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The introduction of the bacterium Wolbachia (wMel strain) into Aedes aegypti mosquitoes reduces their capacity to transmit dengue and other arboviruses. Evidence of a reduction in dengue case incidence following field releases of wMel-infected Ae. aegypti has been reported previously from a cluster randomised controlled trial in Indonesia, and quasi-experimental studies in Indonesia and northern Australia. Following pilot releases in 2015-2016 and a period of intensive community engagement, deployments of adult wMel-infected Ae. aegypti mosquitoes were conducted in Niterói, Brazil during 2017-2019. Deployments were phased across four release zones, with a total area of 83 km2 and a residential population of approximately 373,000. A quasi-experimental design was used to evaluate the effectiveness of wMel deployments in reducing dengue, chikungunya and Zika incidence. An untreated control zone was pre-defined, which was comparable to the intervention area in historical dengue trends. The wMel intervention effect was estimated by controlled interrupted time series analysis of monthly dengue, chikungunya and Zika case notifications to the public health surveillance system before, during and after releases, from release zones and the control zone. Three years after commencement of releases, wMel introgression into local Ae. aegypti populations was heterogeneous throughout Niterói, reaching a high prevalence (>80%) in the earliest release zone, and more moderate levels (prevalence 40-70%) elsewhere. Despite this spatial heterogeneity in entomological outcomes, the wMel intervention was associated with a 69% reduction in dengue incidence (95% confidence interval 54%, 79%), a 56% reduction in chikungunya incidence (95%CI 16%, 77%) and a 37% reduction in Zika incidence (95%CI 1%, 60%), in the aggregate release area compared with the pre-defined control area. This significant intervention effect on dengue was replicated across all four release zones, and in three of four zones for chikungunya, though not in individual release zones for Zika. We demonstrate that wMel Wolbachia can be successfully introgressed into Ae. aegypti populations in a large and complex urban setting, and that a significant public health benefit from reduced incidence of Aedes-borne disease accrues even where the prevalence of wMel in local mosquito populations is moderate and spatially heterogeneous. These findings are consistent with the results of randomised and non-randomised field trials in Indonesia and northern Australia, and are supportive of the Wolbachia biocontrol method as a multivalent intervention against dengue, chikungunya and Zika.

Mosquito blood-feeding behavior is a key determinant of the epidemiology of dengue viruses (DENV), the most-prevalent mosquitoborne viruses. However, despite its importance, how DENV infection influences mosquito blood-feeding and, consequently, transmission remains unclear. Here, we developed a high-resolution, video-based assay to observe the blood-feeding behavior of Aedes aegypti mosquitoes on mice. We then applied multivariate analysis on the high-throughput, unbiased data generated from the assay to ordinate behavioral parameters into complex behaviors. We showed that DENV infection increases mosquito attraction to the host and hinders its biting efficiency, the latter resulting in the infected mosquitoes biting more to reach similar blood repletion as uninfected mosquitoes. To examine how increased biting influences DENV transmission to the host, we established an in vivo transmission model with immuno-competent mice and demonstrated that successive short probes result in multiple transmissions. Finally, to determine how DENV-induced alterations of host-seeking and biting behaviors influence dengue epidemiology, we integrated the behavioral data within a mathematical model. We calculated that the number of infected hosts per infected mosquito, as determined by the reproduction rate, tripled when mosquito behavior was influenced by DENV infection. Taken together, this multidisciplinary study details how DENV infection modulates mosquito blood-feeding behavior to increase vector capacity, proportionally aggravating DENV epidemiology. By elucidating the contribution of mosquito behavioral alterations on DENV transmission to the host, these results will inform epidemiological modeling to tailor improved interventions against dengue.

Dengue, caused by dengue virus (DENV) infection, is a public health problem worldwide. Although DENV pathogenesis has not yet been fully elucidated, the inflammatory response is a hallmark feature in severe DENV infection. Although vitamin D (vitD) can promote the innate immune response against virus infection, no studies have evaluated the effects of vitD on DENV infection, dendritic cells (DCs), and inflammatory response regulation. This study aimed to assess the impact of oral vitD supplementation on DENV-2 infection, Toll-like receptor (TLR) expression, and both pro- and anti-inflammatory cytokine production in monocyte-derived DCs (MDDCs). To accomplish this, 20 healthy donors were randomly divided into two groups and received either 1000 or 4000 international units (IU)/day of vitD for 10 days. During pre- and post-vitD supplementation, peripheral blood samples were taken to obtain MDDCs, which were challenged with DENV-2. We found that MDDCs from donors who received 4000 IU/day of vitD were less susceptible to DENV-2 infection than MDDCs from donors who received 1000 IU/day of vitD. Moreover, these cells showed decreased mRNA expression of TLR3, 7, and 9; downregulation of IL-12/IL-8 production; and increased IL-10 secretion in response to DENV-2 infection. In conclusion, the administration of 4000 IU/day of vitD decreased DENV-2 infection. Our findings support a possible role of vitD in improving the innate immune response against DENV. However, further studies are necessary to determine the role of vitD on DENV replication and its innate immune response modulation in MDDCs.

