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Epidemic arboviral diseases: priorities for research and public health
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Epidemic arboviral diseases: priorities for research and public health Annelies Wilder-Smith, Duane J Gubler, Scott C Weaver, Thomas P Monath, David L Heymann, Thomas W Scott
For decades, arboviral diseases were considered to be only minor contributors to global mortality and disability. As a result, low priority was given to arbovirus research investment and related public health infrastructure. The past five decades, however, have seen an unprecedented emergence of epidemic arboviral diseases (notably dengue, chikungunya, yellow fever, and Zika virus disease) resulting from the triad of the modern world: urbanisation, globalisation, and international mobility. The public health emergency of Zika virus, and the threat of global spread of yellow fever, combined with the resurgence of dengue and chikungunya, constitute a wake-up call for governments, academia, funders, and WHO to strengthen programmes and enhance research in aedes-transmitted diseases. The common features of these diseases should stimulate similar research themes for diagnostics, vaccines, biological targets and immune responses, environmental determinants, and vector control measures. Combining interventions known to be effective against multiple arboviral diseases will offer the most cost-effective and sustainable strategy for disease reduction. New global alliances are needed to enable the combination of efforts and resources for more effective and timely solutions.
Introduction Arboviral diseases are caused by viruses that are spread to people by the bite of an infected arthropod, predominantly mosquitoes and ticks. Traditionally, low priority has been given to arbovirus research. However, over the past 50 years, the unprecedented emergence of epidemic arboviral diseases have changed perceptions about their contribution to global mortality and disability.1,2 The most recent example is Zika virus infection, which moved rapidly from obscurity to a Public Health Emergency of International Concern. Yellow fever virus could become the next arbovirus to reach this level if swift international spread occurs. In 2016, laboratory-documented yellow fever virus was exported to Asia for the first time via international travellers, putting 1·8 billion people at risk because the urban mosquito vector (Aedes aegypti) is present among large unvaccinated populations.3 Chikungunya virus caused havoc in 2013–14 when a re-emerging strain was introduced into the Caribbean and Latin America and swept through at unprecedented speed and scale.4 West Nile virus was introduced into the USA in 1999 and rapidly spread throughout North and South America within a few years.5 Japanese encephalitis virus has spread further west, north, and south in Asia.6 An unprecedented increase in dengue virus infections has occurred over the past five decades, so much so that it is now considered the most common vector-borne virus viral infection worldwide.7 The recent threat posed by Zika, chikungunya, yellow fever, West Nile, and Japanese encephalitis viruses, the massive emergence of epidemic dengue virus across the globe, and the threat of other, as yet unrecognised, arboviruses emerging in epidemic form, highlight the 21st century problem of arboviruses and underscore the need to reassess research priorities and public health interventions.
Important arboviral diseases transmitted by aedes mosquitoes The arboviruses undergoing the most striking resurgence in this century (Zika, dengue, yellow fever, and chikungunya viruses) are all transmitted in urban or periurban areas by Aedes spp mosquitoes of the subgenus Stegomyia. Although the first three are flaviviruses (family Flaviviridae), chikungunya virus is an alphavirus (family Togaviridae). All are transmitted in zoonotic cycles involving non-human primates and arboreal mosquitoes, and have entered human-to-human cycles involving urban A aegypti and, in some cases, Aedes albopictus transmission.8 Aedes spp distributions are now the widest ever recorded; extensive in all continents, including North America and Europe, with more than 3 billion people living in aedes-infested regions. A aegypti, the principal vector, is mainly found in the tropics and subtropics. It is efficient because it is highly susceptible to these viruses, feeds preferentially on human beings, is active during the daytime, thrives in peridomestic environments close to people, and often bites several people in a short period. Overcrowding facilitates transmission via urban aedes mosquitoes, further compounded by man-made larval habitats, suggesting that the unprecedented urbanisation in tropical low-income countries in the past 50 years is the principal driver of A aegypti-borne diseases.9 Furthermore, increasing international travel and globalisation accelerate the introduction of arbovirus into new areas and their geographic expansion.10 Dengue epidemics have been recorded in places where A albopictus is the only vector, although it is a less efficient vector than A aegypti.11 Since 2005, A albopictus has proved highly effective in urban transmission of Indian Ocean lineage chikungunya virus12 and can also transmit Zika virus.13 The global spread of A albopictus, fuelled by global trade and travel14 and its hardiness in more
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Lancet Infect Dis 2016 Published Online December 20, 2016 http://dx.doi.org/10.1016/ S1473-3099(16)30518-7 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore (Prof A Wilder-Smith MD); Partnership for Dengue Control (PDC), Fondation Mérieux, Lyon, France (Prof A Wilder-Smith); Institute of Public Health, University of Heidelberg, Heidelberg, Germany (Prof A Wilder-Smith); Duke–NUS Medical School, Singapore (Prof D J Gubler ScD); Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA (Prof S C Weaver PhD); BioProtection Systems/ NewLink Genetics Corp, Devens, MA, USA (Prof T P Monath MD); London School of Hygiene & Tropical Medicine, London, UK (Prof D L Heymann MD); and Department of Entomology and Nematology, University of California, Davis, CA (Prof T W Scott PhD) Correspondence to: Prof Annelies Wilder-Smith, Lee Kong Chian School of Medicine, Singapore 308232, Singapore [email protected]
