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Introduction: Dengue is a major public health challenge and a growing problem due to climate change. The release of Aedes aegypti mosquitoes infected with the intracellular bacterium Wolbachia is a novel form of vector control against dengue. However, there remains a need to evaluate the benefits of such an intervention at a large scale. In this paper, we evaluate the potential economic impact and cost-effectiveness of scaled Wolbachia deployments as a form of dengue control in Vietnam–targeted at the highest burden urban areas. Methods: Ten settings within Vietnam were identified as priority locations for potential future Wolbachia deployments (using a population replacement strategy). The effectiveness of Wolbachia deployments in reducing the incidence of symptomatic dengue cases was assumed to be 75%. We assumed that the intervention would maintain this effectiveness for at least 20 years (but tested this assumption in the sensitivity analysis). A cost-utility analysis and cost-benefit analysis were conducted. Results: From the health sector perspective, the Wolbachia intervention was projected to cost US$420 per disability-adjusted life year (DALY) averted. From the societal perspective, the overall cost-effectiveness ratio was negative, i.e. the economic benefits outweighed the costs. These results are contingent on the long-term effectiveness of Wolbachia releases being sustained for 20 years. However, the intervention was still classed as cost-effective across the majority of the settings when assuming only 10 years of benefits Conclusion: Overall, we found that targeting high burden cities with Wolbachia deployments would be a cost-effective intervention in Vietnam and generate notable broader benefits besides health gains. Author summary: Dengue is a major public health challenge and a growing problem due to climate change. The release of Aedes aegypti mosquitoes infected with the intracellular bacterium Wolbachia is a novel form of vector control against dengue. However, there remains a need to evaluate the health and economic benefits of such an intervention at a large scale, as well as its value for money. In this paper, we evaluate the potential economic impact and cost-effectiveness of scaled Wolbachia deployments as a form of dengue control in Vietnam–targeted at the highest burden urban areas. Ten settings within Vietnam were identified as priority locations for potential future Wolbachia deployments (using a population replacement strategy). We assumed that the effectiveness of Wolbachia deployments in reducing the incidence of symptomatic dengue cases would be 75%. We found that targeting high burden cities with Wolbachia deployments would be a cost-effective intervention in Vietnam and generate notable broader benefits besides health gains. Overall, this work highlights the value of investment in the scaled implementation of Wolbachia deployments as an effective and cost-effective tool for dengue control in Vietnam, and more generally for addressing the global challenge of dengue control. [ABSTRACT FROM AUTHOR]

This paper summarises the lessons learnt in dengue epidemiology, risk factors, and prevention in Singapore over the last half a century, during which Singapore evolved from a city of 1.9 million people to a highly urban globalised city-state with a population of 5.6 million. Set in a tropical climate, urbanisation among green foliage has created ideal conditions for the proliferation of Aedes aegypti and Aedes albopictus, the mosquito vectors that transmit dengue. A vector control programme, largely for malaria, was initiated as early as 1921, but it was only in 1966 that the Vector Control Unit (VCU) was established to additionally tackle dengue haemorrhagic fever (DHF) that was first documented in the 1960s. Centred on source reduction and public education, and based on research into the bionomics and ecology of the vectors, the programme successfully reduced the Aedes House Index (HI) from 48% in 1966 to <5% in the 1970s. Further enhancement of the programme, including through legislation, suppressed the Aedes HI to around 1% from the 1990s. The current programme is characterised by 4 key features: (i) proactive inter-epidemic surveillance and control that is stepped up during outbreaks; (ii) risk-based prevention and intervention strategies based on advanced data analytics; (iii) coordinated inter-sectoral cooperation between the public, private, and people sectors; and (iv) evidence-based adoption of new tools and strategies. Dengue seroprevalence and force of infection (FOI) among residents have substantially and continuously declined over the 5 decades. This is consistent with the observation that dengue incidence has been delayed to adulthood, with severity highest among the elderly. Paradoxically, the number of reported dengue cases and outbreaks has increased since the 1990s with record-breaking epidemics. We propose that Singapore's increased vulnerability to outbreaks is due to low levels of immunity in the population, constant introduction of new viral variants, expanding urban centres, and increasing human density. The growing magnitude of reported outbreaks could also be attributed to improved diagnostics and surveillance, which at least partially explains the discord between rising trend in cases and the continuous reduction in dengue seroprevalence. Changing global and local landscapes, including climate change, increasing urbanisation and global physical connectivity are expected to make dengue control even more challenging. The adoption of new vector surveillance and control tools, such as the Gravitrap and Wolbachia technology, is important to impede the growing threat of dengue and other Aedes-borne diseases. Author summary: A densely