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Background Matings between male Aedes aegypti mosquitoes infected with w AlbB strain of Wolbachia and wildtype females yield non-viable eggs. We evaluated the efficacy of releasing w AlbB-infected Ae. aegypti male mosquitoes to suppress dengue. Methods We specified the protocol of a two-arm cluster-randomized test-negative controlled trial (cRCT) and emulated it using a nationally representative test-negative/positive database of individuals reporting for febrile illness to any public hospital, general practitioner or polyclinic. We retrospectively built a cohort of individuals who reside in Wolbachia locations vs a comparator control group who do not reside in Wolbachia locations, using a nationally representative database of all individuals whom report for febrile illness and were tested for dengue at the Environmental Health Institute/hospital laboratories/commercial diagnostic laboratories, through general practitioner clinic, polyclinic or public/private hospital from epidemiological week (EW) 1 2019 to EW26 2022. We emulated a constrained randomization protocol used in cRCTs to balance dengue risk between intervention and control arms in the pre-intervention period. We used the inverse probability weighting approach to further balance the intervention and control groups using a battery of algorithmically selected sociodemographic, environmental and anthropogenic variables. Intention-to-treat analyses were conducted to estimate the risk reduction of dengue given Wolbachia exposure. Results Intention-to-treat analyses revealed that, compared with controls, Wolbachia releases for 3, 6 and ≥12 months was associated to 47% (95% confidence interval: 25–69%), 44% (33–77%) and 61% (38–78%) protective efficacy against dengue, respectively. When exposed to ≥12 months of Wolbachia releases, protective efficacies ranged from 49% (13–72%) to 77% (60–94%) across years. The proportion of virologically confirmed dengue cases was lower overall in the intervention arm. Protective efficacies were found across all years, age and sex subgroups, with higher durations of Wolbachia exposure associated to greater risk reductions of dengue. Conclusion Results demonstrated that Wolbachia -mediated sterility can strengthen dengue control in tropical cities, where dengue burden is the greatest. [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]

Aedes (Stegomyia) aegypti, the principal global vector of dengue viruses, has differences in its susceptibility to dengue virus infection. We compared the global expression of genes in the midguts of Colombian Ae. aegypti dengue‐susceptible (Cali‐S) and dengue‐refractory (Cali‐MIB) field derived strains after ingesting either a sugarmeal, a bloodmeal, or a bloodmeal containing dengue virus serotype 2 (DENV‐2). Microarray‐based transcriptome analysis among treatments indicated a total of 4725 transcripts with differential expression between the two strains. Eleven genes were selected from different functional groups based on their significant up or down expression levels as well as reports in the literature suggesting they are associated with dengue virus elimination. We measured mRNA abundance of these 11 genes at 0, 8, 24, and 36 h postinfection using quantitative real time PCR (qPCR) to confirm the microarray results and assess any temporal patterns. Four genes were selected (Gram‐negative binding protein—GNBP [AAEL009176], Niemann Pick Type‐C2—NPC2 [AAEL015136], Keratinocyte lectin [AAEL009842], and Cathepsin‐b [AAEL007585]) for knockdown experiments using RNA interference (RNAi) methodology to determine the phenotype (DENV‐2 susceptible or refractory). Silencing GNBP, Cathepsin‐b and Keratinocyte lectin reduced the percentage of mosquitoes with disseminated virus in the Cali‐S strain to 8%, 20%, and 12% respectively compared with 96% in the controls. Silencing of NPC2 increased the percentage of mosquitos with disseminated virus infections in Cali‐MIB to 66% compared with 35% in the controls. This study provides insight into genes that may contribute to the Cali‐S susceptible and Cali‐MIB refractory phenotypes in Ae. aegypti. [ABSTRACT FROM AUTHOR]