and modeling of vector-tick exposure. American Journal of Tropical Medicine and Hygiene 75(4):669-676. Eisen, R. J., R. E. Enscore, B. J. Biggerstaff, P. J. Reynolds, P. Ettestad, T. Brown, J. Pape, D. Tanda, C. E. Levy, D. M. Engelthaler, J. Cheek, R. Bueno, Jr., J. Targhetta, J. A. Montenieri, and K. L. Gage. 2007a. Human plague in the southwestern United States, 1957-2004: spatial models of elevated risk of human exposure to Yersinia pestis. Journal of Medical Entomology 44(3):530-537. Eisen, R. J., P. J. Reynolds, P. Ettestad, T. Brown, R. E. Enscore, B. J. Biggerstaff, J. Cheek, R. Bueno, Jr., J. Targhetta, J. A. Montenieri, and K. L. Gage. 2007b. Residence-linked human plague in New Mexico: a habitat suitability model. American Journal of Tropical Medicine and Hygiene 77(1):121-125.
290 VECTOR-BORNE DISEASES Enscore, R. E., B. J. Biggerstaff, T. L. Brown, R. F. Fulgham, P. J. Reynolds, D. M. Engelthaler, C. E. Levy, R. R. Parmenter, J. A. Montenieri, J. E. Cheek, R. K. Grinnell, P. J. Ettestad, and K. L. Gage. 2002. Modeling relationships between climate and the frequency of human plague cases in the southwestern United States, 1960-1997. American Journal of Tropical Medicine and Hygiene 66(2):186-196. Fee, E., and R. M. Acheson. 1991. A history of education in public health: health that mocks the doctorsâ rules. Oxford, England: Oxford University Press. Fillinger, U., B. G. Knols, and N. Becker. 2003. Efficacy and efficiency of new Bacillus thuringiensis var israelensis and Bacillus sphaericus formulations against Afrotropical anophelines in Western Kenya. Tropical Medicine and International Health 8(1):37-47. Fish, D. 2001. Wanted: medical entomologist. Vector-Borne and Zoonotic Diseases 1(2):89. Flexner, A. 1910. Medical education in the United States and Canada: a report to the Carnegie Foundation for the Advancement of Teaching. New York: Daniel Berkeley. Fonseca, D. M., S. Campbell, W. J. Crans, M. Mogi, I. Miyagi, T. Toma, M. Bullians, T. G. Andreadis, R. L. Berry, B. Pagac, M. R. Sardelis, and R. C. Wilkerson. 2001. Aedes (Finlaya) japonicus (Diptera: Culicidae), a newly recognized mosquito in the United States: analyses of genetic variation in the United States and putative source populations. Journal of Medical Entomology 38(2):135-146. Fox, A. N., R. J. Pitts, H. M. Robertson, J. R. Carlson, and L. J. Zwiebel. 2001. Candidate odor- ant receptors from the malaria vector mosquito Anopheles gambiae and evidence of down- regulation in response to blood feeding. Proceedings of the National Academy of Sciences 98(25):14693-14967. Foy, B. D., G. F. Killeen, T. Magalhaes, and J. C. Beier. 2002. Immunological targeting of critical insect antigens. American Entomologist 48(3):150-163. Foy, B. D., T. Magalhaes, W. E. Injera, I. Sutherland, M. Devenport, A. Thanawastien, D. Ripley, L. Cardenas-Freytag, and J. C. Beier. 2003. Induction of mosquitocidal activity in mice immu- nized with Anopheles gambiae midgut cDNA. Infection and Immunity 71(4):2032-2040. Franz, A. W., I. Sanchez-Vargas, Z. N. Adelman, C. D. Blair, B. J. Beaty, A. A. James, and K. E. Olson. 