populated, highly urban tropical city-state with long-established populations of Aedes aegypti and Ae. albopictus mosquitoes, plus travel and trade links to all corners of the world, Singapore is ideally suited for dengue transmission. Singapore's experience and rich surveillance data provide important insights for an increasingly large number of territories at risk of dengue epidemics. Decades of vector control efforts, focused on source reduction and surveillance, have successfully lowered the vector population, with accompanying reductions in the resident population's seroprevalence to dengue. We propose that Singapore's vulnerability to outbreaks is due to low levels of immunity in the population, constant introduction of viral variants, expanding urban centres, and increasing human density. The discord between the rising trend in reported cases and falling seroprevalence could be at least partly attributed to improved diagnostics and surveillance. Singapore's evidence-based vector-control programme, which involves strong partnership between the public and private sectors, will continue to adapt to future challenges in this space. [ABSTRACT FROM AUTHOR]

Background: Over the past decades, several viral diseases transmitted by Aedes mosquitoes—dengue, chikungunya, Zika—have spread outside of tropical areas. To limit the transmission of these viruses and preserve human health, the use of mosquito traps has been developed as a complement or alternative to other vector control techniques. The objective of this work was to perform a systematic review of the existing scientific literature to assess the efficacy of interventions based on adult mosquito trap to control Aedes population densities and the diseases they transmit worldwide. Methods and findings: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review was conducted using the PubMed and Scopus databases. Among the 19 selected papers, lethal ovitraps were used in 16 studies, host-seeking female traps in 3 studies. Furthermore, 16 studies focused on the control of Ae. aegypti. Our review showed great heterogeneity in the indicators used to assess trap efficacy: e.g., the number of host-seeking females, the number of gravid females, the proportion of positive containers, the viral infection rate in female mosquitoes or serological studies in residents. Regardless of the type of studied traps, the results of various studies support the efficacy of mass trapping in combination with classical integrated vector control in reducing Aedes density. More studies with standardized methodology, and indicators are urgently needed to provide more accurate estimates of their efficacy. Conclusions: This review highlights gaps in the demonstration of the efficacy of mass trapping of mosquitoes in reducing viral transmission and disease. Thus, further large-scale cluster randomized controlled trials conducted in endemic areas and including epidemiological outcomes are needed to establish scientific evidence for the reduction of viral transmission risk by mass trapping targeting gravid and/or host-seeking female mosquitoes. Author summary: Over the past decades, several viral diseases transmitted by Aedes mosquitoes—dengue, chikungunya, Zika—have spread outside of tropical areas. To limit the transmission of these viruses and preserve environment and human health, the use of mosquito traps has been developed as a complement or alternative to other vector control techniques. This review support the efficacy of mass trapping in combination with classical integrated vector control on the reduction in mosquito vector populations within several weeks of deployment. However, this research highlights gaps in the demonstration of the efficacy of mass trapping of mosquitoes in reducing viral transmission and disease. Thus, further studies are needed to establish scientific evidence for the reduction of viral transmission risk by mass trapping targeting gravid and/or host-seeking female mosquitoes. [ABSTRACT FROM AUTHOR]

Harris County, TX, is the third most populous county in the USA and upon detection of arboviruses Harris County Public Health applies insecticides (e.g., pyrethroid-based Permanone 31–66) against adults of Culex quinquefasciatus to prevent disease transmission. Populations of Aedes aegypti, while not yet a target of public health control, are likely affected by pyrethroid exposure. As this species is a vector of emerging arboviruses, its resistance status to Permanone and the kdr mutations in the voltage-gated sodium channel (VGSC) associated with pyrethroid resistance were investigated. We examined females of known genotype at the V1016I and F1534C sites (N = 716) for their genotype at the 410 amino acid position in the VGSC, and for the influence of their kdr genotype on survival to Permanone at three different distances from the insecticide source in field tests. Most females (81.8%) had at least one resistant L allele at the 410 position, being the first report of the V410L mutation in Ae. aegypti for Texas. When only genotypes at the 410 position were analyzed, the LL genotype exhibited higher survivorship than VL or VV. Out of 27 possible tri-locus kdr genotypes only 23 were found. Analyses of the probability of survival of tri-locus genotypes and for the V410L genotype using a multivariate logistic regression model including area, distance, and genotype found significant interactions between distance and genotype. When only the most common tri-locus genotypes were analyzed (LL/II/CC, 48.2%; VL/II/CC, 19.1%; and VV/II/CC, 10.1%) genotype had no effect on survival, but significant interactions of distance and genotype were found. This indicated that the V410L kdr allele increased survival probability at certain distances. Genotypes did not differ in survivorship at 7.62-m, but LL/II/CC