A Cluster-randomized Trial to EValuate the Efficacy of Wolbachia-InfecTed Aedes Aegypti Mosquitoes in Reducing the Incidence of Arboviral Infection in Brazil (EVITA Dengue)

Study Overview
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Brief Summary
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This is a cluster randomized controlled trial (CRCT) to evaluate the efficacy of Wolbachia-infected A. aegypti mosquito releases in reducing the burden of ARBV infection in Brazil over threefour years. The intervention will be the release of Wolbachia-infected A. aegypti mosquitoes. Standard control measures routinely established by the Belo Horizonte City Hall as recommended by the PNCD, will continue to be performed by the Belo Horizonte Health Department (Zoonoses Management) in all clusters, that is, the standard control measures will be carried out throughout the city of Belo Horizonte, independent of this clinical study. Wolbachia-infected A. aegypti will be deployed by releasing adult mosquitoes in pre-determined, thoroughly spaced release points in easily accessible roads described in a release map. A release map will be generated for each cluster and the numbers of release points will be determined by population density, surface area and mosquito abundance. Wolbachia-infected A. aegypti mosquitoes will be deployed across intervention clusters in two stages: 1) a 4 month establishment stage in which most of the releases will occur and 2) followed by an 8 month consolidation stage in which the abundance of Wolbachia-infected mosquitoes will be measured and remedial deployments will be completed, if needed, with the aim of achieving a high prevalence of Wolbachia amongst A. aegypti mosquitoes in intervention clusters within 12 months from the start of the release. The goal is to reach a Wolbachia prevalence of 60% or higher. Monitoring of Wolbachia prevalence in the cluster will continue throughout the study period, but no further mosquito deployments will occur after the consolidation stage is complete. The primary objective is to evaluate whether release of Wolbachia-infected Aedes aegypti mosquitoes plus standard Aedes vector control measures reduces the sero-incidence of ARBV infection compared to standard Aedes vector control measures alone.

Detailed Description
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This is a cluster randomized controlled trial (CRCT) to evaluate the efficacy of Wolbachia-infected A. aegypti mosquito releases in reducing the burden of ARBV infection in Brazil over threefour years. The intervention will be the release of Wolbachia-infected A. aegypti mosquitoes. Standard control measures routinely established by the Belo Horizonte City Hall as recommended by the PNCD, will continue to be performed by the Belo Horizonte Health Department (Zoonoses Management) in all clusters, that is, the standard control measures will be carried out throughout the city of Belo Horizonte, independent of this clinical study. Wolbachia-infected A. aegypti will be deployed by releasing adult mosquitoes in pre-determined, thoroughly spaced release points in easily accessible roads described in a release map. A release map will be generated for each cluster and the numbers of release points will be determined by population density, surface area and mosquito abundance. Wolbachia-infected A. aegypti mosquitoes will be deployed across intervention clusters in two stages: 1) a 4 month establishment stage in which most of the releases will occur and 2) followed by an 8 month consolidation stage in which the abundance of Wolbachia-infected mosquitoes will be measured and remedial deployments will be completed, if needed, with the aim of achieving a high prevalence of Wolbachia amongst A. aegypti mosquitoes in intervention clusters within 12 months from the start of the release. The goal is to reach a Wolbachia prevalence of 60% or higher. Monitoring of Wolbachia prevalence in the cluster will continue throughout the study period, but no further mosquito deployments will occur after the consolidation stage is complete. The primary objective is to evaluate whether release of Wolbachia-infected Aedes aegypti mosquitoes plus standard Aedes vector control measures reduces the sero-incidence of ARBV infection compared to standard Aedes vector control measures alone. The Secondary objectives are 1.) To evaluate whether release of Wolbachia-infected Aedes aegypti mosquitoes plus standard Aedes vector control measures reduces the sero-incidence of ARBV infection, inferred from model-based reconstruction of serological dynamics compared to standard Aedes vector control measures alone; 2.) To evaluate whether release of Wolbachia-infected Aedes aegypti mosquitoes plus standard Aedes vector control measures reduces the sero-incidence of FLAV or CHIKV infection amongst individuals who are seronegative to each of these viruses, respectively, at study entry, compared to standard Aedes vector control measures alone; 3.) To evaluate whether release of Wolbachia-infected Aedes aegypti mosquitoes plus standard Aedes vector control measures reduces the overall sero-incidence of FLAV (DENV + ZIKV) infection; 4.) To evaluate whether release of Wolbachia-infected Aedes aegypti mosquitoes plus standard Aedes vector control measures reduces the sero-incidence of DENV infection; 5.) To evaluate whether release of Wolbachia-infected Aedes aegypti mosquitoes plus standard Aedes vector control measures reduces the sero-incidence of ZIKV infection; 6.) To evaluate whether release of Wolbachia-infected Aedes aegypti mosquitoes plus standard Aedes vector control measures reduces the sero-incidence of CHIKV infection among those who are CHIKV seronegative at baseline; 7.) To evaluate whether release of Wolbachia-infected Aedes aegypti mosquitoes plus standard Aedes vector control measures reduces the sero-incidence of DENV infection amongst individuals who are seropositive to any DENV serotype(s) at study entry, compared to standard Aedes vector control measures alone; 8.) To evaluate the extent to proportion of Wolbachia-infected Aedes aegypti mosquitoes in intervention clusters during the study period; 9.) To evaluate the proportion of Wolbachia-infected Aedes aegypti mosquitoes in control clusters during the study period.