2006. Engineering RNA interference-based resistance to dengue virus type 2 in genetically mod- ified Aedes aegypti. Proceedings of the National Academy of Sciences 103(11):4198-4203. Frederici, B. A. 2005. Insecticidal bacteria: an overwhelming success for invertebrate pathology. Journal of Invertebrate Pathology 89(1):30-38. GAO (Government Accountability Office). 2000 (September). West Nile virus outbreak: lessons for public health preparedness. GAO/HEHS-00-180, http://www.gao.gov/new.items/he00180.pdf (accessed September 6, 2007). Glass, G. E., B. S. Schwartz, J. M. Morgan III, D. T. Johnson, P. M. Noy, and E. Israel. 1995. Environ- mental risk factors for Lyme disease identified with geographic information systems. American Journal of Public Health 85(7):944-948. Glass, G. E., J. E. Cheek, J. A. Patz, T. M. Shields, T. J. Doyle, D. A. Thoroughman, D. K. Hunt, R. E. Enscore, K. L. Gage, C. Irland, C. J. Peters, and R. Bryan. 2000. Using remotely sensed data to identify areas at risk for hantavirus pulmonary syndrome. Emerging Infectious Diseases 6(3):238-247. Glass, G. E., T. L. Yates, J. B. Fine, T. M. Shields, J. B. Kendall, A. G. Hope, C. A. Parmenter, C. J. Peters, T. G. Ksiazek, C. S. Li, J. A. Patz, and J. N. Mills. 2002. Satellite imagery character- izes local animal reservoir populations of Sin Nombre virus in the southwestern United States. Proceedings of the National Academy of Sciences 99(26):16817-16822. Gorrochotegui-Escalante, N., M. L. Munoz, I. Fernandez-Salas, B. J. Beaty, and W. C. Black IV. 2000. Genetic isolation by distance among Aedes aegypti populations along the northeastern coast of Mexico. American Journal of Tropical Medicine and Hygiene 62(2):200-209. Gratz, N. G. 1999. Emerging and resurging vector-borne diseases. Annual Review of Entomology 44:51-75. Gubler, D. J. 1998. Resurgent vector-borne diseases as a global health problem. Emerging Infectious Diseases 4(3):442-450.
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 291 Gubler, D. J. 2001. Prevention and control of tropical diseases in the 21st century: back to the field. American Journal of Tropical Medicine and Hygiene 65(1):V-Xi. Gubler, D. J. 2002a. Epidemic dengue/dengue hemorrhagic fever as a public health, social, and eco- nomic problem in the 21st century. Trends in Microbiology 10(2):100-103. Gubler, D. J. 2002b. The global emergence/resurgence of arboviral diseases as public health problems. Archives of Medical Research 33(4):330-342. Guillet, P., R. NâGuessan, F. Darriet, M. Traore-Lamizana, F. Chandre, and P. Carnevale. 2001. Combined pyrethroid and carbamate âtwo-in-oneâ treated mosquito nets: field efficacy against pyrethroid-resistant Anopheles gambiae and Culex quinquefasciatus. Medical and Veterinary Entomology 15(1):105-112. Hansen, I. A., G. M. Attardo, J. H. Park, Q. Peng, and A. S. Raikhel. 2004. Target of rapamycin- mediated amino acid signaling in mosquito anautogeny. Proceedings of the National Academy of Sciences 101(29):10626-10631. Hawley, W. A., F. O. ter Kuile, R. S. Steketee, B. L. Nahlen, D. J. Terlouw, J. E. Gimnig, Y. P. Shi, J. M. Vulule, J. A. Alaii, A. W. Hightower, M. S. Kolczak, S. K. Kariuki, and P. A. Phillips- Howard. 