had higher survivorship than VL/II/CC at 15.24- and 22.86-m. The model also identified differences in survivorship among the operational areas investigated. Author summary: Preventing Aedes aegypti populations from spreading arboviruses in highly populated areas primarily relies upon chemical control with insecticides, such as pyrethroids, applied by public health agencies to target the female mosquito vector. However, the development of insecticide resistance in mosquito populations jeopardizes these vector control strategies. The impact of the different kdr mutations conferring resistance to pyrethroids on the survival of Ae. aegypti in the field is not fully understood. We previously found that two knockdown resistance (kdr) mutations in the voltage gated sodium channel (VGSC) did not increase survivorship in field cage tests despite their widespread presence and high frequency. In this paper, we report the first detection of the V410L kdr mutation in combination with the V1016I and F1534C genotypes. Most females were detected with kdr mutations at one, two or three of these sites in the VGSC. Genotyping females after insecticide application in field cage tests showed that the V410L mutations were associated with higher survivorship only at the 15.24- and 22.86-meter distances from the source of the spray application, as we observed that the LL/II/CC genotype had higher survivorship than the VL/II/CC genotype at these distances. [ABSTRACT FROM AUTHOR]

Introduction: In Colombia, organochloride, organophosphate, carbamate, and pyrethroid insecticides are broadly used to control Aedes aegypti populations. However, Colombian mosquito populations have shown variability in their susceptibility profiles to these insecticides, with some expressing high resistance levels. Materials and methods: In this study, we analyzed the susceptibility status of ten Colombian field populations of Ae. aegypti to two pyrethroids; permethrin (type-I pyrethroid) and lambda-cyhalothrin (type-II pyrethroid). In addition, we evaluated if mosquitoes pressured with increasing lambda-cyhalothrin concentrations during some filial generations exhibited altered allelic frequency of these kdr mutations and the activity levels of some metabolic enzymes. Results: Mosquitoes from all field populations showed resistance to lambda-cyhalothrin and permethrin. We found that resistance profiles could only be partially explained by kdr mutations and altered enzymatic activities such as esterases and mixed-function oxidases, indicating that other yet unknown mechanisms could be involved. The molecular and biochemical analyses of the most pyrethroid-resistant mosquito population (Acacías) indicated that kdr mutations and altered metabolic enzyme activity are involved in the resistance phenotype expression. Conclusions: In this context, we propose genetic surveillance of the mosquito populations to monitor the emergence of resistance as an excellent initiative to improve mosquito-borne disease control measures. Author summary: The main method of preventing Aedes-borne diseases such as dengue, Zika, and chikungunya is by targeting the primary mosquito vector, Aedes aegypti, with insecticides. However, the success of these vector control strategies is jeopardized by the widespread development of insecticide resistance in mosquito populations. Furthermore, the molecular mechanisms of insecticide resistance in Ae. aegypti are still not well understood, resulting in limited resistance mitigation and management strategies. In this paper, we found that resistance to some pyrethroid insecticides in different Colombian cities is associated with three allelic substitutions V419L, V1016I, and F1534C, on the voltage-gated sodium channel gene, known as kdr ('knock-down resistance') mutations, with all three mutations present in mosquitoes resistant to pyrethroids. The data also showed that kdr mutations are important in conferring low resistance levels, but after around 10-fold intensity, the allele frequencies don't change, indicating that other mechanisms contribute to the resistance. Thus, we found that mosquitoes under selective pressure with insecticides present also altered enzymatic activities such as esterases and mixed-function oxidases, indicating that kdr mutations and metabolic enzymes are involved in the resistance expression. The findings on the extent of insecticide resistance and the molecular mechanisms underpinning the problem will impact the surveillance, selection, and rational use of insecticides by local health authorities. [ABSTRACT FROM AUTHOR]

African populations of the mosquito Aedes aegypti are usually considered less susceptible to infection by human-pathogenic flaviviruses than globally invasive populations found outside Africa. Although this contrast has been well documented for Zika virus (ZIKV), it is unclear to what extent it is true for dengue virus (DENV), the most prevalent flavivirus of humans. Addressing this question is complicated by substantial genetic diversity among DENV strains, most notably in the form of four genetic types (DENV1 to DENV4), that can lead to genetically specific interactions with mosquito populations. Here, we carried out a survey of DENV susceptibility using a panel of seven field-derived Ae. aegypti colonies from across the African range of the species and a colony from Guadeloupe, French West Indies as non-African reference. We found considerable variation in the ability of African Ae. aegypti populations to acquire and replicate a panel of six DENV strains spanning the four DENV types. Although African Ae. aegypti populations were generally less susceptible than the reference non-African population from Guadeloupe, in several instances some African populations were equally or more susceptible than the Guadeloupe