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temperate climates,15 puts areas of North America and Europe at risk for transmission of aedes-borne viruses, as exemplified by the 2007 Italian outbreak of chikungunya. Modelling studies predict that climate change, including extreme weather, with large daily temperature fluctuations will increase the potential for a dengue epidemic in temperate regions, reducing the differences between tropical and temperate zones.16,17 Zika virus emerged as a public health concern in Yap (Federated States of Micronesia) in 2007.18 Although it causes asymptomatic infection or a clinically mild disease in most cases, Zika virus has an unusual tropism for progenitor neural cells in the developing human fetus, resulting in clusters of neurodevelopmental birth defects that are further compounded by clusters of severe neurological disease in adults. Thus, it is considered a threat to public health security.19 50 years after the successful control of congenital rubella syndrome, we are now confronted by an arbovirus that causes congenital disease with major disabilities. The clusters of Guillain-Barré syndrome and other neurological complications raise questions about whether these phenomena are due to direct neuroinvasion or due to post-infectious autoimmunity. The ability of Zika virus to be transmitted sexually between human beings and the persistence of viral RNA in semen for many months is the first example of this transmission mode for any arbovirus. Recent modelling suggests that herd immunity to Zika virus could result in cessation of major epidemics within 3 years, but outbreaks could occur again after herd immunity from natural infection wanes.20 Yellow fever virus is maintained in enzootic cycles involving monkeys and mosquitoes in 34 countries of Africa and 13 in South America. Although introduction of yellow fever virus into Asia has long been feared, it has never been detected, despite it having a similar tropical environment to Africa and the presence of A aegypti.21 Most yellow fever virus infections are asymptomatic; the majority of symptomatic patients have fever, headache, chills, muscle pain, and nausea, usually limited to less than 1 week. About 10–25% of patients develop haemorrhagic manifestations and kidney and liver damage, with a case-fatality rate of 20–50% in symptomatic cases.21 Since December, 2015, a yellow fever epidemic has been underway in Angola; by September, 2016, 884 laboratory-confirmed cases have been reported, of 4188 suspected cases, with 373 deaths.22 International travel led to disease spread to Kenya, the Democratic Republic of the Congo, and China. 11 unvaccinated Chinese workers from Angola imported yellow fever virus to China, representing the first laboratory-documented cases in Asia.23 In April, 2016, WHO declared the current yellow fever epidemic a global threat. With an estimated 390 million infections annually and worldwide, of which about 100 million are 2
symptomatic, dengue is the most common arboviral disease of human beings, disproportionately affecting Asia and Latin America.7 The past four decades have seen a more than 30-times increase, mainly thought to be due to population growth and density, urbanisation, human movement, virus evolution, and socioeconomic factors.24 Substantial geographical expansion has been coupled with exponential increases in cases, epidemics, and co-circulation of all four dengue serotypes, leading to the more severe forms of disease.10 Chikungunya is characterised by a sudden onset of fever, accompanied by moderate-to-severe joint pain. It is often misdiagnosed as dengue fever in areas where these viruses co-circulate, but by contrast with dengue, the joint pain can last much longer, up to several years, and can be highly debilitating. Also, by contrast with yellow fever and dengue, most chikungunya cases are symptomatic and attack rates can exceed 50% during epidemics. Although A aegypti is considered the principal vector of chikungunya, yellow fever, and dengue viruses, a strain of chikungunya virus that has recently emerged, termed the Indian Ocean lineage, is sometimes more efficiently transmitted by A albopictus because of a series of vector-adaptive mutations in the envelope glycoprotein genes.25 The Asian chikungunya virus strain that recently spread to the Americas, however, appears to be genetically constrained in its ability to adapt to A albopictus.26 The minimal requirements for sustained endemic arbovirus transmission via A aegypti or A albopictus might be met by three other viruses with the potential to become major human pathogens: Venezuelan equine encephalitis virus, already a cause of human and equine neurological disease throughout tropical regions of the Americas, and Mayaro virus and Ross River virus, which are close relatives of chikungunya virus and produce a comparably debilitating arthralgic disease in South America and Australia, respectively.8
Diagnostics The co-circulation of multiple aedes-transmitted diseases with similar epidemiology, which often result in clinically indistinguishable febrile syndromes, underscores a desperate need for point-of-care diagnostic tests that can differentiate between them. Antibody detection tests can distinguish between the alphaviruses (chikungunya, Venezuelan equine encephalitis, Mayaro, and Ross River viruses) and the flaviviruses (dengue, Zika, yellow fever, West Nile, and Japanese encephalitis viruses), but because of previous exposure to related flaviviruses and extensive cross-reactions among flaviviruses, serological tests such as IgM ELISA and even neutralisation assays are not reliable for identifying the infecting flavivirus. The most reliable tests are nucleic acid tests such as reverse transcription-PCR, and non-structural glycoprotein-1 (NS1) ELISA, which detect acute-phase infections, although NS1 ELISA is not available for all of these viruses. Another factor confounding diagnosis is the
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increasing use of dengue, yellow fever, and Japanese encephalitis vaccines, which complicate serodiagnosis of natural infections. There is a crucial need, therefore, to develop sensitive and specific multiplex diagnostic tests that are reliable for differential diagnosis of these viruses.
