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The intention-to-treat (ITT) analysis of the Applying Wolbachia to Eliminate Dengue (AWED) trial estimated a protective efficacy of 77.1% for participants resident in areas randomised to receive releases of wMel-infected Aedes aegypti mosquitoes, an emerging dengue preventive intervention. The limiting assumptions of ITT analyses in cluster randomised trials and the mobility of mosquitoes and humans across cluster boundaries indicate the primary analysis is likely to underestimate the full public health benefit. Using spatiotemporally-resolved data on the distribution of Wolbachia mosquitoes and on the mobility of AWED participants (n = 6306), we perform complier-restricted and per-protocol re-examinations of the efficacy of the Wolbachia intervention. Increased intervention efficacy was estimated in all analyses by the refined exposure measures. The complier-restricted analysis returned an estimated efficacy of 80.7% (95% CI 65.9, 89.0) and the per-protocol analysis estimated 82.7% (71.7, 88.4) efficacy when comparing participants with an estimated wMel exposure of ≥ 80% compared to those with

The intention-to-treat (ITT) analysis of the Applying Wolbachia to Eliminate Dengue (AWED) trial estimated a protective efficacy of 77.1% for participants resident in areas randomised to receive releases of wMel-infected Aedes aegypti mosquitoes, an emerging dengue preventive intervention. The limiting assumptions of ITT analyses in cluster randomised trials and the mobility of mosquitoes and humans across cluster boundaries indicate the primary analysis is likely to underestimate the full public health benefit. Using spatiotemporally-resolved data on the distribution of Wolbachia mosquitoes and on the mobility of AWED participants (n = 6306), we perform complier-restricted and per-protocol re-examinations of the efficacy of the Wolbachia intervention. Increased intervention efficacy was estimated in all analyses by the refined exposure measures. The complier-restricted analysis returned an estimated efficacy of 80.7% (95% CI 65.9, 89.0) and the per-protocol analysis estimated 82.7% (71.7, 88.4) efficacy when comparing participants with an estimated wMel exposure of ≥ 80% compared to those with <20%. These reanalyses demonstrate how human and mosquito movement can lead to underestimation of intervention effects in trials of vector interventions and indicate that the protective efficacy of Wolbachia is even higher than reported in the primary trial results. [ABSTRACT FROM AUTHOR]

Children contribute to one-half of the total painful rabies mortalities in India. The state-of-the-art rabies mortality averting strategies need exploration for the effective implementation of pre-exposure prophylaxis (PrEP) in India. This study reports on the economic evaluation of various PrEP and post-exposure prophylaxis (PEP) strategies to avert rabies mortalities in school-aged children in India. A decision tree model has been developed for children in the age group of 5–15 years to evaluate various PrEP + PEP and PEP only regimens. The 2-site intradermal regimen administered on day zero and seven was chosen as the intervention [PrEP (I)]. ICER was calculated from the quasi-societal and quasi-health systems' perspectives for the base case analysis, along with one-way sensitivity, and scenario analyses for each regimen. The incremental DALYs averted per million population with the implementation of PrEP (I) ranged between 451 and 85,069 in 2020. The ICER was reported in the range of USD 384–352/DALY averted (non-dominant) in comparison to PEP regimens from a quasi-societal perspective. PrEP (I) is reported to be 'very cost effective' in comparison with PEP regimens from the quasi-societal and quasi-health systems' perspectives and reduce deaths by up to 89.9%. This study concludes that the PrEP (I) regimen is a cost-effective and life-saving strategy to avert painful mortalities due to rabies in school-aged children in India. [ABSTRACT FROM AUTHOR]

Releases of Wolbachia (wMel)-infected Aedes aegypti mosquitoes significantly reduced the incidence of virologically confirmed dengue in a previous cluster randomised trial in Yogyakarta City, Indonesia. Following the trial, wMel releases were extended to the untreated control areas, to achieve city-wide coverage of Wolbachia. In this predefined analysis, we evaluated the impact of the wMel deployments in Yogyakarta on dengue hemorrhagic fever (DHF) case notifications and on the frequency of perifocal insecticide spraying by public health teams. Monthly counts of DHF cases notified to the Yogyakarta District Health Office between January 2006 and May 2022 were modelled as a function of time-varying local wMel treatment status (fully- and partially-treated vs untreated, and by quintile of wMel prevalence). The frequency of insecticide fogging in wMel-treated and untreated areas was analysed using negative binomial regression. Notified DHF incidence was 83% lower in fully treated vs untreated periods (IRR 0.17 [95% CI 0.14, 0.20]), and 78% lower in areas with 80–100% wMel prevalence compared to areas with 0–20% wMel (IRR 0.23 [0.17, 0.30]). A similar intervention effect was observed at 60–80% wMel prevalence as at 80–100% prevalence (76% vs 78% efficacy, respectively). Pre-intervention, insecticide fogging occurred at similar frequencies in areas later randomised to wMel-treated and untreated arms of the trial. After wMel deployment, fogging occurred significantly less frequently in treated areas (IRR 0.17 [0.10, 0.30]). Deployments of wMel-infected Aedes aegypti mosquitoes resulted in an 83% reduction in the application of perifocal insecticide spraying, consistent with lower dengue case notifications in wMel-treated areas. These results show that the Wolbachia intervention effect demonstrated previously in a cluster randomised trial was also measurable from routine surveillance data. [ABSTRACT FROM AUTHOR]