population. Moreover, the relative level of susceptibility between African mosquito populations depended on the DENV strain, indicating genetically specific interactions. We conclude that unlike ZIKV susceptibility, there is no clear-cut dichotomy in DENV susceptibility between African and non-African Ae. aegypti. DENV susceptibility of African Ae. aegypti populations is highly heterogeneous and largely governed by the specific pairing of mosquito population and DENV strain. Author summary: African populations of the mosquito Aedes aegypti are usually thought to be less likely to get infected by flaviviruses compared to Ae. aegypti mosquitoes found outside Africa. While this has been well-demonstrated for Zika virus, it is not clear if the same is true for dengue virus, which is the most common flavivirus in humans. Studying this is complicated by the strain diversity of dengue virus, including four main genetic types, potentially causing different interactions. In this study, we compared several mosquito populations and found that, in general, African mosquitoes were less likely to get infected by dengue virus compared to mosquitoes from outside Africa. However, in some cases, African mosquitoes were just as or even more likely to get infected. The specific strain of dengue virus also influenced how likely African mosquitoes were to get infected, showing that the relationship between African mosquitoes and dengue virus is complex. [ABSTRACT FROM AUTHOR]

Pyrethroid resistance in Aedes aegypti has become widespread after almost two decades of frequent applications to reduce the transmission of mosquito-borne diseases. Because few insecticide classes are available for public health use, insecticide resistance management (IRM) is proposed as a strategy to retain their use. A key hypothesis of IRM assumes that negative fitness is associated with resistance, and when insecticides are removed from use, susceptibility is restored. In Tapachula, Mexico, pyrethroids (PYRs) were used exclusively by dengue control programs for 15 years, thereby contributing to selection for high PYR resistance in mosquitoes and failure in dengue control. In 2013, PYRs were replaced by organophosphates—insecticides from a class with a different mode of action. To test the hypothesis that PYR resistance is reversed in the absence of PYRs, we monitored Ae. aegypti's PYR resistance from 2016 to 2021 in Tapachula. We observed significant declining rates in the lethal concentration 50 (LC50), for permethrin and deltamethrin. For each month following the discontinuation of PYR use by vector control programs, we observed increases in the odds of mosquitoes dying by 1.5% and 8.4% for permethrin and deltamethrin, respectively. Also, knockdown-resistance mutations (kdr) in the voltage-gated sodium channel explained the variation in the permethrin LC50s, whereas variation in the deltamethrin LC50s was only explained by time. This trend was rapidly offset by application of a mixture of neonicotinoid and PYRs by vector control programs. Our results suggest that IRM strategies can be used to reverse PYR resistance in Ae. aegypti; however, long-term commitment by operational and community programs will be required for success. Author summary: The mosquito Aedes aegypti is the principal urban vector of the viruses that cause three globally significant diseases: dengue fever, chikungunya, and Zika fever, for which vaccines and effective treatments are currently absent. The only way to control dengue, chikungunya, and Zika fever outbreaks is to diminish vector populations. During epidemics, the most frequent way of targeting adult mosquitoes is outdoor spatial spraying of insecticides. Control of Ae. aegypti is difficult because limited insecticide classes are available for public health, leading to operational practices that overuse single molecules for long periods of time, imposing great selection pressure on mosquito populations for insecticide resistance. Insecticide resistance management (IRM) is proposed as a strategy to prevent resistance and avoid depleting the susceptibility resource in mosquito populations. IRM strategies assume that alternation of insecticides with different toxicological modes of action will prevent the selection of resistance. Unfortunately, very few field evaluations have reported IRM schemes to control Ae. aegypti. In our study, the exclusive use of pyrethroids in vector control programs in Mexico from 1999 to 2013, led in the selection of knockdown resistance (kdr) to pyrethroid insecticides. To address this issue, vector control programs temporarily phased out pyrethroids from 2013 to 2019, substituting them with an insecticide class with a different mode of action: organophosphates (OPs). During six years, we monitored pyrethroid resistance in 24 mosquito populations from Tapachula, Mexico. We show that discontinuing pyrethroids for six years led in pyrethroid resistance reversal in Ae. aegypti in the field. However, high levels of pyrethroid resistance continue to jeopardize operational application, necessitating longer periods of pyrethroid cessation and novel IRM strategies to achieve lower resistance thresholds. [ABSTRACT FROM AUTHOR]