Measures to mitigate Aedes spp-transmitted diseases A change of focus Successful control of mosquito-borne diseases has traditionally been associated with malaria and anopheles mosquitoes, which transmit malaria, and has been associated with higher mortality and morbidity than have arboviral diseases. This emphasis resulted in the neglect of research and development for aedes mosquito biology and control, which is different from anopheles control, with a resulting gap in entomological expertise and deficiencies in the understanding of essential epidemiological aspects of aedes-transmitted diseases. Reducing vector–human interactions is particularly challenging. For example, insecticide-treated bednets that are so successful for malaria control are of limited use to mitigate diseases caused by aedes, which mainly bites during the day.
Vector control Previous successes indicate that careful and thorough A aegypti control can reduce disease.27 During the 1950s and 1960s, application of dichlorodiphenyltrichloroethane (DDT) and intensive source reduction to eliminate and control breeding sites across much of central and South America, dramatically reduced or eliminated A aegypti populations and effectively decreased epidemic yellow fever and dengue incidence. During the 1970–80s in Singapore, and during the 1980–90s in Cuba, adult and larval A aegypti control was used to reduce dengue virus transmission and disease. More recently, insecticide trials with indoor residual spraying and space spraying were associated with reduced dengue incidence. Unfortunately, these successes were unsustainable exceptions. Epidemic dengue virus returned to Latin America after the A aegypti eradication programme ended, and after 15–20 years of control, it increased in Singapore and Cuba. Rebounding transmission demonstrated the difficulty of sustaining A aegypti control and the capacity for rapid resurgence of mosquito populations when control efforts are relaxed. Unsuccessful interventions are typically attributed to several factors, including inadequate responses to the virus’ strength of transmission, insecticide resistance, expanding A aegypti populations, expansion of urban centres with poor sanitation, human travel networks that disperse the virus and mosquitoes, inadequate vector control infrastructure, insufficient resources, inadequate political will, and unsuccessful application of existing strategies. Epidemiological evidence of efficacy from well designed field trials is urgently needed to guide application and evaluation.28 Because A aegypti is difficult
to control, effective interventions must be expedient, comprehensive, and sustained.29 Community mobilisation and participation to reduce Aedes larval habitats have shown variable success.30 However, a multicentre randomised controlled trial done in 2015 provides evidence that community mobilisation can enhance dengue vector control.31 Personal protective measures include mosquito repellents, wearing adequate clothing, insecticide treatment, spatial repellent chemicals that discourage mosquitoes from entering a space, and mosquito traps. Applying repellents on a daily basis is impractical, and will not be scalable on a population basis. Rethinking home construction, including the use of screens with or without insecticide treatment, could be a long-term solution for decreasing contact between aedes vectors and people. The development of technologies that can be applied during the day to protect against mosquito bites should similarly be a priority. Safe technologies for longlasting insecticide-treated clothing materials that can be used for school and workplace uniforms and maternity clothing should be an urgent subject of research.32,33 Various new approaches in development show promise for enhanced disease prevention. These include infecting A aegypti with the bacteria of the genus Wolbachia either to decrease their capacity to transmit viruses (yellow fever, dengue, chikungunya, and Zika viruses) or to reduce mosquito populations, inducing sterility in male mosquitoes through genetic engineering or irradiation (the wild females with which they mate produce infertile eggs, reducing populations), using spatial repellents and vapour-active insecticides to remove mosquitoes from homes where they bite and infect human hosts, and installing insecticide-treated screens in homes.34 Advances in genetic engineering technology (eg, CRISPR–Cas9) that allow highly efficient, targeted transformation and gene-drive systems in mosquitoes, are being explored as ways to block transmission or reduce vector populations.35 Like other tools, these novel approaches will have to be shown to be effective and scalable across the vast areas in which A aegypti-borne disease persists. On the basis of the growing consensus that no single intervention will be sufficient to reduce disease from the increasing number of A aegypti-borne viruses, there is increasing interest in combining mosquito interventions with vaccination.27 Vaccination can increase herd immunity, making it easier to sustain reduced virus transmission with vector control. Vector control can complement a vaccine by lowering the risk of infection, making vaccine delivery goals easier to achieve.
Vaccines A safe, effective yellow fever vaccine has been available for more than half a century. The yellow fever vaccine is a live-attenuated yellow fever virus strain that produces rapid immunity of long (probably lifelong) duration.
