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Background: Dengue, chikungunya and Zika are viral infections transmitted by Aedes aegypti mosquitoes, and present major public health challenges in tropical regions. Traditional vector control methods have been ineffective at halting disease transmission. The World Mosquito Program has developed a novel approach to arbovirus control using Ae. aegypti stably transfected with the Wolbachia bacterium, which have significantly reduced ability to transmit dengue, Zika and chikungunya in laboratory experiments. Field releases in eight countries have demonstrated Wolbachia establishment in local Ae. aegypti populations. Methods: We describe a pragmatic approach to measuring the epidemiological impact of city-wide Wolbachia deployments in Bello and Medellín, Colombia. First, an interrupted time-series analysis will compare the incidence of dengue, chikungunya and Zika case notifications before and after Wolbachia releases, across the two municipalities. Second, a prospective case-control study using a test-negative design will be conducted in one quadrant of Medellín. Three of the six contiguous release zones in the case-control area were allocated to receive the first Wolbachia deployments in the city and three to be treated last, approximating a parallel two-arm trial for the >12-month period during which Wolbachia exposure remains discordant. Allocation, although non-random, aimed to maximise balance between arms in historical dengue incidence and demographics. Arboviral disease cases and arbovirus-negative controls will be enrolled concurrently from febrile patients presenting to primary care, with case/control status classified retrospectively following laboratory diagnostic testing. Intervention effect is estimated from an aggregate odds ratio comparing Wolbachia-exposure odds among test-positive cases versus test-negative controls. Discussion: The study findings will add to an accumulating body of evidence from global field sites on the efficacy of the Wolbachia method in reducing arboviral disease incidence, and can inform decisions on wider public health implementation of this intervention in the Americas and beyond. Trial registration: ClinicalTrials.gov: NCT03631719. Registered on 15 August 2018.

Dengue virus (DENV) is an endemic disease in the hot and humid low-lands of Colombia. We characterize diverse temporal and spatial patterns of monthly series of dengue incidence in diverse regions of Colombia during the period 2007-2017 at different spatial scales, and their association with indices of El Niño/Southern Oscillation (ENSO) at the tropical Pacific and local climatic variables. For estimation purposes, we use linear analysis tools including lagged cross-correlations (Pearson test), cross wavelet analysis (wavelet cross spectrum, and wavelet coherence), as well as a novel nonlinear causality method, PCMCI, that allows identifying common causal drivers and links among high dimensional simultaneous and time-lagged variables. Our results evidence the strong association of DENV cases in Colombia with ENSO indices and with local temperature and rainfall. El Niño (La Niña) phenomenon is related to an increase (decrease) of dengue cases nationally and in most regions and departments, with maximum correlations occurring at shorter time lags in the Pacific and Andes regions, closer to the Pacific Ocean. This association is mainly explained by the ENSO-driven increase in temperature and decrease in rainfall, especially in the Andes and Pacific regions. The influence of ENSO is not stationary (there is a reduction of DENV cases since 2005) and local climate variables vary in space and time, which prevents to extrapolate results from one site to another. The association between DENV and ENSO varies at national and regional scales when data are disaggregated by seasons, being stronger in DJF and weaker in SON. Specific regions (Pacific and Andes) control the overall relationship between dengue dynamics and ENSO at national scale, and the departments of Antioquia and Valle del Cauca determine those of the Andes and Pacific regions, respectively. Cross wavelet analysis indicates that the ENSO-DENV relation in Colombia exhibits a strong coherence in the 12 to 16-months frequency band, which implies the frequency locking between the annual cycle and the interannual (ENSO) timescales. Results of nonlinear causality metrics reveal the complex concomitant effects of ENSO and local climate variables, while offering new insights to develop early warning systems for DENV in Colombia.

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