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Advances in the development of new dengue control tools, including vaccines and vector control, herald a new era of desperately needed dengue prevention and control. The burden of dengue has expanded for decades, and now affects more than 120 countries. Complex, large-scale global forces have and will continue to contribute to the expansion of dengue, including population growth, unplanned urbanisation, and suboptimal mosquito control in urban centres. Although no so-called magic bullets are available, there is new optimism following the first licensure of a dengue vaccine and other promising vaccine candidates, and the development of novel vector control interventions to help control dengue and other expanding mosquito-borne diseases such as Zika virus. Implementation of effective and sustainable immunisation programmes to complement existing methods will add complexity to the health systems of affected countries, which have varying levels of robustness and maturity. Long-term high prioritisation and adequate resources are needed. The way forward is full commitment to addressing a complex disease with a set of solutions integrating vaccination and vector control methods. A whole systems approach is thus needed to integrate these various approaches and strategies for controlling dengue within the goal of universal health coverage. The ultimate objective of these interventions will be to reduce the disease burden in a sustainable and equitable manner., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Viral diseases transmitted via Aedes mosquitoes are on the rise, such as Zika, dengue, and chikungunya. Novel tools to mitigate Aedes mosquitoes-transmitted diseases are urgently needed. We tested whether commercially insecticide-impregnated school uniforms can reduce dengue incidence in school children., Methods: We designed a cluster-randomised controlled trial in Thailand. The primary endpoint was laboratory-confirmed dengue infections. Secondary endpoints were school absenteeism; and impregnated uniforms' 1-hour knock-down and 24 hour mosquito mortality as measured by standardised WHOPES bioassay cone tests at baseline and after repeated washing. Furthermore, entomological assessments inside classrooms and in outside areas of schools were conducted., Results: We enrolled 1,811 pupils aged 6-17 from 5 intervention and 5 control schools. Paired serum samples were obtained from 1,655 pupils. In the control schools, 24/641 (3.7%) and in the intervention schools 33/1,014 (3.3%) students had evidence of new dengue infections during one school term (5 months). There was no significant difference in proportions of students having incident dengue infections between the intervention and control schools, with adjustment for clustering by school. WHOPES cone tests showed a 100% knock down and mortality of Aedes aegypti mosquitoes exposed to impregnated clothing at baseline and up to 4 washes, but this efficacy rapidly declined to below 20% after 20 washes, corresponding to a weekly reduction in knock-down and mosquito mortality by 4.7% and 4.4% respectively. Results of the entomological assessments showed that the mean number of Aedes aegypti mosquitoes caught inside the classrooms of the intervention schools was significantly reduced in the month following the introduction of the impregnated uniforms, compared to those collected in classrooms of the control schools (p = 0.04)., Conclusions: Entomological assessments showed that the intervention had some impact on the number of Aedes mosquitoes inside treatment schools immediately after impregnation and before insecticidal activity declined. However, there was no serological evidence of protection against dengue infections over the five months school term, best explained by the rapid washing-out of permethrin after 4 washes. If rapid washing-out of permethrin could be overcome by novel technological approaches, insecticide-treated clothes might become a potentially cost-effective and scalable intervention to protect against diseases transmitted by Aedes mosquitoes such as dengue, Zika, and chikungunya., Trial Registration: ClinicalTrials.gov NCT01563640., Competing Interests: The authors have declared that no competing interests exist.

Recently, the Vaccines to Vaccinate (v2V) initiative was reconfigured into the Partnership for Dengue Control (PDC), a multi-sponsored and independent initiative. This redirection is consistent with the growing consensus among the dengue-prevention community that no single intervention will be sufficient to control dengue disease. The PDC's expectation is that when an effective dengue virus (DENV) vaccine is commercially available, the public health community will continue to rely on vector control because the two strategies complement and enhance one another. Although the concept of integrated intervention for dengue prevention is gaining increasingly broader acceptance, to date, no consensus has been reached regarding the details of how and what combination of approaches can be most effectively implemented to manage disease. To fill that gap, the PDC proposed a three step process: (1) a critical assessment of current vector control tools and those under development, (2) outlining a research agenda for determining, in a definitive way, what existing tools work best, and (3) determining how to combine the best vector control options, which have systematically been defined in this process, with DENV vaccines. To address the first step, the PDC convened a meeting of international experts during November 2013 in Washington, DC, to critically assess existing vector control interventions and tools under development. This report summarizes those deliberations.