Background: The wMel strain of Wolbachia has been successfully introduced into Aedes aegypti mosquitoes and has been shown to reduce the transmission of dengue and other Aedes-borne viruses. Here we report the entomological results from phased, large-scale releases of Wolbachia infected Ae. aegypti mosquitoes throughout three contiguous cities located in the Aburrá Valley, Colombia. Methodology/principal findings: Local wMel Wolbachia-infected Ae. aegypti mosquitoes were generated and then released in an initial release pilot area in 2015–2016, which resulted in the establishment of Wolbachia in the local mosquito populations. Subsequent large-scale releases, mainly involving vehicle-based releases of adult mosquitoes along publicly accessible roads and streets, were undertaken across 29 comunas throughout Bello, Medellín and Itagüí Colombia between 2017–2022. In 9 comunas these were supplemented by egg releases that were undertaken by staff or community members. By the most recent monitoring, Wolbachia was found to be stable and established at consistent levels in local mosquito populations (>60% prevalence) in the majority (67%) of areas. Conclusion: These results, from the largest contiguous releases of wMel Wolbachia mosquitoes to date, highlight the operational feasibility of implementing the method in large urban settings. Based on results from previous studies, we expect that Wolbachia establishment will be sustained long term. Ongoing monitoring will confirm Wolbachia persistence in local mosquito populations and track its establishment in the remaining areas. Author summary: The introduction of the naturally occurring wMel Wolbachia strain into Aedes aegypti mosquitoes has been shown to reduce the ability of the mosquitoes to transmit dengue and other viruses. Following engagement with communities to gain acceptance and support, a series of large-scale releases of Ae. aegypti mosquitoes that contained wMel Wolbachia, were undertaken across the cities of Bello, Medellín and Itagüí in Colombia. These releases were undertaken under operational conditions with the aim of rapidly scaling the intervention in response to the Zika virus crisis. Mosquito populations were monitored during and after releases to determine the levels of Wolbachia and whether it persisted in the local mosquitoes. Wolbachia was found to be stable and established at consistent levels in local mosquito populations in the majority of areas. On-going monitoring in these areas will determine whether Wolbachia persists and also whether it establishes at a high level in the remaining areas. This intervention forms the basis of an epidemiological study to assess the impact of operational deployment of wMel Wolbachia on the reduction of the incidence of notified dengue cases and virologically-confirmed dengue. [ABSTRACT FROM AUTHOR]

Aedes aegypti is the vector of viruses such as chikungunya, dengue, yellow fever and Zika that have a critical impact on human health. Control of adult mosquitoes is widely done using pyrethroids, but resistance has reduced the effectiveness of this class of insecticides. Resistance to pyrethroids in mosquitoes is commonly due to mutations in the voltage-gated sodium channel (Vgsc) gene (these mutations are known as knockdown resistance, kdr). In the Americas and the Caribbean, the most common kdr alleles are 410L+1016I+1534C and 1534C. In this study, we conducted a population cage experiment to evaluate changes in the allele and genotype frequencies of the 410L+1016I+1534C allele by crossing two congenic strains; one carrying the 410L+1016I+1534C and another with the 1534C allele. Changes in allele frequencies were measured over 10 generations in the absence of insecticide exposure. We also applied one cycle of selection with deltamethrin at F9 to evaluate the changes in allele and genotype frequencies. Our findings indicate that fitness costs were higher with the 410L+1016I+1534C allele, relative to the 1534C allele, in the absence of deltamethrin exposure, but that the 410L+1016I+1534C allele provides a stronger advantage when exposed to deltamethrin relative to the 1534C allele. Changes in genotype frequencies were not in Hardy-Weinberg equilibrium and could not be explained by drift. Our results suggest the diametrically opposed fitness costs in the presence and absence of insecticides is a reason for the variations in frequencies between the 410L+1016I+1534C and 1534C alleles in field populations. Author summary: Insecticide resistance limits our ability to control vectors of human diseases. Resistance to widely used pyrethroid insecticides can occur by mutations in the voltage gated sodium channel (Vgsc) and alleles with these mutations are collectively known as knockdown resistance (kdr). The frequency of resistance alleles is driven by selection with pyrethroid insecticides, but kdr alleles decrease in frequency in the absence of insecticide. The relative fitness of different kdr alleles to each other is largely unknown. We show that the 1534C allele is favored in the absence of pyrethroid, but that the 410L+1016I+1534C allele is favored when deltamethrin selection occurs. These results help to explain the relative frequency of these alleles that have been detected in field collections. [ABSTRACT FROM AUTHOR]

Background: Aedes aegypti, the main vector of dengue, yellow fever, and other arboviruses thrives in tropical and subtropical areas around the globe putting half of the world's population at risk. Despite aggressive efforts to control the transmission of those viruses, an unacceptable number of cases occur every year, emphasizing the need to develop new control strategies. Proposals for vector control focused on population suppression could offer a feasible alternative method to reduce disease transmission. The induction of extreme male-biased sex ratios has been hypothesized to be able to suppress or collapse a population, with previous experiments showing that stable expression of the male determining factor Nix in A. aegypti is sufficient to convert females into fertile males. Methodology/Principal findings: Here, we report on the conditional expression of Nix in transgenic A. aegypti under the control of the tetracycline-dependent (Tet-off) system, with the goal of establishing repressible sex distortion. A masculinization phenotype was observed in three of the seven transgenic lines with females exhibiting male-like long maxillary