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By 1988, recommendations were made to include the yellow fever vaccine in routine childhood immunisation programmes in African countries at risk of yellow fever. In 2006, the Yellow Fever Initiative recommended, in addition to routine vaccination, mass preventive vaccination campaigns to protect susceptible, older people, focusing on highly endemic African countries. Yellow fever mass vaccination is highly effective, but unfortunately coverage remains inadequate, as underscored by the outbreak in Angola and other parts of Africa. The introduction of yellow fever vaccine into routine infant immunisation is a long-term strategy that takes decades before the entire population is protected. Mass immunisation, which would require more than 300 million doses for Africa alone, needs to be implemented before further outbreaks occur. In South America, over 75% of the population lives in heavily urban and narrow coastal areas, which are juxtaposed with forested regions that are enzootic for yellow fever, and people in these coastal areas remain largely unvaccinated. Yellow fever resurgence in Africa clearly shows minimal engagement of governments with routine and mass vaccination campaigns. The failure to protect travellers shows circumvention of WHO International Health Regulations. Limited manufacturing capacity, along with financial and logistical challenges, contribute to inadequate coverage. Should yellow fever outbreaks occur elsewhere in Africa, Latin America, or Asia, current global supplies of the vaccine will continue to be inadequate.3 The annual production of about 80 million doses would not be able to cover the at-risk population should yellow fever spread to Asia.3 The Strategic Advisory Group of Experts at WHO has recommended a fractional dose (one-fifth) at the time of an outbreak to cover a larger population.36 In late 2015, after decades of research, the world’s first dengue vaccine was licensed: CYD-TDV vaccine (Dengvaxia). Data generated by a large phase 3 trial37,38 in ten endemic countries in Asia and Latin America showed an unpredicted complexity of vaccine performance with efficacy dependent on serotype, baseline serostatus, and age. Dengue is a complex disease because secondary infections are thought to enhance severity. The CYDTDV vaccine does not present a simple solution, but despite substantial imperfections, it has public health use as an additional tool in the otherwise scarce armamentarium for dengue control in high endemicity settings.39 Two other live virus dengue vaccines are in phase 3 trials and several other dengue vaccines are in phase 1 and 2 trials, so the prospects for vaccine control of dengue are good. Research on vaccines against chikungunya virus has been slow, although a few replication-defective and attenuated vaccine candidates have shown some promise in phase 1/2 trials, and others have proven to be safe and immunogenic in mouse and non-human primate models.40 A vaccine based on virus-like particles 4
was successfully tested in a phase 1 trial.41 However, given that chikungunya virus appears to be associated with major outbreaks only every 10–30 years, a return on investments is not guaranteed and thus there is limited incentive for the pharmaceutical industry. These challenges are compounded by the difficulty for policy makers of deciding how to roll out chikungunya vaccination both during and between epidemics, and by the difficulty of identifying a suitable location for clinical efficacy studies during interepidemic periods. Given the international public health emergency of Zika virus, there is considerable effort to develop multiple vaccine types for Zika virus disease. Replication-defective viral vectors, DNA, inactivated whole virion, or recombinant virus-like particle vaccines for Zika virus are being fast-tracked, and some phase 1 clinical trials are underway. As with chikungunya virus, however, the long-term market and prospects for clinical efficacy trials remain uncertain if current epidemics peak and transmission quickly subsides.
Conclusions Although modernisation and increasing standards of medical care are reducing the incidence of malaria and other diseases of poverty,1 diseases transmitted by aedes mosquitoes are expanding their geographical range and effect on public health as a result of urbanisation, globalisation, and international mobility.42 It is time for policy makers and the scientific community alike to pay more attention to the effect of urbanisation and globalisation on aedes-borne viruses. The public health emergency of Zika virus, the threat of yellow fever, and the resurgence of dengue and chikungunya should serve as a wake-up call for governments, academia, funders, and WHO to strengthen programmes and research in aedes-transmitted diseases. The shared features of these viruses should stimulate similar research themes for diagnostics, vaccines, biological targets and immune responses, environmental determinants, and vector control. Point-of-care multiplex diagnostics to diagnose arboviruses are needed urgently given the co-circulation of these viruses, including more specific serological assays for seroprevalence studies. Vaccine development needs to leverage the successes of the yellow fever vaccine, and to be extended to Zika and chikungunya viruses. The concern that antibody-dependent enhancement from a previous dengue infection (or possibly live dengue vaccines) is enhancing Zika virus infection, and, vice versa, needs to be addressed in carefully designed observational and laboratory studies. Biological targets that are common for all flaviviral infections might be applicable across all related diseases. Similar considerations apply to new antiviral drugs that could be used prophylactically and therapeutically. The lessons learned from anopheles control for malaria are unfortunately not universally transferable to aedes
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control; the paucity of reliable epidemiological evidence for the effectiveness of any vector control method for aedes-borne diseases is remarkable.28 We need strategic innovation, updated guidelines for rigorous assessment of intervention options, and an expanded prevention toolbox that is supported by solid empirical, epidemiological data.29 Technologies are needed for enhanced personal protection that could be used for maternity clothing to protect pregnant women, school uniforms to protect children, and leisure and work clothes to protect adults. Socioeconomic and environmental factors that drive vector proliferation, in particular in cities in low-income countries, need to be better explored and mitigated. A critical assessment of vector control tools and those under development should guide a research agenda for determining which existing techniques work best, and how to best combine state-of-the-art vector control with vaccination. Vaccines are the most cost-effective means to prevent infectious diseases, but take many years to develop with a high cost. Combining interventions that are effective against multiple arboviral diseases will offer the most cost-effective and sustainable strategy for disease reduction.43 New global alliances, such as the Global Dengue and Aedes-transmitted Diseases Consortium, are needed to enable the combination of such efforts and resources for more effective and timely solutions to arboviral diseases. Contributors AWS wrote the initial draft; all authors made extensive contributions to the final draft.