2003. Implications of the western Kenya permethrin-treated bed net study for policy, program implementation, and future research. American Journal of Tropical Medicine and Hygiene 68(Suppl 4):168-173. Hay, S. I., J. A. Omumbo, M. H. Craig, and R. W. Snow. 2000. Earth observation, geographic in- formation systems and Plasmodium falciparum malaria in sub-Saharan Africa. Advances in Parasitology 47:173-215. Hayes, E. B., N. Komar, R. S. Nasci, S. P. Montgomery, D. R. OâLeary, and G. L. Campbell. 2005. Epidemiology and transmission dynamics of West Nile virus disease. Emerging Infectious Diseases 11(8):1167-1173. Hemingway, J., L. Field, and J. Vontas. 2002. An overview of insecticide resistance. Science 298(5591):96-97. Hemingway, J., B. J. Beaty, M. Rowland, T. W. Scott, and B. L. Sharp. 2006. The Innovative Vec- tor Control Consortium: improved control of mosquito-borne diseases. Parasitology Today 22(7):308-312. Hill, C. A., A. N. Fox, R. J. Pitts, L. B. Kent, P. L. Tan, M. A. Chrystal, A. Cravchik, F. H. Collins, H. M. Robertson, and L. J. Zwiebel. 2002. G protein-coupled receptors in Anopheles gambiae. Science 298(5591):176-178. Hjelle, B., and G. E. Glass. 2000. Outbreak of hantavirus infection in the Four Corners region of the ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ United States in the wake of the 1997-1998 El NiÃ±o-Southern Oscillation. Journal of Infectious Diseases 181(5):1569-1573. Holt, R. A., G. M. Subramanian, A. Halpern, G. G. Sutton, R. Charlab, D. R. Nusskern, P. Wincker, A. G. Clark, J. M. Ribeiro, R. Wides, S. L. Salzberg, B. Loftus, M. Yandell, W. H. Majoros, D. B. Rusch, Z. Lai, C. L. Kraft, J. F. Abril, V. Anthouard, P. Arensburger, P. W. Atkinson, H. Baden, V. de Berardinis, D. Baldwin, V. Benes, J. Biedler, C. Blass, R. Bolanos, D. Boscus, M. Barnstead, S. Cai, A. Center, K. Chaturverdi, G. K. Christophides, M. A. Chrystal, M. Clamp, A. Cravchik, V. Curwen, A. Dana, A. Delcher, I. Dew, C. A. Evans, M. Flanigan, A. Grundschober-Freimoser, L. Friedli, Z. Gu, P. Guan, R. Guigo, M. E. Hillenmeyer, S. L. Hladun, J. R. Hogan, Y. S. Hong, J. Hoover, O. Jaillon, Z. Ke, C. Kodira, E. Kokoza, A. Koutsos, I. Letunic, A. Levitsky, Y. Liang, J. J. Lin, N. F. Lobo, J. R. Lopez, J. A. Malek, T. C. McIntosh, S. Meister, J. Miller, C. Mobarry, E. Mongin, S. D. Murphy, D. A. OâBrochta, C. Pfannkoch, R. Qi, M. A. Regier, K. Remington, H. Shao, M. V. Sharakhova, C. D. Sitter, J. Shetty, T. J. Smith, R. Strong, J. Sun, D. Thomasova, L. Q. Ton, P. Topalis, Z. Tu, M. F. Unger, B. Walenz, A. Wang, J. Wang, M. Wang, X. Wang, K. J. Woodford, J. R. Wortman, M. Wu, A. Yao, E. M. Zdobnov, H. Zhang, Q. Zhao, S. Zhao, S. C. Zhu, I. Zhimulev, M. Coluzzi, A. della torre, C. W. Roth, C. Louis, F. Kalush, R. J. Mural, E. W. Myers, M. D. Adams, H. O. Smith, S. Broder, M. J. Gardner, C. M. Fraser, E. Birney, P. Bork, P. T. Brey, J. C. Venter, J. Weissenbach, F. C. Kafatos, F. H. Collins, and S. L. Hoffman. 2002. The genome sequence of the malaria mosquito Anopheles gambiae. Science 298(5591):129-149.