CELADEN was a randomized placebo-controlled trial of 50 patients with confirmed dengue fever to evaluate the efficacy and safety of celgosivir (A study registered at ClinicalTrials.gov, number NCT01619969). Celgosivir was given as a 400 mg loading dose and 200 mg bid (twice a day) over 5 days. Replication competent virus was measured by plaque assay and compared to reverse transcription quantitative PCR (qPCR) of viral RNA. Pharmacokinetics (PK) correlations with viremia, immunological profiling, next generation sequence (NGS) analysis and hematological data were evaluated as exploratory endpoints here to identify possible signals of pharmacological activity. Viremia by plaque assay strongly correlated with qPCR during the first four days. Immunological profiling demonstrated a qualitative shift in T helper cell profile during the course of infection. NGS analysis did not reveal any prominent signature that could be associated with drug treatment; however the phylogenetic spread of patients' isolates underlines the importance of strain variability that may potentially confound interpretation of dengue drug trials conducted during different outbreaks and in different countries. Celgosivir rapidly converted to castanospermine (Cast) with mean peak and trough concentrations of 5727 ng/mL (30.2 μM) and 430 ng/mL (2.3 μM), respectively and cleared with a half-life of 2.5 (± 0.6) hr. Mean viral log reduction between day 2 and 4 (VLR2-4) was significantly greater in secondary dengue than primary dengue (p = 0.002). VLR2-4 did not correlate with drug AUC but showed a trend of greater response with increasing Cmin. PK modeling identified dosing regimens predicted to achieve 2.4 to 4.5 times higher Cmin. than in the CELADEN trial for only 13% to 33% increase in overall dose. A small, non-statistical trend towards better outcome on platelet nadir and difference between maximum and minimum hematocrit was observed in celgosivir-treated patients with secondary dengue infection. Optimization of the dosing regimen and patient stratification may enhance the ability of a clinical trial to demonstrate celgosivir activity in treating dengue fever based on hematological endpoints. A new clinical trial with a revised dosing regimen is slated to start in 2016 (NCT02569827). Furthermore celgosivir's potential value for treatment of other flaviruses such as Zika virus should be investigated urgently. ClinicalTrials.gov NCT01619969.

Vaccine efficacy (VE) estimates are crucial for assessing the suitability of dengue vaccine candidates for public health implementation, but efficacy trials are subject to a known bias to estimate VE toward the null if heterogeneous exposure is not accounted for in the analysis of trial data. In light of many well-characterized sources of heterogeneity in dengue virus (DENV) transmission, our goal was to estimate the potential magnitude of this bias in VE estimates for a hypothetical dengue vaccine. To ensure that we realistically modeled heterogeneous exposure, we simulated city-wide DENV transmission and vaccine trial protocols using an agent-based model calibrated with entomological and epidemiological data from long-term field studies in Iquitos, Peru. By simulating a vaccine with a true VE of 0.8 in 1,000 replicate trials each designed to attain 90% power, we found that conventional methods underestimated VE by as much as 21% due to heterogeneous exposure. Accounting for the number of exposures in the vaccine and placebo arms eliminated this bias completely, and the more realistic option of including a frailty term to model exposure as a random effect reduced this bias partially. We also discovered a distinct bias in VE estimates away from the null due to lower detectability of primary DENV infections among seronegative individuals in the vaccinated group. This difference in detectability resulted from our assumption that primary infections in vaccinees who are seronegative at baseline resemble secondary infections, which experience a shorter window of detectable viremia due to a quicker immune response. This resulted in an artefactual finding that VE estimates for the seronegative group were approximately 1% greater than for the seropositive group. Simulation models of vaccine trials that account for these factors can be used to anticipate the extent of bias in field trials and to aid in their interpretation.

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. 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. 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). 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. ClinicalTrials.gov NCT01563640.