An accurate measure of infectious dengue virus in human and mosquito tissues is critical to fully understand virus-host relationships, disease severity, viral fitness, and pathogenesis. In recent years, RNA copy number measured by quantitative real time-polymerase chain reaction has been used to measure dengue virus concentration in vitro and in vivo. In this study, we detail important differences in the measurement of viral growth kinetics in Vero and C6/36 tissue cultures, in Aedes aegypti mosquitoes, and in viremic human sera using RNA genomic equivalents and mosquito infectious dose 50 (MID50). Although there was reasonably good correlation between the two methods, RNA copy number was 2 to 5 logs greater than infectious virus titers. These differences varied significantly depending on virus strain, viral platform, infectious virus assay, and viral growth phase. The results have important implications for the correct interpretation of biological and epidemiological data from experimental and clinical studies, and show that genomic equivalents should be interpreted with caution when used as a proxy for infectious virus in such studies.

After a 15-year period of low incidence, dengue has reemerged in Singapore in the past decade. We identify potential causes of this resurgence. A combination of lowered herd immunity, virus transmission outside the home, an increase in the age of infection, and the adoption of a case-reactive approach to vector control contribute to the increased dengue incidence. Singapore's experience with dengue indicates that prevention efforts may not be sustainable. For renewed success, Singapore needs to return to a vector control program that is based on carefully collected entomologic and epidemiologic data. Singapore's taking on a leadership role in strengthening disease surveillance and control in Southeast Asia may also be useful in reducing virus importation.

Autochthonous dengue virus transmission, last identified in the state of Hawaii in 1945, was detected again in 2001. A seroepidemiological survey in a high-incidence community (Nahiku) and a nearby low-incidence community (Hana Subdivision) was implemented. The two communities studied differed in median household size (two vs. four persons), median lot size (2.8 vs. 0.8acres), proportion of households with mosquito larvae (81 vs. 28%) and incidence of recent infection (39% [28/72] vs. 1% [1/131]). The average number of reported anti-mosquito actions by residents of both locations remained low, and approximately 50% (42/80) of the inspected houses had larvae, evidencing the need for more effective community mosquito control. Logistic regression analysis of risk factors for infection in Nahiku identified residing in properties with birds in the house or yard as significantly associated with infection (odds ratio 7.0, 95% CI 1.7-28.5), probably as an indicator of unspecified environmental characteristics that were attractive to the vector. We documented that nearly 40% of Nahiku residents had acquired dengue locally in 2001 and that undetected dengue outbreaks had occurred in Hawaii. Our data suggest that ecological characteristics may help Hawaii health officials identify communities at increased risk of dengue infection.

The first recorded outbreak of yellow fever in Kenya occurred from mid-1992 through March 1993 in the south Kerio Valley, Rift Valley Province. We conducted entomologic studies in February-March 1993 to identify the likely vectors and determine the potential for transmission in the surrounding rural and urban areas. Mosquitoes were collected by landing capture and processed for virus isolation. Container surveys were conducted around human habitation. Transmission was mainly in woodland of varying density, at altitudes of 1,300-1,800 m. The abundance of Aedes africanus in this biotope, and two isolations of virus from pools of this species, suggest that it was the principal vector in the main period of the outbreak. A third isolate was made from a pool of Ae. keniensis, a little-known species that was collected in the same biotope. Other known yellow fever vectors that were collected in the arid parts of the valley may have been involved at an earlier stage of the epidemic. Vervet monkeys and baboons were present in the outbreak area. Peridomestic mosquito species were absent but abundant at urban sites outside the outbreak area. The entomologic and epidemiologic evidence indicate that this was a sylvatic outbreak in which human cases were directly linked to the epizootic and were independent of other human cases. The region of the Kerio Valley is probably subject to recurrent wandering epizootics of yellow fever, although previous episodes of scattered human infection have gone unrecorded. The risk that the disease could emerge as an urban problem in Kenya should not be ignored.