Official Title
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A Cluster-Randomized Trial to Evaluate the Efficacy of Wolbachia-Infected Aedes Aegypti Mosquitoes in Reducing the Incidence of Arboviral Infection in Brazil

Conditions
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Dengue Fever

Intervention / Treatment
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* Other: Brazilian National Dengue Control Program
* Other: Wolbachia-infected Aedes aegypti


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children aged 6-11 years at enrollment. Child's parent or legal guardian agrees to provide written informed consent. Child agrees to provide informed assent. Child is enrolled in a public school selected for this trial (and which define the clusters). Child resides within geographic boundaries at least 5 days a week in the cluster area corresponding to his/her school. Exclusion Criteria: Children planning to move outside of the cluster boundary within the study period. Child has poor venous access. Child has received an experimental or licensed vaccine against dengue, Zika or chikungunya. Child has any medical condition that would prevent them from completing a blood draw.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 11 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control<br>29 school-based clusters of healthy individuals, age 6-11, exposed to standard vector control efforts recommended by the Brazilian National Dengue Control Program (PNCD). n=1740 | Other: Brazilian National Dengue Control Program<br>* This program has 4 basic principles: 1) Adequate case finding, classification and treatment; 2) Epidemiological surveillance and reporting of all cases; 3) Mobilization and communication of risks to the public; 4) mosquito monitoring and control which consists fundamentally of detection of larva using a rapid larval index (LIRAa) followed by removal of breeding sites and local spraying.<br>|
| Experimental: Intervention<br>29 school-based clusters of healthy individuals, age 6-11, exposed to standard vector control efforts recommended by the Brazilian National Dengue Control Program (PNCD) and Wolbachia-infected Aedes aegypti (wMel) mosquitoes. n=1740 | Other: Brazilian National Dengue Control Program<br>* This program has 4 basic principles: 1) Adequate case finding, classification and treatment; 2) Epidemiological surveillance and reporting of all cases; 3) Mobilization and communication of risks to the public; 4) mosquito monitoring and control which consists fundamentally of detection of larva using a rapid larval index (LIRAa) followed by removal of breeding sites and local spraying.<br>Other: Wolbachia-infected Aedes aegypti<br>* Brazilian strain of Aedes aegypti infected with Wolbachia pipientis released into geographic clusters.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of arbovirus (ARBV) infection | Defined as seroconversion to flavivirus (FLAV) or chikungunya virus (CHIKV), as detected during annual serological evaluations. | Year 2 through Year 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of arbovirus (ARBV) infections, specifically due to flavivirus (FLAV) or chikungunya virus (CHIKV) | As detected during annual serological evaluations; inferred from model-based reconstruction of serological dynamics | Year 2 through Year 4 | 
| Incidence of Chikungunya virus (CHIKV) infection is defined by seroconversion to CHIKV | As detected during annual serological evaluations | Year 2 through Year 4 | 
| Incidence of Dengue virus (DENV) infection as defined by seroconversion to DENV | As detected during annual serological evaluations | Year 2 through Year 4 | 
| Incidence of Dengue virus (DENV) infection is defined by seroconversion | As detected during annual serological evaluations in the subgroup of participants who are seropositive at baseline (time of enrollment) to any DENV serotype(s) regardless of Zika Virus (ZIKV) serostatus | Year 2 through Year 4 | 
| Incidence of Flavivirus (FLAV) infection as defined by seroconversion to FLAV | As detected during annual serological evaluations | Year 2 through Year 4 | 
| Incidence of Zika virus (ZIKV) infection is defined as seroconversion to ZIKV | As detected during annual serological evaluations | Year 2 through Year 4 | 
| Incident Arbovirus (ARBV) infections, as defined by seroconversion to Flavivirus (FLAV) | Among the subgroup of participants who have a Focus Reduction Neutralization Test (FRNT) 50 titer <1:20 at the baseline survey (time of enrollment) OR seroconversion to chikungunya virus (CHIKV) | Year 2 through Year 4 | 
| Proportion of Wolbachia-infected (PCR positive) Aedes aegypti (wMel) adults in control clusters |  | From Year 1 through Year 4 | 
| Proportion of Wolbachia-infected (PCR positive) Aedes aegypti (wMel) adults in intervention clusters |  | From Year 1 through Year 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Arbovirus, Brazil, Chikungunya, Cluster-Randomized, Dengue, Flavivirus, Mosquitoes, Wolbachia-infected, Zika virus