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      Reduced dengue incidence following deployments of Wolbachia-infected Aedes aegypti in Yogyakarta, Indonesia: a quasi-experimental trial using controlled interrupted time series analysis

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      Gates Open Research
      F1000 Research Limited
      Wolbachia, Aedes aegypti, dengue, vector-borne disease, mosquito release, quasi-experimental study, interrupted time series analysis, Indonesia, World Mosquito Program

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          Abstract

          Background: Ae. aegypti mosquitoes stably transfected with the intracellular bacterium Wolbachia pipientis ( wMel strain) have been deployed for biocontrol of dengue and related arboviral diseases in multiple countries. Field releases in northern Australia have previously demonstrated near elimination of local dengue transmission from Wolbachia-treated communities, and pilot studies in Indonesia have demonstrated the feasibility and acceptability of the method. We conducted a quasi-experimental trial to evaluate the impact of scaled Wolbachia releases on dengue incidence in an endemic setting in Indonesia.

          Methods: In Yogyakarta City, Indonesia, following extensive community engagement, wMel Wolbachia-carrying mosquitoes were released every two weeks for 13–15 rounds over seven months in 2016–17, in a contiguous 5 km 2 area (population 65,000). A 3 km 2 area (population 34,000) on the opposite side of the city was selected a priori as an untreated control area. Passive surveillance data on notified hospitalised dengue patients was used to evaluate the epidemiological impact of Wolbachia deployments, using controlled interrupted time-series analysis.

          Results: Rapid and sustained introgression of wMel Wolbachia into local Ae. aegypti populations was achieved. Thirty-four dengue cases were notified from the intervention area and 53 from the control area (incidence 26 vs 79 per 100,000 person-years) during 24 months following Wolbachia deployment. This corresponded in the regression model to a 73% reduction in dengue incidence (95% confidence interval 49%,86%) associated with the Wolbachia intervention. Exploratory analysis including 6 months additional post-intervention observations showed a small strengthening of this effect (30 vs 115 per 100,000 person-years; 76% reduction in incidence, 95%CI 60%,86%).

          Conclusions: We demonstrate a significant reduction in dengue incidence following successful introgression of Wolbachia into local Ae. aegypti populations in an endemic setting in Indonesia. These findings are consistent with previous field trials in northern Australia, and support the effectiveness of this novel approach for dengue control.

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          Most cited references16

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          Interrupted time series regression for the evaluation of public health interventions: a tutorial

          Abstract Interrupted time series (ITS) analysis is a valuable study design for evaluating the effectiveness of population-level health interventions that have been implemented at a clearly defined point in time. It is increasingly being used to evaluate the effectiveness of interventions ranging from clinical therapy to national public health legislation. Whereas the design shares many properties of regression-based approaches in other epidemiological studies, there are a range of unique features of time series data that require additional methodological considerations. In this tutorial we use a worked example to demonstrate a robust approach to ITS analysis using segmented regression. We begin by describing the design and considering when ITS is an appropriate design choice. We then discuss the essential, yet often omitted, step of proposing the impact model a priori. Subsequently, we demonstrate the approach to statistical analysis including the main segmented regression model. Finally we describe the main methodological issues associated with ITS analysis: over-dispersion of time series data, autocorrelation, adjusting for seasonal trends and controlling for time-varying confounders, and we also outline some of the more complex design adaptations that can be used to strengthen the basic ITS design.
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            Mapping global variation in dengue transmission intensity

            Intervention planning for dengue requires reliable estimates of dengue transmission intensity. However, current maps of dengue risk provide estimates of disease burden or the boundaries of endemicity rather than transmission intensity. We therefore developed a global high-resolution map of dengue transmission intensity by fitting environmentally driven geospatial models to geolocated force of infection estimates derived from cross-sectional serological surveys and routine case surveillance data. We assessed the impact of interventions on dengue transmission and disease using Wolbachia -infected mosquitoes and the Sanofi-Pasteur vaccine as specific examples. We predicted high transmission intensity in all continents straddling the tropics, with hot spots in South America (Colombia, Venezuela, and Brazil), Africa (western and central African countries), and Southeast Asia (Thailand, Indonesia, and the Philippines). We estimated that 105 [95% confidence interval (CI), 95 to 114] million dengue infections occur each year with 51 (95% CI, 32 to 66) million febrile disease cases. Our analysis suggests that transmission-blocking interventions such as Wolbachia , even at intermediate efficacy (50% transmission reduction), might reduce global annual disease incidence by up to 90%. The Sanofi-Pasteur vaccine, targeting only seropositive recipients, might reduce global annual disease incidence by 20 to 30%, with the greatest impact in high-transmission settings. The transmission intensity map presented here, and made available for download, may help further assessment of the impact of dengue control interventions and prioritization of global public health efforts.
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              Inhibition of Zika virus by Wolbachia in Aedes aegypti