palps and most importantly, the masculinized females were unable to blood feed. Doxycycline treatment of the transgenic lines only partially restored the normal phenotype from the masculinized transgenic lines, while RT-qPCR analysis of early embryos or adults showed no correlation between the level of masculinization and ectopic Nix expression. Conclusions/Significance: While the conditional expression of Nix produced intersex phenotypes, the level of expression was insufficient to program full conversion. Modifications that increase both the level of activation (no tet) and the level of repression (with tet) will be necessary, as such this study represents one step forward in the development of genetic strategies to control vector-borne diseases via sex ratio distortion. Author summary: Morbidity and mortality from vector-borne diseases are an increasing public health problem. Approaches to reduce mosquito abundance to control pathogen transmission, known as population suppression, have been under development in an attempt to decrease the burden imposed by such diseases. One proposed strategy to collapse vector populations relies on skewing the sex ratio equilibrium to compromise fertility. Based on that, this research demonstrates the conditional expression of the male determining factor of the mosquito Ae. aegypti with the goal of establishing repressible sex distortion. Although full conversion of females into males was not achieved, a masculinization phenotype was observed in some transgenic lines, providing the foundation for the development of a new category of genetic vector control strategy via sex ratio distortion. [ABSTRACT FROM AUTHOR]

The Applying Wolbachia to Eliminate Dengue (AWED) trial was a parallel cluster randomised trial that demonstrated Wolbachia (wMel) introgression into Ae. aegypti populations reduced dengue incidence. In this predefined substudy, we compared between treatment arms, the relative abundance of Ae. aegypti and Ae. albopictus before, during and after wMel-introgression. Between March 2015 and March 2020, 60,084 BG trap collections yielded 478,254 Ae. aegypti and 17,623 Ae. albopictus. Between treatment arms there was no measurable difference in Ae. aegypti relative abundance before or after wMel-deployments, with a count ratio of 0.96 (95% CI 0.76, 1.21) and 1.00 (95% CI 0.85, 1.17) respectively. More Ae. aegypti were caught per trap per week in the wMel-intervention arm compared to the control arm during wMel deployments (count ratio 1.23 (95% CI 1.03, 1.46)). Between treatment arms there was no measurable difference in the Ae. albopictus population size before, during or after wMel-deployment (overall count ratio 1.10 (95% CI 0.89, 1.35)). We also compared insecticide resistance phenotypes of Ae. aegypti in the first and second years after wMel-deployments. Ae. aegypti field populations from wMel-treated and untreated arms were similarly resistant to malathion (0.8%), permethrin (1.25%) and cyfluthrin (0.15%) in year 1 and year 2 of the trial. In summary, we found no between-arm differences in the relative abundance of Ae. aegypti or Ae. albopictus prior to or after wMel introgression, and no between-arm difference in Ae. aegypti insecticide resistance phenotypes. These data suggest neither Aedes abundance, nor insecticide resistance, confounded the epidemiological outcomes of the AWED trial. Author summary: Dengue is a mosquito-borne viral disease and a major public health problem in the tropical and subtropical world. It is caused by any of the four dengue virus serotypes. In a previously published randomised clinical trial, called the AWED trial, we demonstrated that releases of Aedes aegypti mosquitoes infected with the insect bacterium Wolbachia can reduce the case incidence of dengue by 77%. In this current study, we compared the abundance of Ae. aegypti mosquitoes in the neighbourhoods where Wolbachia-infected mosquitoes were released versus the untreated neighbourhoods. This was important to do so that scientists could understand the mechanism for how Wolbachia releases reduced dengue incidence. Between March 2015 and March 2020, we did not observe any differences in Ae. aegypti abundance before or after Wolbachia-deployments in the AWED trial area. There was also no difference in the abundance of the related mosquito, Ae. albopictus, before, during or after wMel-deployment. We also compared insecticide resistance characteristics amongst Ae. aegypti in the first and second years after Wolbachia -deployments and found no difference between mosquitoes from Wolbachia-treated and untreated neighbourhoods. These data suggest neither Aedes abundance, nor insecticide resistance, were confounding sources to the epidemiological outcomes of the AWED trial. [ABSTRACT FROM AUTHOR]

The dengue virus affects millions of people every year worldwide, causing large epidemic outbreaks that disrupt people's lives and severely strain healthcare systems. In the absence of a reliable vaccine against dengue or an effective treatment to manage the illness in humans, most efforts to combat dengue infections have focused on preventing its vectors, mainly the Aedes aegypti mosquito, from flourishing across the world. These mosquito-control strategies need reliable disease activity surveillance systems to be deployed. Despite significant efforts to estimate dengue incidence using a variety of data sources and methods, little work has been done to understand the relative contribution of the different data sources to improved prediction. Additionally, scholarship on the topic had initially focused on prediction systems at the national- and state-levels, and much remains to be done at the finer spatial resolutions at which health policy interventions often occur. We develop a methodological framework to assess and