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      Successful introgression of wMel Wolbachia into Aedes aegypti populations in Fiji, Vanuatu and Kiribati

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      PLOS Neglected Tropical Diseases
      Public Library of Science

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          Abstract

          Pacific Island countries have experienced periodic dengue, chikungunya and Zika outbreaks for decades. The prevention and control of these mosquito-borne diseases rely heavily on control of Aedes aegypti mosquitoes, which in most settings are the primary vector. Introgression of the intracellular bacterium Wolbachia pipientis ( wMel strain) into Ae. aegypti populations reduces their vector competence and consequently lowers dengue incidence in the human population. Here we describe successful area-wide deployments of wMel-infected Ae. aegypti in Suva, Lautoka, Nadi (Fiji), Port Vila (Vanuatu) and South Tarawa (Kiribati). With community support, weekly releases of wMel-infected Ae. aegypti mosquitoes for between 2 to 5 months resulted in wMel introgression in nearly all locations. Long term monitoring confirmed a high, self-sustaining prevalence of wMel infecting mosquitoes in almost all deployment areas. Measurement of public health outcomes were disrupted by the Covid19 pandemic but are expected to emerge in the coming years.

          Author summary

          For decades, dengue, Zika and chikungunya have been public health issues across the Pacific Island region. Aedes aegypti mosquitoes are considered most responsible for the transmission of dengue between people. The introduction of a bacteria called Wolbachia pipientis ( wMel strain) to these mosquitoes is known to reduce the transmission of these diseases. Herein, we describe the production and release of wMel-carrying Ae. aegypti mosquitoes into several Pacific Island cities, including Suva, Lautoka, and Nadi in Fiji, Port Vila in Vanuatu, and South Tarawa in Kiribati. With community support, these mosquitoes were released on a weekly basis for periods ranging from 2 to 5 months. The result was a widespread integration of the wMel bacteria into local mosquito populations. Long-term monitoring has shown that the wMel bacteria has been sustained at high levels in mosquitoes in nearly all of the areas where it was introduced. This innovative approach could potentially improve the way we combat mosquito-borne diseases, protecting communities in the Pacific Islands and beyond from the devastating effects of dengue, chikungunya, and Zika.

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          Successful establishment of Wolbachia in Aedes populations to suppress dengue transmission.

          Genetic manipulations of insect populations for pest control have been advocated for some time, but there are few cases where manipulated individuals have been released in the field and no cases where they have successfully invaded target populations. Population transformation using the intracellular bacterium Wolbachia is particularly attractive because this maternally-inherited agent provides a powerful mechanism to invade natural populations through cytoplasmic incompatibility. When Wolbachia are introduced into mosquitoes, they interfere with pathogen transmission and influence key life history traits such as lifespan. Here we describe how the wMel Wolbachia infection, introduced into the dengue vector Aedes aegypti from Drosophila melanogaster, successfully invaded two natural A. aegypti populations in Australia, reaching near-fixation in a few months following releases of wMel-infected A. aegypti adults. Models with plausible parameter values indicate that Wolbachia-infected mosquitoes suffered relatively small fitness costs, leading to an unstable equilibrium frequency <30% that must be exceeded for invasion. These findings demonstrate that Wolbachia-based strategies can be deployed as a practical approach to dengue suppression with potential for area-wide implementation.
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            The wMel Wolbachia strain blocks dengue and invades caged Aedes aegypti populations.