292 VECTOR-BORNE DISEASES Hotez, P. J. 2004. Should we establish a North American school of global health sciences? American Journal of the Medical Sciences 328(2):71-77. IOM (Institute of Medicine). 2002. The emergence of zoonotic diseases: understanding the impact on animal and human health. Washington, DC: The National Academies Press. IOM. 2003. Microbial threats to health: emergence, detection, and response. Washington, DC: The National Academies Press. IOM. 2006. Ensuring an infectious disease workforce: education and training needs for the 21st century. Washington, DC: The National Academies Press. Ito, J., A. Ghosh, L. A. Moreira, E. A. Wimmer, and M. Jacobs-Lorena. 2002. Transgenic anopheline mosquitoes impaired in transmission of a malaria parasite. Nature 417(6887):452-455. James, A. A., K. Blackmer, and J. V. Racioppi. 1989. A salivary gland-specific, maltase-like gene of the vector mosquito, Aedes aegypti. Gene 75(1):73-83. Johnson, B. W., K. E. Olson, A. Allen-Miura, A. Rayms-Keller, J. O. Carlson, C. J. Coates, N. Jasinskien, A. A. James, B. J. Beaty, and S. Higgs. 1999. Inhibition of luciferase expression in transgenic Aedes aegypti mosquitoes by Sindbis virus expression of antisense luciferase RNA. Proceedings of the National Academy of Sciences 96(23):13399-13403. Kamhawi, S., Y. Belkaid, G. Modi, E. Rowton, and D. Sacks. 2000. Protection against cutaneous leishmaniasis resulting from bites of uninfected sand flies. Science 290(5495):1351-1354. Keene, K. M., B. D. Foy, I. Sanchez-Vargas, B. J. Beaty, C. D. Blair, and K. E. Olson. 2004. RNA interference acts as a natural antiviral response to Oânyong-nyong virus (Alphavirus; Toga- viridae) infection of Anopheles gambiae. Proceedings of the National Academy of Sciences 101(49):17240-17245. Kitron, U., J. K. Bouseman, and C. J. Jones. 1991. Use of the ARC/INFO GIS to study the distribution of Lyme disease ticks in an Illinois county. Preventive Veterinary Medicine 11:243-248. LaBeaud, A., Y. Ochiai, C. Peters, E. Muchiri, and C. King. 2007. Spectrum of Rift Valley fever virus transmission in Kenya: insights from three distinct regions. American Journal of Tropical Medicine and Hygiene 76(5):795-800. Lanciotti, R. S., J. T. Roehrig, V. Deubel, J. Smith, M. Parker, K. Steele, B. Crise, K. E. Volpe, M. B. Crabtree, J. H. Scherret, R. A. Hall, J. S. MacKenzie, C. B. Cropp, B. Panigrahy, E. Ostlund, B. Schmitt, M. Malkinson, C. Banet, J. Weissman, N. Komar, H. M. Savage, W. Stone, T. McNamara, and D. J. Gubler. 1999. Origin of the West Nile virus responsible for an outbreak of encephalitis in the northeastern United States. Science 286(5448):2333-2337. Lanzaro, G. C., L. Zheng, Y. T. Toure, S. F. Traore, F. C. Kafatos, and K. D. Vernick. 1995. Microsat- ellite DNA and isozyme variability in a west African population of Anopheles gambiae. Insect Molecular Biology 4(2):105-112. Lawson, D., P. Arensburger, P. Atkinson, N. J. Besansky, R. V. Bruggner, R. Butler, K. S. Campbell, G. K. Christophides, S. Christley, E. Dialynas, D. Emmert, M. Hammond, C. A. Hill, R. C. Kennedy, N. F. Lobo, M. R. MacCallum, G. Madey, K. Megy, S. Redmond, S. Russo, D. W. Severson, E. O. Stinson, P. Topalis, E. M. Zdobnov, E. Birney, W. M. Gelbart, F. C. Kafatos, C. Louis, and F. H. Collins. 2007. VectorBase: a home for invertebrate vectors of human patho- gens. Nucleic Acids Research 35(Database Issue):D503-D505. Levashina, E. A., L. F. Moita, S. Blandin, G. Vriend, M. Lagueux, and F. C. Kafatos. 2001. Conserved role of a complement-like protein in phagocytosis revealed by dsRNA knockout in cultured cells of the mosquito, Anopheles gambiae. Cell 104(5):709-718. Lima, J. B. P., M. P. Da-Cunha, R. C. Da Silva, Jr., A. K. R. Galardo, S. D. S. Soares, I. A. Braga, R. P. Ramos, and D. Valle. 2003. Resistance of Aedes aegypti to organophosphates in several ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ municipalities in the State of Rio de Janeiro and Espirito Santo, Brazil. American Journal of Tropical Medicine and Hygiene 68(3):329-333. Lounibos, L. P. 2002. Invasions by insect vectors of human disease. Annual Review of Entomology 47:233-266. Monath, T. P. 2001. Yellow fever: an update. Lancet Infectious Diseases 1(1):11-19.