compare dengue incidence estimates at the city level, and evaluate the performance of a collection of models on 20 different cities in Brazil. The data sources we use towards this end are weekly incidence counts from prior years (seasonal autoregressive terms), weekly-aggregated weather variables, and real-time internet search data. We find that both random forest-based models and LASSO regression-based models effectively leverage these multiple data sources to produce accurate predictions, and that while the performance between them is comparable on average, the former method produces fewer extreme outliers, and can thus be considered more robust. For real-time predictions that assume long delays (6–8 weeks) in the availability of epidemiological data, we find that real-time internet search data are the strongest predictors of dengue incidence, whereas for predictions that assume short delays (1–3 weeks), in which the error rate is halved (as measured by relative RMSE), short-term and seasonal autocorrelation are the dominant predictors. Despite the difficulties inherent to city-level prediction, our framework achieves meaningful and actionable estimates across cities with different demographic, geographic and epidemic characteristics. Author summary: As the incidence of infectious diseases like dengue continues to increase throughout the world, tracking their spread in real time poses a significant challenge to local and national health authorities. Accurate incidence data are often difficult to obtain as outbreaks emerge and unfold, both due the partial reach of serological surveillance (especially in rural areas), and due to delays in reporting, which result in post-hoc adjustments to what should have been real-time data. Thus, a range of 'nowcasting' tools have been developed to estimate disease trends, using different mathematical and statistical methodologies to fill the temporal data gap. Over the past several years, researchers have investigated how to best incorporate internet search data into predictive models, since these can be obtained in real-time. Still, most such models have been regression-based, and have tended to underperform in cases when epidemiological data are only available after long reporting delays. Moreover, in tropical countries, attention has increasingly turned from testing and applying models at the national level to models at higher spatial resolutions, such as states and cities. Here, we develop machine learning models based on both LASSO regression and on random forest ensembles, and proceed to apply and compare them across 20 cities in Brazil. We find that our methodology produces meaningful and actionable disease estimates at the city level with both underlying model classes, and that the two perform comparably across most metrics, although the ensemble method produces fewer outliers. We also compare model performance and the relative contribution of different data sources across diverse geographic, demographic and epidemic conditions. [ABSTRACT FROM AUTHOR]

Background: This systematic review aims to assess how different urbanisation patterns related to rapid urban growth, unplanned expansion, and human population density affect the establishment and distribution of Aedes aegypti and Aedes albopictus and create favourable conditions for the spread of dengue, chikungunya, and Zika viruses. Methods and findings: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review was conducted using the PubMed, Virtual Health Library, Cochrane, WHO Library Database (WHOLIS), Google Scholar, and and the Institutional Repository for Information Sharing (IRIS) databases. From a total of 523 identified studies, 86 were selected for further analysis, and 29 were finally analysed after applying all inclusion and exclusion criteria. The main explanatory variables used to associate urbanisation with epidemiological/entomological outcomes were the following: human population density, urban growth, artificial geographical space, urban construction, and urban density. Associated with the lack of a global definition of urbanisation, several studies provided their own definitions, which represents one of the study's limitations. Results were based on 8 ecological studies/models, 8 entomological surveillance studies, 7 epidemiological surveillance studies, and 6 studies consisting of spatial and predictive models. According to their focus, studies were categorised into 2 main subgroups, namely "Aedes ecology" and "transmission dynamics." There was a consistent association between urbanisation and the distribution and density of Aedes mosquitoes in 14 of the studies and a strong relationship between vector abundance and disease transmission in 18 studies. Human population density of more than 1,000 inhabitants per square kilometer was associated with increased levels of arboviral diseases in 15 of the studies. Conclusions: The use of different methods in the included studies highlights the interplay of multiple factors linking urbanisation with ecological, entomological, and epidemiological parameters and the need to consider a variety of these factors for designing effective public health approaches. Author summary: The expansion of urbanisation is often associated with the emergence and spread of vector-borne diseases by creating favourable conditions for the survival of Aedes species and the spread of dengue, chikungunya, and Zika viruses. This systematic review examined the relationship of urbanisation to the emergence and spread of Aedes mosquito–borne diseases and epidemics. From a total of 523 identified studies, 29 were included in the analysis. Studies were categorised into 2 main subgroups, namely "Aedes ecology" and "transmission dynamics" according to the main influence factors posed by urbanisation. Selected articles showed a clear relationship of urbanisation with distribution and density of Aedes mosquitoes and a robust association between vector production, human population density, and disease transmission. Differing definitions of 'urbanisation' and the interplay of numerous factors linking urbanisation with ecological, entomological, and epidemiological parameters highlight the need for a multidimensional perspective when assessing the impacts of rapid and unplanned urban expansion and when designing effective control programmes. [ABSTRACT FROM AUTHOR]