Dengue has been endemic in Yogyakarta, Indonesia for decades. Here, we report the dengue epidemiology, entomology, and virology in Yogyakarta in 2016–2017, prior to the commencement of the Applying Wolbachia to Eliminate Dengue (AWED) randomized trial. Dengue epidemiological data were compiled and blood samples from dengue-suspected patients were tested for dengue virus (DENV). Ae. aegypti mosquito samples were caught from the field using BG-Sentinel traps and tested for the presence of DENV infection. Sequencing of the DENV E gene was used to determine the phylogeny and genotypes of circulating DENV. Within the last decade, the 2016–2017 dengue incidence was considered very high. Among the 649 plasma samples collected between March 2016–February 2017; and 36,910 mosquito samples collected between December 2016–May 2017, a total of 197 and 38 samples were DENV-positive by qRT-PCR, respectively. All four DENV serotypes were detected, with DENV-3 (n = 88; 44.67%) and DENV-1 (n = 87; 44.16%) as the predominant serotype, followed by DENV-4 (n = 12; 6.09%) and DENV-2 (n = 10; 5.08%). The Yogyakarta DENV-1 isolates were classified into Genotype I and IV, while DENV-2, DENV-3, and DENV-4 isolates were classified into the Cosmopolitan genotype, Genotype I, and Genotype II, respectively. Yogyakarta DENV isolates were closely related to Indonesian strains from neighboring Javanese cities, consistent with the endemic circulation of DENV on this highly populous island. Our study provides comprehensive baseline information on the DENV population genetic characteristics in Yogyakarta, which are useful as baseline data for the AWED trial and the future DENV surveillance in the city in the presence of a Wolbachia -infected Ae. aegypti population. • Dengue has been endemic in Yogyakarta, Indonesia for decades. • Introgression of Wolbachia -infected Ae. aegypti reduces dengue cases in the city. • We studied the molecular epidemiology of dengue in the city prior to the trial. • We obtain the epidemiological, entomological, and virological data. • The data provide baseline information for monitoring the Wolbachia technology. [ABSTRACT FROM AUTHOR]

Background: Releases of Wolbachia ( w Mel)-infected Aedes aegypti mosquitoes significantly reduced the incidence of virologically confirmed dengue in a previous cluster randomised trial in Yogyakarta City, Indonesia. Following the trial, w Mel releases were extended to the untreated control areas, to achieve city-wide coverage of Wolbachia., Objective: In this predefined analysis, we evaluated the impact of the wMel deployments in Yogyakarta on dengue hemorrhagic fever (DHF) case notifications and on the frequency of perifocal insecticide spraying by public health teams., Methods: Monthly counts of DHF cases notified to the Yogyakarta District Health Office between January 2006 and May 2022 were modelled as a function of time-varying local wMel treatment status (fully- and partially-treated vs untreated, and by quintile of wMel prevalence). The frequency of insecticide fogging in wMel-treated and untreated areas was analysed using negative binomial regression., Results: Notified DHF incidence was 83% lower in fully treated vs untreated periods (IRR 0.17 [95% CI 0.14, 0.20]), and 78% lower in areas with 80-100% wMel prevalence compared to areas with 0-20% w Mel (IRR 0.23 [0.17, 0.30]). A similar intervention effect was observed at 60-80% wMel prevalence as at 80-100% prevalence (76% vs 78% efficacy, respectively). Pre-intervention, insecticide fogging occurred at similar frequencies in areas later randomised to wMel-treated and untreated arms of the trial. After w Mel deployment, fogging occurred significantly less frequently in treated areas (IRR 0.17 [0.10, 0.30])., Conclusions: Deployments of w Mel-infected Aedes aegypti mosquitoes resulted in an 83% reduction in the application of perifocal insecticide spraying, consistent with lower dengue case notifications in wMel-treated areas. These results show that the Wolbachia intervention effect demonstrated previously in a cluster randomised trial was also measurable from routine surveillance data.