            Dengue fever is the most important mosquito-borne viral disease of humans with more than 50 million cases estimated annually in more than 100 countries. Disturbingly, the geographic range of dengue is currently expanding and the severity of outbreaks is increasing. Control options for dengue are very limited and currently focus on reducing population abundance of the major mosquito vector, Aedes aegypti. These strategies are failing to reduce dengue incidence in tropical communities and there is an urgent need for effective alternatives. It has been proposed that endosymbiotic bacterial Wolbachia infections of insects might be used in novel strategies for dengue control. For example, the wMelPop-CLA Wolbachia strain reduces the lifespan of adult A. aegypti mosquitoes in stably transinfected lines. This life-shortening phenotype was predicted to reduce the potential for dengue transmission. The recent discovery that several Wolbachia infections, including wMelPop-CLA, can also directly influence the susceptibility of insects to infection with a range of insect and human pathogens has markedly changed the potential for Wolbachia infections to control human diseases. Here we describe the successful transinfection of A. aegypti with the avirulent wMel strain of Wolbachia, which induces the reproductive phenotype cytoplasmic incompatibility with minimal apparent fitness costs and high maternal transmission, providing optimal phenotypic effects for invasion. Under semi-field conditions, the wMel strain increased from an initial starting frequency of 0.65 to near fixation within a few generations, invading A. aegypti populations at an accelerated rate relative to trials with the wMelPop-CLA strain. We also show that wMel and wMelPop-CLA strains block transmission of dengue serotype 2 (DENV-2) in A. aegypti, forming the basis of a practical approach to dengue suppression.
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              Efficacy of Wolbachia-infected mosquito deployments for the control of dengue