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Epidemic arboviral diseases: priorities for research and public health Annelies Wilder-Smith, Duane J Gubler, Scott C Weaver, Thomas P Monath, David L Heymann, Thomas W Scott
For decades, arboviral diseases were considered to be only minor contributors to global mortality and disability. As a result, low priority was given to arbovirus research investment and related public health infrastructure. The past five decades, however, have seen an unprecedented emergence of epidemic arboviral diseases (notably dengue, chikungunya, yellow fever, and Zika virus disease) resulting from the triad of the modern world: urbanisation, globalisation, and international mobility. The public health emergency of Zika virus, and the threat of global spread of yellow fever, combined with the resurgence of dengue and chikungunya, constitute a wake-up call for governments, academia, funders, and WHO to strengthen programmes and enhance research in aedes-transmitted diseases. The common features of these diseases should stimulate similar research themes for diagnostics, vaccines, biological targets and immune responses, environmental determinants, and vector control measures. Combining interventions known to be effective against multiple arboviral diseases will offer the most cost-effective and sustainable strategy for disease reduction. New global alliances are needed to enable the combination of efforts and resources for more effective and timely solutions.
Introduction Arboviral diseases are caused by viruses that are spread to people by the bite of an infected arthropod, predominantly mosquitoes and ticks. Traditionally, low priority has been given to arbovirus research. However, over the past 50 years, the unprecedented emergence of epidemic arboviral diseases have changed perceptions about their contribution to global mortality and disability.1,2 The most recent example is Zika virus infection, which moved rapidly from obscurity to a Public Health Emergency of International Concern. Yellow fever virus could become the next arbovirus to reach this level if swift international spread occurs. In 2016, laboratory-documented yellow fever virus was exported to Asia for the first time via international travellers, putting 1·8 billion people at risk because the urban mosquito vector (Aedes aegypti) is present among large unvaccinated populations.3 Chikungunya virus caused havoc in 2013–14 when a re-emerging strain was introduced into the Caribbean and Latin America and swept through at unprecedented speed and scale.4 West Nile virus was introduced into the USA in 1999 and rapidly spread throughout North and South America within a few years.5 Japanese encephalitis virus has spread further west, north, and south in Asia.6 An unprecedented increase in dengue virus infections has occurred over the past five decades, so much so that it is now considered the most common vector-borne virus viral infection worldwide.7 The recent threat posed by Zika, chikungunya, yellow fever, West Nile, and Japanese encephalitis viruses, the massive emergence of epidemic dengue virus across the globe, and the threat of other, as yet unrecognised, arboviruses emerging in epidemic form, highlight the 21st century problem of arboviruses and underscore the need to reassess research priorities and public health interventions.
Important arboviral diseases transmitted by aedes mosquitoes The arboviruses undergoing the most striking resurgence in this century (Zika, dengue, yellow fever, and chikungunya viruses) are all transmitted in urban or periurban areas by Aedes spp mosquitoes of the subgenus Stegomyia. Although the first three are flaviviruses (family Flaviviridae), chikungunya virus is an alphavirus (family Togaviridae). All are transmitted in zoonotic cycles involving non-human primates and arboreal mosquitoes, and have entered human-to-human cycles involving urban A aegypti and, in some cases, Aedes albopictus transmission.8 Aedes spp distributions are now the widest ever recorded; extensive in all continents, including North America and Europe, with more than 3 billion people living in aedes-infested regions. A aegypti, the principal vector, is mainly found in the tropics and subtropics. It is efficient because it is highly susceptible to these viruses, feeds preferentially on human beings, is active during the daytime, thrives in peridomestic environments close to people, and often bites several people in a short period. Overcrowding facilitates transmission via urban aedes mosquitoes, further compounded by man-made larval habitats, suggesting that the unprecedented urbanisation in tropical low-income countries in the past 50 years is the principal driver of A aegypti-borne diseases.9 Furthermore, increasing international travel and globalisation accelerate the introduction of arbovirus into new areas and their geographic expansion.10 Dengue epidemics have been recorded in places where A albopictus is the only vector, although it is a less efficient vector than A aegypti.11 Since 2005, A albopictus has proved highly effective in urban transmission of Indian Ocean lineage chikungunya virus12 and can also transmit Zika virus.13 The global spread of A albopictus, fuelled by global trade and travel14 and its hardiness in more
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Lancet Infect Dis 2016 Published Online December 20, 2016 http://dx.doi.org/10.1016/ S1473-3099(16)30518-7 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore (Prof A Wilder-Smith MD); Partnership for Dengue Control (PDC), Fondation Mérieux, Lyon, France (Prof A Wilder-Smith); Institute of Public Health, University of Heidelberg, Heidelberg, Germany (Prof A Wilder-Smith); Duke–NUS Medical School, Singapore (Prof D J Gubler ScD); Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA (Prof S C Weaver PhD); BioProtection Systems/ NewLink Genetics Corp, Devens, MA, USA (Prof T P Monath MD); London School of Hygiene & Tropical Medicine, London, UK (Prof D L Heymann MD); and Department of Entomology and Nematology, University of California, Davis, CA (Prof T W Scott PhD) Correspondence to: Prof Annelies Wilder-Smith, Lee Kong Chian School of Medicine, Singapore 308232, Singapore [email protected]