A dengue fever/dengue hemorrhagic fever (DF/DHF) outbreak in Yap State caused by dengue-4 virus was confirmed serologically and by virus isolation from serum samples collected on each of three island groups. Most DF/DHF cases occurred during a three-month period between mid-May and early August 1995. Five fatal cases, three of which were in children between the ages of four and 11, occurred between June 20 and July 26. A serosurvey conducted in late August revealed anti-dengue IgM prevalence rates of 18% on Yap, 36% on Eauripik, and 6% on Woleai. The majority of residents (93-100%) on the three islands were positive for anti-dengue IgG antibodies, indicating widespread exposure to dengue viruses. The IgG titers indicative of secondary antibody response were noted on Eauripik (6.5%) and Woleai (17%), but were rare on Yap (0.7%). Entomologic investigations implicated the native mosquito species, Aedes hensilli, a member of the Scutellaris Group of Aedes (Stegomyia), as a previously unrecognized epidemic vector of dengue viruses. Aedes hensilli was the most abundant and widespread member of Ae. (Stegomyia) in Yap State, the only species of Ae. (Stegomyia) on Woleai, and the only mosquito species present on Eauripik. New distribution records for mosquito species are reported.

In the past 15 years, there has been a dramatic resurgence of dengue and dengue hemorrhagic fever worldwide, with increased frequency of epidemics and geographic expansion of both the mosquito vectors and the viruses. The reasons for this resurgence are not well understood, but include uncontrolled and unplanned urbanization, increased movement of people and viruses by airplane and lack of effective control of Aedes aegypti, the principal mosquito vector of dengue viruses. The recommended method for Ae. aegypti control during the past 20 years has been ultra-low volume (ULV) application of insecticides, a method which targets the adult mosquito. Lack of efficacy of the ULV approach led to a reevaluation of recommended strategies for prevention and control of epidemic dengue and ultimately, resulted in development and widespread use of community-based, integrated approaches to Ae. aegypti control. This chapter reviews the use of community participation for controlling Ae. aegypti via larval source reduction and critically discusses programs in four countries from the standpoint of effectiveness and sustainability. It is concluded that a combination of vertically structured centralized and community-based approaches should provide short-term success as well as long-term sustainability.

Dengue viruses are maintained in endemic transmission cycles in tropical urban areas where epidemics periodically occur. Until about 30 years ago, there were long intervals (10-40 years) between epidemics but they are now occurring in many areas at 3-5-year intervals. These epidemics are most likely caused by virus strains with different epidemic potential. Accompanying this increased frequency in epidemic activity has been a change in the disease pattern with cases of the severe form of dengue (dengue hemorrhagic fever) becoming much more common. The occurrence of these factors and the expanding geographic distribution of dengue hemorrhagic fever in the past 15 years have made it necessary to re-evaluate currently recommended methods for prevention and control. The result has been increasing emphasis on the development of effective sustainable Aedes aegypti control programs based on source reduction using community participation. A brief overview of global programs using this approach is presented with emphasis on the Puerto Rican program, one of the earliest developed.