              Background: Aedes aegypti mosquitoes infected with Wolbachia pipientis ( w Mel strain) have reduced potential to transmit dengue viruses. Methods: We conducted a cluster randomised trial of deployments of w Mel-infected Ae. aegypti for control of dengue in Yogyakarta City, Indonesia. Twenty-four geographic clusters were randomly allocated to receive w Mel deployments as an adjunct to local mosquito control measures; or to continue with local mosquito control measures only. A test-negative design was used to measure efficacy. Study participants were persons 3–45 years old attending primary care clinics with acute undifferentiated fever. Laboratory testing identified virologically-confirmed dengue cases and test-negative controls. The primary endpoint was efficacy of w Mel in reducing the incidence of symptomatic, virologically-confirmed dengue, caused by any dengue virus serotype. Results: Following successful introgression of w Mel in intervention clusters, 8144 participants were enrolled; 3721 from w Mel-treated clusters and 4423 from untreated clusters. In the ITT analysis virologically-confirmed dengue occurred in 67 of 2905 (2.3%) participants in the w Mel-treated and 318 of 3401 (9.4%) in the untreated arm (OR 0.23, 95% CI, 0.15 to 0.35; P=0.004): protective efficacy of 77.1% (95% CI, 65.3 to 84.9). Protective efficacy was similar for the four serotypes. Hospitalisation for virologically-confirmed dengue was less frequent for participants resident in the w Mel-treated (13/2905, 2.8%) compared to the untreated arm (102/3401, 6.3%): protective efficacy 86.2% (95% CI, 66.2 to 94.3) Conclusions: w Mel introgression into Ae. aegypti populations was efficacious in reducing the incidence of symptomatic dengue, and also led to fewer dengue hospitalisations. Trial registration number: ClinicalTrials.gov Identifier: NCT03055585 and INA-A7OB6TW
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Writing – review & editing
                Role: Investigation
                Role: Investigation
                Role: InvestigationRole: Supervision
                Role: Investigation
                Role: InvestigationRole: Supervision
                Role: Investigation
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                Role: Investigation
                Role: InvestigationRole: Writing – review & editing
                Role: Investigation
                Role: InvestigationRole: Supervision
                Role: InvestigationRole: Supervision
                Role: InvestigationRole: Supervision
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Formal analysisRole: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Project administration
                Role: InvestigationRole: Project administration
                Role: InvestigationRole: Project administration
                Role: InvestigationRole: Project administrationRole: Supervision
                Role: InvestigationRole: Project administration
                Role: InvestigationRole: Project administration
                Role: Project administration
                Role: Data curationRole: Visualization
                Role: Project administrationRole: Supervision
                Role: Project administration
                Role: InvestigationRole: Project administrationRole: Supervision
                Role: Project administration
                Role: Project administration
                Role: Project administration
                Role: Project administration
                Role: Investigation
                Role: Investigation
                Role: InvestigationRole: Project administrationRole: Writing – review & editing
                Role: Project administration
                Role: Project administration
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administration
                Role: Data curationRole: Formal analysisRole: InvestigationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Project administrationRole: Supervision
                Role: Formal analysisRole: Project administrationRole: VisualizationRole: Writing – original draft
                Role: InvestigationRole: Project administration
                Role: InvestigationRole: Project administration
                Role: Project administration
                Role: Project administration
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                PLOS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                14 March 2024
                March 2024
                : 18
                : 3
                : e0012022
                Affiliations
                [1 ] World Mosquito Program, Monash University, Clayton, Australia
                [2 ] Ministry of Health, Government of Vanuatu, Port Vila, Vanuatu
                [3 ] World Mosquito Program, Port Vila, Vanuatu
                [4 ] Vanuatu Red Cross Society, Port Vila, Vanuatu
                [5 ] Ministry of Health and Medical Services, Kiribati Government, Kiribati
                [6 ] Ministry of Health and Medical Services, Government of Fiji, Suva, Fiji
                [7 ] World Mosquito Program, Suva, Fiji
                Universita degli Studi di Pavia, ITALY
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0002-9039-7392
                https://orcid.org/0000-0002-5259-4221
                Article
                PNTD-D-23-00714
                10.1371/journal.pntd.0012022
                10980184
                38484041
                bacd3337-9ead-4946-8fe5-fb833b3b25e2
                © 2024 Simmons et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 12 June 2023
                : 25 February 2024
                Page count
                Figures: 8, Tables: 2, Pages: 24
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100000996, Department of Foreign Affairs and Trade, Australian Government;
                Award Recipient :
                This work was supported by a grant award from the Commonwealth of Australia represented by the Department of Foreign Affairs and Trade titled; Operational pilot of Wolbachia technology to reduce the transmission of Aedes aegypti-borne diseases (“the Project”) awarded to SLO. The following authors received full or part salary from this grant for the work described here; WD, LT, TQ, RT, TN, EM, LK, TTA, VR, AT, WV, RP, ES, LN, AR, MH, NK, SCB, AGB, AM, MB, GW, LQD, JBB, DS, CF, NW, KR, PAR, JAD, RS, SKT, PK, YD, AK, LH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Medical Conditions
                Tropical Diseases
                Neglected Tropical Diseases
                Dengue Fever
                Medicine and Health Sciences
                Medical Conditions
                Infectious Diseases
                Viral Diseases
                Dengue Fever
                Medicine and Health Sciences
                Medical Conditions
                Infectious Diseases
                Disease Vectors
                Insect Vectors
                Mosquitoes
                Biology and Life Sciences
                Species Interactions
                Disease Vectors
                Insect Vectors
                Mosquitoes
                Biology and Life Sciences
                Zoology
                Entomology
                Insects
                Mosquitoes
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Invertebrates
                Arthropoda
                Insects
                Mosquitoes
                Biology and Life Sciences
                Zoology
                Animals
                Invertebrates
                Arthropoda
                Insects
                Mosquitoes
                Biology and Life Sciences
                Organisms
                Bacteria
                Wolbachia
                People and Places
                Geographical Locations
                Oceania
                Kiribati
                Biology and Life Sciences
                Physiology
                Reproductive Physiology
                Eggs
                People and Places
                Geographical Locations
                Oceania
                Vanuatu
                People and Places
                Geographical Locations
                Oceania
                Fiji
                Biology and Life Sciences
                Evolutionary Biology
                Evolutionary Processes
                Introgression
                Custom metadata
                vor-update-to-uncorrected-proof
                2024-03-29
                Raw data is available on figshare at doi.org/10.6084/m9.figshare.24720948.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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