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temperate climates,15 puts areas of North America and Europe at risk for transmission of aedes-borne viruses, as exemplified by the 2007 Italian outbreak of chikungunya. Modelling studies predict that climate change, including extreme weather, with large daily temperature fluctuations will increase the potential for a dengue epidemic in temperate regions, reducing the differences between tropical and temperate zones.16,17 Zika virus emerged as a public health concern in Yap (Federated States of Micronesia) in 2007.18 Although it causes asymptomatic infection or a clinically mild disease in most cases, Zika virus has an unusual tropism for progenitor neural cells in the developing human fetus, resulting in clusters of neurodevelopmental birth defects that are further compounded by clusters of severe neurological disease in adults. Thus, it is considered a threat to public health security.19 50 years after the successful control of congenital rubella syndrome, we are now confronted by an arbovirus that causes congenital disease with major disabilities. The clusters of Guillain-Barré syndrome and other neurological complications raise questions about whether these phenomena are due to direct neuroinvasion or due to post-infectious autoimmunity. The ability of Zika virus to be transmitted sexually between human beings and the persistence of viral RNA in semen for many months is the first example of this transmission mode for any arbovirus. Recent modelling suggests that herd immunity to Zika virus could result in cessation of major epidemics within 3 years, but outbreaks could occur again after herd immunity from natural infection wanes.20 Yellow fever virus is maintained in enzootic cycles involving monkeys and mosquitoes in 34 countries of Africa and 13 in South America. Although introduction of yellow fever virus into Asia has long been feared, it has never been detected, despite it having a similar tropical environment to Africa and the presence of A aegypti.21 Most yellow fever virus infections are asymptomatic; the majority of symptomatic patients have fever, headache, chills, muscle pain, and nausea, usually limited to less than 1 week. About 10–25% of patients develop haemorrhagic manifestations and kidney and liver damage, with a case-fatality rate of 20–50% in symptomatic cases.21 Since December, 2015, a yellow fever epidemic has been underway in Angola; by September, 2016, 884 laboratory-confirmed cases have been reported, of 4188 suspected cases, with 373 deaths.22 International travel led to disease spread to Kenya, the Democratic Republic of the Congo, and China. 11 unvaccinated Chinese workers from Angola imported yellow fever virus to China, representing the first laboratory-documented cases in Asia.23 In April, 2016, WHO declared the current yellow fever epidemic a global threat. With an estimated 390 million infections annually and worldwide, of which about 100 million are 2
symptomatic, dengue is the most common arboviral disease of human beings, disproportionately affecting Asia and Latin America.7 The past four decades have seen a more than 30-times increase, mainly thought to be due to population growth and density, urbanisation, human movement, virus evolution, and socioeconomic factors.24 Substantial geographical expansion has been coupled with exponential increases in cases, epidemics, and co-circulation of all four dengue serotypes, leading to the more severe forms of disease.10 Chikungunya is characterised by a sudden onset of fever, accompanied by moderate-to-severe joint pain. It is often misdiagnosed as dengue fever in areas where these viruses co-circulate, but by contrast with dengue, the joint pain can last much longer, up to several years, and can be highly debilitating. Also, by contrast with yellow fever and dengue, most chikungunya cases are symptomatic and attack rates can exceed 50% during epidemics. Although A aegypti is considered the principal vector of chikungunya, yellow fever, and dengue viruses, a strain of chikungunya virus that has recently emerged, termed the Indian Ocean lineage, is sometimes more efficiently transmitted by A albopictus because of a series of vector-adaptive mutations in the envelope glycoprotein genes.25 The Asian chikungunya virus strain that recently spread to the Americas, however, appears to be genetically constrained in its ability to adapt to A albopictus.26 The minimal requirements for sustained endemic arbovirus transmission via A aegypti or A albopictus might be met by three other viruses with the potential to become major human pathogens: Venezuelan equine encephalitis virus, already a cause of human and equine neurological disease throughout tropical regions of the Americas, and Mayaro virus and Ross River virus, which are close relatives of chikungunya virus and produce a comparably debilitating arthralgic disease in South America and Australia, respectively.8
Diagnostics The co-circulation of multiple aedes-transmitted diseases with similar epidemiology, which often result in clinically indistinguishable febrile syndromes, underscores a desperate need for point-of-care diagnostic tests that can differentiate between them. Antibody detection tests can distinguish between the alphaviruses (chikungunya, Venezuelan equine encephalitis, Mayaro, and Ross River viruses) and the flaviviruses (dengue, Zika, yellow fever, West Nile, and Japanese encephalitis viruses), but because of previous exposure to related flaviviruses and extensive cross-reactions among flaviviruses, serological tests such as IgM ELISA and even neutralisation assays are not reliable for identifying the infecting flavivirus. The most reliable tests are nucleic acid tests such as reverse transcription-PCR, and non-structural glycoprotein-1 (NS1) ELISA, which detect acute-phase infections, although NS1 ELISA is not available for all of these viruses. Another factor confounding diagnosis is the
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increasing use of dengue, yellow fever, and Japanese encephalitis vaccines, which complicate serodiagnosis of natural infections. There is a crucial need, therefore, to develop sensitive and specific multiplex diagnostic tests that are reliable for differential diagnosis of these viruses.