The mosquito Aedes aegypti is the primary vector of many disease-causing viruses, including dengue (DENV), Zika, chikungunya, and yellow fever. As consequences of climate change, we expect an increase in both global mean temperatures and extreme climatic events. When temperatures fluctuate, mosquito vectors will be increasingly exposed to temperatures beyond their upper thermal limits. Here, we examine how DENV infection alters Ae. aegypti thermotolerance by using a high-throughput physiological 'knockdown' assay modeled on studies in Drosophila. Such laboratory measures of thermal tolerance have previously been shown to accurately predict an insect's distribution in the field. We show that DENV infection increases thermal sensitivity, an effect that may ultimately limit the geographic range of the virus. We also show that the endosymbiotic bacterium Wolbachia pipientis, which is currently being released globally as a biological control agent, has a similar impact on thermal sensitivity in Ae. aegypti. Surprisingly, in the coinfected state, Wolbachia did not provide protection against DENV-associated effects on thermal tolerance, nor were the effects of the two infections additive. The latter suggests that the microbes may act by similar means, potentially through activation of shared immune pathways or energetic tradeoffs. Models predicting future ranges of both virus transmission and Wolbachia's efficacy following field release may wish to consider the effects these microbes have on host survival. Author summary: Changes in global climate, which include higher temperatures and more frequent extreme temperature events, are expected to cause dramatic shifts in the distributions of infectious diseases. The geographic range of the mosquito Aedes aegypti continues to expand, risking greater incidence of viral diseases including dengue (DENV), Zika, chikungunya, and yellow fever. One emerging solution to control these viruses is the release of the insect bacterium Wolbachia, whose infection in mosquitoes reduces virus transmission to humans. However, the effects of rising temperatures on the efficacy of this tool are unclear. Here, we studied whether DENV and Wolbachia can alter the thermal sensitivity of the mosquito Ae. aegypti by using a heat-based physiological assay. We demonstrate that, separately, DENV and Wolbachia infections increase mosquito thermal sensitivity, causing more rapid death when mosquitoes are exposed to extreme heat. The impacts of the microbes on mosquito thermal sensitivity were similar but not additive, suggesting they effect the mosquito in similar ways. Our work demonstrates that future global projections of DENV transmission risk and of Wolbachia's potential efficacy may need to consider the impact of these microbes on vector survival. [ABSTRACT FROM AUTHOR]

Background: Volatile pyrethroid insecticides, such as transfluthrin, have received increasing attention for their potent repellent activities in recent years for controlling human disease vectors. It has been long understood that pyrethroids kill insects by promoting activation and inhibiting inactivation of voltage-gated sodium channels. However, the mechanism of pyrethroid repellency remains poorly understood and controversial. Methodology/Principal findings: Here, we show that transfluthrin repels Aedes aegypti in a hand-in-cage assay at nonlethal concentrations as low as 1 ppm. Contrary to a previous report, transfluthrin does not elicit any electroantennogram (EAG) responses, indicating that it does not activate olfactory receptor neurons (ORNs). The 1S-cis isomer of transfluthrin, which does not activate sodium channels, does not elicit repellency. Mutations in the sodium channel gene that reduce the potency of transfluthrin on sodium channels decrease transfluthrin repellency but do not affect repellency by DEET. Furthermore, transfluthrin enhances DEET repellency. Conclusions/Significance: These results provide a surprising example that sodium channel activation alone is sufficient to potently repel mosquitoes. Our findings of sodium channel activation as the principal mechanism of transfluthrin repellency and potentiation of DEET repellency have broad implications in future development of a new generation of dual-target repellent formulations to more effectively repel a variety of human disease vectors. Author summary: Vector-transmitted human diseases, such as dengue fever, represent serious global health burdens. Pyrethroids, including transfluthrin, are widely used as insecticides and repellents due to their low mammalian toxicity and relatively benign environmental impact. Pyrethroids target voltage-gated sodium channels for their insecticidal action. However, the mechanism of pyrethroid repellency remains unclear and controversial. Insect repellency is traditionally thought to be mediated by olfactory receptors. We made two important discoveries in this study, showing that transfluthrin repellency is via activation of sodium channels and transfluthrin enhances DEET repellency. Discovery of sodium channel activation as a major mechanism of pyrethroid repellency has broad significance in insect olfaction study, repellents development, and control of human disease vectors. [ABSTRACT FROM AUTHOR]