The implementation of vector control interventions and potential introduction new tools requires baseline data to evaluate their direct and indirect effects. The objective of the study is to present the seroprevalence of dengue infection in a cohort of children 0 to 15 years old followed during 2015 to 2016, the risk factors and the role of enhanced surveillance strategies in three urban sites (Merida, Ticul and Progreso) in Yucatan, Mexico. A cohort of school children and their family members was randomly selected in three urban areas with different demographic, social conditions and levels of transmission. We included results from 1,844 children aged 0 to 15 years. Serum samples were tested for IgG, NS1 and IgM. Enhanced surveillance strategies were established in schools (absenteeism) and cohort families (toll-free number). Seroprevalence in children 0 to 15 years old was 46.8 (CI 95% 44.1-49.6) with no difference by sex except in Ticul. Prevalence increased with age and was significantly lower in 0 to 5 years old (26.9%, 95% CI:18.4-35.4) compared with 6 to 8 years old (43.9%, 95% CI:40.1-47.7) and 9 to 15 years old (61.4%, 95% CI:58.0-64.8). Sharing the domestic space with other families increased the risk 1.7 times over the individual families that own or rented their house, while risk was significantly higher when kitchen and bathroom were outside. Complete protection with screens in doors and windows decreased risk of infection. Seroprevalence was significantly higher in the medium and high risk areas. The prevalence of antibodies in children 0 to 15 years in three urban settings in the state of Yucatan describe the high exposure and the heterogenous transmission of dengue virus by risk areas and between schools in the study sites. The enhanced surveillance strategy was useful to improve detection of dengue cases with the coincident transmission of chikungunya and Zika viruses.

Dengue virus is transmitted by mosquitoes and has four serotypes. Cross-protection to other serotypes lasting for a few months is observed following infection with one serotype. There is evidence that low-affinity T and/or B cells from primary infections contribute to the severe syndromes often associated with secondary dengue infections. such pronounced immune-mediated enhancement suggests a dengue-specific pattern of immune cell activation. This study investigates the acute and early convalescent B cell response leading to the generation of cross-reactive and neutralizing antibodies following dengue infection. We assayed blood samples taken from dengue patients with primary or secondary infection during acute disease and convalescence and compared them to samples from patients presenting with non-dengue related fever. Dengue induced massive early plasmablast formation, which correlated with the appearance of polyclonal, cross-reactive IgG for both primary and secondary infection. Surprisingly, the contribution of IgG to the neutralizing titer 4-7 days after fever onset was more than 50% even after primary infection. Poly-reactive and virus serotype cross-reactive IgG are an important component of the innate response in humans during both primary and secondary dengue infection, and \"innate specificities\" seem to constitute part of the adaptive response in dengue. While of potential importance for protection during secondary infection, cross-reactive B cells will also compete with highly neutralizing B cells and possibly interfere with their development.

Background. Because infection with any of the 4 Dengue virus serotypes may elicit both protective neutralizing antibodies and nonneutralizing antibodies capable of enhancing subsequent heterotypic Dengue virus infections, the greatest risk for severe dengue occurs during a second, heterotypic Dengue virus infection. It remains unclear whether the replication of live attenuated vaccine viruses will be similarly enhanced when administered to Dengue-immune individuals. Methods. We recruited 36 healthy adults who had previously received a monovalent live Dengue virus vaccine 0.6–7.4 years earlier. Participants were assigned to 1 of 4 cohorts and were randomly chosen to receive placebo or a heterotypic vaccine. The level of replication, safety, and immunogenicity of the heterotypic vaccine virus was compared with that of Dengue virus immunologically naive vaccinees. Results. Vaccine virus replication and reactogenicity after monovalent Dengue virus vaccination in naive and heterotypically immune vaccinees was similar. In contrast to naive vaccinees, the antibody response in heterotypically immune vaccinees was broadly neutralizing and mimicked the response observed by natural secondary Dengue virus infection. Conclusions. Enhanced replication of these live attenuated Dengue virus vaccines was minimal in heterotypically immune vaccinees and suggests that the further evaluation of these candidate vaccines in populations with preexisting DENV immunity can proceed safely.

Dengue, caused by infection of any of four dengue virus serotypes (DENV-1 to DENV-4), is a mosquito-borne disease of major public health concern associated with significant morbidity, mortality, and economic cost, particularly in developing countries. Dengue incidence has increased 30-fold in the last 50 years and over 50% of the world’s population, in more than 100 countries, live in areas at risk of DENV infection. We reviews DENV biology, epidemiology, transmission dynamics including circulating serotypes and genotypes, the immune response, the pathogenesis of the disease as well as updated diagnostic methods, treatments, vector control and vaccine developments.