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 293 Moore, C. G. 1999. Aedes albopictus in the United States: current status and prospects for further spread. Journal of the American Mosquito Control Association 15(2):221-227. Morens, D. M., G. K. Folkers, and A. S. Fauci. ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ 2004. The challenge of emerging and re-emerging infectious diseases. Nature 430(6996):242-249. Nene, V., J. R. Wortman, D. Lawson, B. Haas, C. Kodira, Z. J. Tu, B. Loftus, Z. Xi, K. Megy, M. Grabherr, Q. Ren, E. M. Zdobnov, N. F. Lobo, K. S. Campbell, S. E. Brown, M. F. Bonaldo, J. Zhu, S. P. Sinkins, D. G. Hogenkamp, P. Amedeo, P. Arensburger, P. W. Atkinson, S. Bidwell, J. Biedler, E. Birney, R. V. Bruggner, J. Costas, M. R. Coy, J. Crabtree, M. Crawford, B. Debruyn, D. Decaprio, K. Eiglmeier, E. Eisenstadt, H. El-Dorry, W. M. Gelbart, S. L. Gomes, M. Hammond, L. I. Hannick, J. R. Hogan, M. H. Holmes, D. Jaffe, J. S. Johnston, R. C. Kennedy, H. Koo, S. Kravitz, E. V. Kriventseva, D. Kulp, K. Labutti, E. Lee, S. Li, D. D. Lovin, C. Mao, E. Mauceli, C. F. Menck, J. R. Miller, P. Montgomery, A. Mori, A. L. Nascimento, H. F. Naveira, C. Nusbaum, S. OâLeary, J. Orvis, M. Pertea, H. Quesneville, K. R. Reidenbach, Y. H. Rogers, C. W. Roth, J. R. Schneider, M. Schatz, M. Shumway, M. Stanke, E. O. Stinson, J. M. Tubio, J. P. Vanzee, S. Verjovski-Almeida, D. Werner, O. White, S. Wyder, Q. Zeng, Q. Zhao, Y. Zhao, C. A. Hill, A. S. Raikhel, M. B. Soares, D. L. Knudson, N. H. Lee, J. Galagan, S. L. Salzberg, I. T. Paulsen, G. Dimopoulos, F. H. Collins, B. Birren, C. M. Fraser-Liggett, and D. W. Severson. 2007. Genome sequence of Aedes aegypti, a major arbovirus vector. Science 316(5832):1718-1723. NâGuessan, R., V. Corbel, M. Akogbeto, and M. Rowland. 2007. Reduced efficacy of insecticide- treated nets and indoor residual spraying for malaria control in pyrethroid resistance area, Benin. Emerging Infectious Diseases 13(2):199-206. Nicholson, W. L., J. McQuiston, T. J. Vannieuwenhoven, and E. W. Morgan. 2003. Rapid deployment and operation of a Q fever field laboratory in Bosnia and Herzegovina. Annals of the New York Academy of Sciences 990:320-326. NRC (National Research Council). 1983. Manpower needs and career opportunities in the field aspects of vector biology, report of a workshop. Washington, DC: National Academy Press. Pp. 1-53. OâConnor, C., E. C. Halperin, and E. G. Buckley. 2007. A curricular model for the training of physi- cian scientists: the evolution of the Duke University School of Medicine curriculum. Academic Medicine 82(4):375-382. Olson, K. E., S. Higgs, P. J. Gaines, A. M. Powers, B. S. Davis, K. I. Kamrud, J. O. Carlson, C. D. Blair, and B. J. Beaty. 1996. Genetically engineered resistance to dengue-2 virus transmis- sion in mosquitoes. Science 272(5263):884-886. Peterson, A. T., C. Martinez-Campos, Y. Nakazawa, and E. Martinez-Meyer. 