During 1990 and 1991, adult mosquitoes were collected along the Ob River and its tributaries in western Siberia from approximately 51 degrees 18'N to 66 degrees 4'N. Fifteen virus strains were isolated from 74,196 mosquitoes tested in 1,874 pools. These included Tahyna virus from Aedes cataphylla-punctor subgroup (one) and Ae. excrucians (one), and Inkoo (INK) virus from Ae. communis (one), Ae. communis subgroup (one), Ae. hexodontus (two), Ae. punctor subgroup (two), Ae. punctor complex (one), and unidentified Aedes species (three). In addition, a single Ae. euedes yielded a strain of snowshoe hare (SSH) virus and a strain of Getah, an alphavirus. A Bunyamwera serogroup virus was isolated from Ae. excrucians. With the exception of the two isolates from a single mosquito, minimum infection rates among mosquito taxa ranged from 0.4 to 16.7 per 1,000. The INK virus isolates were widely distributed geographically; however, seven of the 10 isolates were from two sites north of the Arctic Circle. During 1991, sera from two mouse species, five vole species, and four shrew species were collected along the upper Ob River for serologic tests. The prevalence of neutralizing antibody to SSH virus in these sera was 80%. Prevalence rates in the four most abundant species were Apodemus agrarius, 73%; Clethrionomys rutilus, 71%; Microtus arvalis, 80%; and Sorex araneus, 91%. This is the first attempt to clarify the vector and vertebrate host relationships of California serogroup viruses in western Siberia.

Laboratory studies were carried out with two geographic strains of Aedes polynesiensis and one strain of Aedes aegypti to determine whether they could transmit Ross River virus (RRV). Both species were shown to be good vectors of RRV, but Ae. polynesiensis was the most susceptible. Ae. polynesiensis represents a new vector for this virus and the epidemiologic implications of RRV spread by both mosquito species are discussed.

The vector competence of geographic strains of Aedes albopictus and Ae. polynesiensis and Fiji strains of Ae. pseudoscutellaris and Ae. aegypti was assessed for Ross River (RR) virus, the etiologic agent of epidemic polyarthritis. Strains of Ae. polynesiensis from Fiji, Rarotonga, Somoa and Tahiti were the most susceptible to infection per os (MID50 less than or equal to 10(1.2) Vero cell plaque-forming units [PFU]/blood meal). Virus transmission data were variable, but all strains except the one from Fiji transmitted virus at 14 to 21 days postinfection. Shanghai and Hawaii Ae. albopictus and Fiji Ae. pseudoscutellaris were also highly susceptible to per os infection with RR virus (MID50 10(2.0) to 10(2.6) PFU). Singapore and Sri Lanka Ae. albopictus and Fiji Ae. aegypti were the least susceptible (MID50 10(4.0) to 10(4.2) PFU). With one exception, virus transmission rates for Ae. pseudoscutellaris and Ae. aegypti and the four strains of Ae. albopictus ranged from 52 to 100%. A total of 4,718 third- and fourth-instar larvae from the second gonotrophic cycle of potentially infected females were tested for RR virus in 39 pools. Infection rates in parental females ranged from 87 to 100% in Ae. albopictus, Ae. pseudoscutellaris and Ae. polynesiensis and 40 to 48% in Ae. aegypti. Virus was not isolated from larval progeny.

Entomological studies were carried out during a dengue hemorrhagic fever epidemic in Central Java in December 1976. Both Aedes aegypti and Aedes albopictus were widely distributed in Bantul, but the latter species was more abundant. Comparative studies on the vector competence of the two species showed that Ae. albopictus had a higher susceptibility than Ae. aegypti to oral infection with all four dengue serotypes. The two species were equally compentent in transmitting the Bantul strain of dengue 3 virus after parenteral infection. The data suggest that Ae. albopictus could have been an important vector in this epidemic, but no direct observations were obtained to define the respective contribution of either Ae. albopictus or Ae. aegypti.

A combination of virus infection and transmission experiments showed that a Houston, Texas strain of Aedes albopictus is a competent vector for dengue (DEN), yellow fever (YF) and Ross River (RR) viruses. However, at 14 days incubation, DEN virus infection rates in a Puerto Rican strain of Aedes aegypti were significantly higher for each of the four DEN serotypes, except DEN-1, than in Houston Ae. albopictus fed simultaneously on the same virus suspensions. The degree of correlation between disseminated DEN infection rates in Houston Ae. albopictus and transmission to an in vitro system ranged from 42 to 88% for the four DEN serotypes. No significant difference was noted in YF virus infection rates or transmission rates in the two mosquito species fed on the same virus suspensions and incubated for the same time period. Also, RR virus infection and transmission rates in Houston and Hawaiian strains of Ae. albopictus were generally comparable.