Measures to mitigate Aedes spp-transmitted diseases A change of focus Successful control of mosquito-borne diseases has traditionally been associated with malaria and anopheles mosquitoes, which transmit malaria, and has been associated with higher mortality and morbidity than have arboviral diseases. This emphasis resulted in the neglect of research and development for aedes mosquito biology and control, which is different from anopheles control, with a resulting gap in entomological expertise and deficiencies in the understanding of essential epidemiological aspects of aedes-transmitted diseases. Reducing vector–human interactions is particularly challenging. For example, insecticide-treated bednets that are so successful for malaria control are of limited use to mitigate diseases caused by aedes, which mainly bites during the day.
Vector control Previous successes indicate that careful and thorough A aegypti control can reduce disease.27 During the 1950s and 1960s, application of dichlorodiphenyltrichloroethane (DDT) and intensive source reduction to eliminate and control breeding sites across much of central and South America, dramatically reduced or eliminated A aegypti populations and effectively decreased epidemic yellow fever and dengue incidence. During the 1970–80s in Singapore, and during the 1980–90s in Cuba, adult and larval A aegypti control was used to reduce dengue virus transmission and disease. More recently, insecticide trials with indoor residual spraying and space spraying were associated with reduced dengue incidence. Unfortunately, these successes were unsustainable exceptions. Epidemic dengue virus returned to Latin America after the A aegypti eradication programme ended, and after 15–20 years of control, it increased in Singapore and Cuba. Rebounding transmission demonstrated the difficulty of sustaining A aegypti control and the capacity for rapid resurgence of mosquito populations when control efforts are relaxed. Unsuccessful interventions are typically attributed to several factors, including inadequate responses to the virus’ strength of transmission, insecticide resistance, expanding A aegypti populations, expansion of urban centres with poor sanitation, human travel networks that disperse the virus and mosquitoes, inadequate vector control infrastructure, insufficient resources, inadequate political will, and unsuccessful application of existing strategies. Epidemiological evidence of efficacy from well designed field trials is urgently needed to guide application and evaluation.28 Because A aegypti is difficult
to control, effective interventions must be expedient, comprehensive, and sustained.29 Community mobilisation and participation to reduce Aedes larval habitats have shown variable success.30 However, a multicentre randomised controlled trial done in 2015 provides evidence that community mobilisation can enhance dengue vector control.31 Personal protective measures include mosquito repellents, wearing adequate clothing, insecticide treatment, spatial repellent chemicals that discourage mosquitoes from entering a space, and mosquito traps. Applying repellents on a daily basis is impractical, and will not be scalable on a population basis. Rethinking home construction, including the use of screens with or without insecticide treatment, could be a long-term solution for decreasing contact between aedes vectors and people. The development of technologies that can be applied during the day to protect against mosquito bites should similarly be a priority. Safe technologies for longlasting insecticide-treated clothing materials that can be used for school and workplace uniforms and maternity clothing should be an urgent subject of research.32,33 Various new approaches in development show promise for enhanced disease prevention. These include infecting A aegypti with the bacteria of the genus Wolbachia either to decrease their capacity to transmit viruses (yellow fever, dengue, chikungunya, and Zika viruses) or to reduce mosquito populations, inducing sterility in male mosquitoes through genetic engineering or irradiation (the wild females with which they mate produce infertile eggs, reducing populations), using spatial repellents and vapour-active insecticides to remove mosquitoes from homes where they bite and infect human hosts, and installing insecticide-treated screens in homes.34 Advances in genetic engineering technology (eg, CRISPR–Cas9) that allow highly efficient, targeted transformation and gene-drive systems in mosquitoes, are being explored as ways to block transmission or reduce vector populations.35 Like other tools, these novel approaches will have to be shown to be effective and scalable across the vast areas in which A aegypti-borne disease persists. On the basis of the growing consensus that no single intervention will be sufficient to reduce disease from the increasing number of A aegypti-borne viruses, there is increasing interest in combining mosquito interventions with vaccination.27 Vaccination can increase herd immunity, making it easier to sustain reduced virus transmission with vector control. Vector control can complement a vaccine by lowering the risk of infection, making vaccine delivery goals easier to achieve.
Vaccines A safe, effective yellow fever vaccine has been available for more than half a century. The yellow fever vaccine is a live-attenuated yellow fever virus strain that produces rapid immunity of long (probably lifelong) duration.