2005. Time-specific ecological niche modeling predicts spatial dynamics of vector insects and human dengue cases. Transactions of the Royal Society of Tropical Medicine and Hygiene 99(9):647-655. Pittendrigh, B. R., and P. J. Gaffney. 2001. Pesticide resistance: can we make it a renewable resource? Journal of Theoretical Biology 211(4):365-375. Pitts, R. J., A. N. Fox, and L. J. Zwiebel. 2004. A highly conserved candidate chemoreceptor ex- pressed in both olfactory and gustatory tissues in the malaria vector Anopheles gambiae. Pro- ceedings of the National Academy of Sciences 101(14):5058-5063. Raymond, M., C. Chevillon, T. Guillemaud, T. Lenormand, and N. Pasteur. 1998. An overview of the evolution of overproduced esterases in the mosquito Culex pipiens. Philosophical Transactions of the Royal Society of LondonâSeries B: Biological Sciences 353:1707-1711. Reiter, P., S. Lathrop, M. Bunning, B. Biggerstaff, D. Singer, T. Tiwari, L. Baber, M. Amador, J. Thirion, J. Hayes, C. Seca, J. Mendez, B. Ramirez, J. Robinson, J. Rawlings, V. Vorndam, S. Waterman, D. Gubler, G. Clark, and E. Hayes. 2003. Texas lifestyle limits transmission of dengue virus. Emerging Infectious Diseases 9(1):86-89. Roberts, D. R., L. L. Laughlin, P. Hsheih, and L. J. Legters. 1997. DDT, global strategies, and a ma- laria control crisis in South America. Emerging Infectious Diseases 3(3):295-302.
294 VECTOR-BORNE DISEASES Roehrig, J. T., M. Layton, P. Smith, G. L. Campbell, R. Nasci, and R. S. Lanciotti. 2002. The emer- gence of West Nile virus in North America: ecology, epidemiology, and surveillance. Current Topics in Microbiology and Immunology 267:223-240. Rogers, D. J., S. E. Randolph, R. W. Snow, and S. I. Hay. 2002. Satellite imagery in the study and forecast of malaria. Nature 415(6872):710-715. Root, J. J., W. C. Black IV, C. H. Calisher, K. R. Wilson, R. S. Mackie, T. Schountz, J. N. Mills, and B. J. Beaty. 2003. Analyses of gene flow among populations of deer mice (Peromyscus maniculatus) at sites near hantavirus pulmonary syndrome case-patient residences. Journal of Wildlife Diseases 39(2):287-298. Sanders, H. R., B. D. Foy, A. M. Evans, L. S. Ross, B. J. Beaty, K. E. Olson, and S. S. Gill. 2005. Sindbis virus induces transport processes and alters expression of innate immunity pathway genes in the midgut of the disease vector, Aedes aegypti. Insect Biochemistry and Molecular Biology 35(11):1293-1307. Spielman, A. 1994. A commentary on research needs for monitoring and containing emergent vector- borne infections. Annals of the New York Academy of Sciences 740(1):457-461. Sutherst, R. W. 2004. Global change and human vulnerability to vector-borne diseases. Clinical Microbiology Reviews 17(1):136-173. Tabachnick, W. J., G. P. Wallis, T. H. Aitken, B. R. Miller, G. D. Amato, L. Lorenz, J. R. Powell, and B. J. Beaty. 