              Through association with cases of microcephaly in 2015, Zika virus (ZIKV) has transitioned from a relatively unknown mosquito-transmitted pathogen to a global health emergency, emphasizing the need to improve existing mosquito control programs to prevent future disease outbreaks. The response to Zika must involve a paradigm shift from traditional to novel methods of mosquito control, and according to the World Health Organization should incorporate the release of mosquitoes infected with the bacterial endosymbiont Wolbachia pipientis. In our recent paper [Dutra, HLC et al., Cell Host & Microbe 2016] we investigated the potential of Wolbachia infections in Aedes aegypti to restrict infection and transmission of Zika virus recently isolated in Brazil. Wolbachia is now well known for its ability to block or reduce infection with a variety of pathogens in different mosquito species including the dengue (DENV), yellow fever, and chikungunya viruses, and malaria-causing Plasmodium, and consequently has great potential to control mosquito-transmitted diseases across the globe. Our results demonstrated that the wMel Wolbachia strain in Brazilian Ae. aegypti is a strong inhibitor of ZIKV infection, and furthermore appears to prevent transmission of infectious viral particles in mosquito saliva, which highlights the bacterium’s suitability for more widespread use in Zika control.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data CurationRole: InvestigationRole: MethodologyRole: Project AdministrationRole: Writing – Original Draft Preparation
                Role: ConceptualizationRole: Data CurationRole: InvestigationRole: MethodologyRole: Project AdministrationRole: Writing – Original Draft Preparation
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project AdministrationRole: Writing – Review & Editing
                Role: InvestigationRole: MethodologyRole: Writing – Review & Editing
                Role: Investigation
                Role: Data CurationRole: InvestigationRole: Visualization
                Role: Data CurationRole: InvestigationRole: Project AdministrationRole: Writing – Review & Editing
                Role: Data CurationRole: InvestigationRole: Visualization
                Role: InvestigationRole: MethodologyRole: Writing – Review & Editing
                Role: Investigation
                Role: Data CurationRole: InvestigationRole: Visualization
                Role: Investigation
                Role: Investigation
                Role: InvestigationRole: Methodology
                Role: Data CurationRole: Resources
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project Administration
                Role: Formal AnalysisRole: Writing – Review & Editing
                Role: Formal AnalysisRole: Writing – Review & Editing
                Role: ConceptualizationRole: MethodologyRole: Writing – Review & Editing
                Role: Data CurationRole: MethodologyRole: Software
                Role: Data CurationRole: MethodologyRole: Software
                Role: ConceptualizationRole: Funding AcquisitionRole: MethodologyRole: Writing – Review & Editing
                Role: Formal AnalysisRole: MethodologyRole: Writing – Original Draft Preparation
                Role: ConceptualizationRole: MethodologyRole: Writing – Original Draft Preparation
                Role: Formal AnalysisRole: MethodologyRole: VisualizationRole: Writing – Original Draft Preparation
                Role: ConceptualizationRole: Funding AcquisitionRole: MethodologyRole: Project AdministrationRole: Writing – Review & Editing
                Journal
                Gates Open Res
                Gates Open Res
                Gates Open Res
                Gates Open Research
                F1000 Research Limited (London, UK )
                2572-4754
                11 May 2020
                2020
                : 4
                : 50
                Affiliations
                [1 ]Centre of Tropical Medicine, Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
                [2 ]Department of Epidemiology Biostatistics and Public Health, Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
                [3 ]Institute of Vector Borne Disease, Monash University, Melbourne, Australia
                [4 ]Department of Paediatrics, Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
                [5 ]Yogyakarta City Health Office, Yogyakarta, Indonesia
                [6 ]Division of Epidemiology and Biostatistics, School of Public Health, University of California, Berkeley, Berkeley, USA
                [7 ]Centre for Statistical Methodology, London School of Hygiene & Tropical Medicine, London, UK
                [8 ]Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
                [9 ]Department of Health Policy and Management, Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
                [1 ]Department of Medical Entomology, Centre for Research in Infectious Diseases, Yaoundé, Cameroon
                [1 ]Entomology and Ecology Activity, Dengue Branch, Centers for Disease Control and Prevention, San Juan, Puerto Rico
                Author notes

                No competing interests were disclosed.

                Competing interests: No competing interests were disclosed.

                Competing interests: No competing interests were disclosed.

                Author information
                https://orcid.org/0000-0003-3517-613X
                https://orcid.org/0000-0001-7462-7904
                https://orcid.org/0000-0003-0674-4441
                https://orcid.org/0000-0002-4131-3615
                https://orcid.org/0000-0003-0485-5826
                Article
                10.12688/gatesopenres.13122.1
                7403856
                32803130
                283d1fd1-f1bf-49e1-977b-eb6befb9336c
                Copyright: © 2020 Indriani C et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 1 May 2020
                Funding
                Funded by: Tahija Foundation
                Funded by: Bill and Melinda Gates Foundation
                Award ID: OPP1180815
                This work was funded by the Tahija Foundation, Indonesia. WMP Global is funded in part by the Bill and Melinda Gates Foundation (OPP1180815).
                The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Articles

                wolbachia,aedes aegypti,dengue,vector-borne disease,mosquito release,quasi-experimental study,interrupted time series analysis,indonesia,world mosquito program

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