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By 1988, recommendations were made to include the yellow fever vaccine in routine childhood immunisation programmes in African countries at risk of yellow fever. In 2006, the Yellow Fever Initiative recommended, in addition to routine vaccination, mass preventive vaccination campaigns to protect susceptible, older people, focusing on highly endemic African countries. Yellow fever mass vaccination is highly effective, but unfortunately coverage remains inadequate, as underscored by the outbreak in Angola and other parts of Africa. The introduction of yellow fever vaccine into routine infant immunisation is a long-term strategy that takes decades before the entire population is protected. Mass immunisation, which would require more than 300 million doses for Africa alone, needs to be implemented before further outbreaks occur. In South America, over 75% of the population lives in heavily urban and narrow coastal areas, which are juxtaposed with forested regions that are enzootic for yellow fever, and people in these coastal areas remain largely unvaccinated. Yellow fever resurgence in Africa clearly shows minimal engagement of governments with routine and mass vaccination campaigns. The failure to protect travellers shows circumvention of WHO International Health Regulations. Limited manufacturing capacity, along with financial and logistical challenges, contribute to inadequate coverage. Should yellow fever outbreaks occur elsewhere in Africa, Latin America, or Asia, current global supplies of the vaccine will continue to be inadequate.3 The annual production of about 80 million doses would not be able to cover the at-risk population should yellow fever spread to Asia.3 The Strategic Advisory Group of Experts at WHO has recommended a fractional dose (one-fifth) at the time of an outbreak to cover a larger population.36 In late 2015, after decades of research, the world’s first dengue vaccine was licensed: CYD-TDV vaccine (Dengvaxia). Data generated by a large phase 3 trial37,38 in ten endemic countries in Asia and Latin America showed an unpredicted complexity of vaccine performance with efficacy dependent on serotype, baseline serostatus, and age. Dengue is a complex disease because secondary infections are thought to enhance severity. The CYDTDV vaccine does not present a simple solution, but despite substantial imperfections, it has public health use as an additional tool in the otherwise scarce armamentarium for dengue control in high endemicity settings.39 Two other live virus dengue vaccines are in phase 3 trials and several other dengue vaccines are in phase 1 and 2 trials, so the prospects for vaccine control of dengue are good. Research on vaccines against chikungunya virus has been slow, although a few replication-defective and attenuated vaccine candidates have shown some promise in phase 1/2 trials, and others have proven to be safe and immunogenic in mouse and non-human primate models.40 A vaccine based on virus-like particles 4
was successfully tested in a phase 1 trial.41 However, given that chikungunya virus appears to be associated with major outbreaks only every 10–30 years, a return on investments is not guaranteed and thus there is limited incentive for the pharmaceutical industry. These challenges are compounded by the difficulty for policy makers of deciding how to roll out chikungunya vaccination both during and between epidemics, and by the difficulty of identifying a suitable location for clinical efficacy studies during interepidemic periods. Given the international public health emergency of Zika virus, there is considerable effort to develop multiple vaccine types for Zika virus disease. Replication-defective viral vectors, DNA, inactivated whole virion, or recombinant virus-like particle vaccines for Zika virus are being fast-tracked, and some phase 1 clinical trials are underway. As with chikungunya virus, however, the long-term market and prospects for clinical efficacy trials remain uncertain if current epidemics peak and transmission quickly subsides.
Conclusions Although modernisation and increasing standards of medical care are reducing the incidence of malaria and other diseases of poverty,1 diseases transmitted by aedes mosquitoes are expanding their geographical range and effect on public health as a result of urbanisation, globalisation, and international mobility.42 It is time for policy makers and the scientific community alike to pay more attention to the effect of urbanisation and globalisation on aedes-borne viruses. The public health emergency of Zika virus, the threat of yellow fever, and the resurgence of dengue and chikungunya should serve as a wake-up call for governments, academia, funders, and WHO to strengthen programmes and research in aedes-transmitted diseases. The shared features of these viruses should stimulate similar research themes for diagnostics, vaccines, biological targets and immune responses, environmental determinants, and vector control. Point-of-care multiplex diagnostics to diagnose arboviruses are needed urgently given the co-circulation of these viruses, including more specific serological assays for seroprevalence studies. Vaccine development needs to leverage the successes of the yellow fever vaccine, and to be extended to Zika and chikungunya viruses. The concern that antibody-dependent enhancement from a previous dengue infection (or possibly live dengue vaccines) is enhancing Zika virus infection, and, vice versa, needs to be addressed in carefully designed observational and laboratory studies. Biological targets that are common for all flaviviral infections might be applicable across all related diseases. Similar considerations apply to new antiviral drugs that could be used prophylactically and therapeutically. The lessons learned from anopheles control for malaria are unfortunately not universally transferable to aedes
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control; the paucity of reliable epidemiological evidence for the effectiveness of any vector control method for aedes-borne diseases is remarkable.28 We need strategic innovation, updated guidelines for rigorous assessment of intervention options, and an expanded prevention toolbox that is supported by solid empirical, epidemiological data.29 Technologies are needed for enhanced personal protection that could be used for maternity clothing to protect pregnant women, school uniforms to protect children, and leisure and work clothes to protect adults. Socioeconomic and environmental factors that drive vector proliferation, in particular in cities in low-income countries, need to be better explored and mitigated. A critical assessment of vector control tools and those under development should guide a research agenda for determining which existing techniques work best, and how to best combine state-of-the-art vector control with vaccination. Vaccines are the most cost-effective means to prevent infectious diseases, but take many years to develop with a high cost. Combining interventions that are effective against multiple arboviral diseases will offer the most cost-effective and sustainable strategy for disease reduction.43 New global alliances, such as the Global Dengue and Aedes-transmitted Diseases Consortium, are needed to enable the combination of such efforts and resources for more effective and timely solutions to arboviral diseases. Contributors AWS wrote the initial draft; all authors made extensive contributions to the final draft.
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