1985. Oral infection of Aedes aegypti with yellow fever virus: geographic variation and genetic considerations. American Journal of Tropical Medicine and Hygiene 34(6):1219-1224. Titus, R. G., and J. M. Ribeiro. 1988. Salivary gland lysates from the sand fly Lutzomyia longipalpis enhance Leishmania infectivity. Science 239(4845):1306-1308. United Nations General Assembly. 2005. 2001-2010: decade to roll back malaria in developing coun- tries, particularly in Africa. Sixtieth Session of the UN General Assembly, Agenda item 47. USAHA (United States Animal Health Association). 1998. Foreign animal diseases. Committee on Foreign Animal Diseases of the United States Animal Health Association. Richmond, VA: Pat Campbell & Associates and Carter Printing Company. USDA (U.S. Department of Agriculture). 2007a. Animal health monitoring and surveillance, http:// www.aphis.usda.gov/vs/ceah/ncahs/nsu/ (accessed September 26, 2007). USDA. 2007b. Center for Emerging Issues (CEI), http://www.aphis.usda.gov/vs/ceah/cei/ (accessed September 26, 2007). USDA. 2007c. NAHLN laboratories, http://www.aphis.usda.gov/vs/nahln/html/Laboratories.html (ac- cessed September 26, 2007). USDA. 2007d. CEAH GIS overview, http://www.aphis.usda.gov/vs/ceah/cei/gis/ (accessed September 26, 2007). Valenzuela, J. G., I. M. Francischetti, V. M. Pham, M. K. Garfield, and J. M. Ribeiro. 2003. Explor- ing the salivary gland transcriptome and proteome of the Anopheles stephensi mosquito. Insect Biochemistry and Molecular Biology 33(7):717-732. Waterhouse, R. M., E. V. Kriventseva, S. Meister, Z. Xi, K. S. Alvarez, L. C. Bartholomay, C. Barillas-Mury, G. Bian, S. Blandin, B. M. Christensen, Y. Dong, H. Jiang, M. R. Kanost, A. C. Koutsos, E. A. Levashina, J. Li, P. Ligoxygakis, R. M. Maccallum, G. F. Mayhew, A. Mendes, K. Michel, M. A. Osta, S. Paskewitz, S. W. Shin, D. Vlachou, L. Wang, W. Wei, L. Zheng, Z. Zou, D. W. Severson, A. S. Raikhel, F. C. Kafatos, G. Dimopoulos, E. M. Zdobnov, and G. K. Christophides. 2007. Evolutionary dynamics of immune-related genes and pathways in disease-vector mosquitoes. Science 316(5832):1738-1743. Watson, R. T., J. Patz, D. J. Gubler, E. A. Parson, and J. H. Vincent. 2005. Environmental health implications of global climate change. Journal of Environmental Monitoring 7(9):834-843.
INTEGRATING STRATEGIES TO ADDRESS VECTOR-BORNE DISEASE 295 WHO (World Health Organization). 2004. Report of the fourth meeting of the Global Collaboration for Development of Pesticides for Public Health (GCDPP). Geneva, Switzerland: World Health Organization, http://whqlibdoc.who.int/hq/2004/WHO_CDS_WHOPES_GCDPP_2004.8.pdf (accessed September 6, 2007). Willadsen, P. 2001. The molecular revolution in the development of vaccines against ectoparasites. Veterinary Parasitology 101(3-4):353-368. Worboys, M. 2000. Spreading germs: diseases, theories, and medical practice in Britain, 1865-1900. Cambridge, England: Cambridge University Press.