Dengue virus genomic surveillance in the applying Wolbachia to eliminate dengue trial reveals genotypic efficacy and disruption of focal transmission

Release of Aedes aegypti mosquitoes infected with Wolbachia pipientis ( w Mel strain) is a biocontrol approach against Ae. aegypti -transmitted arboviruses. The Applying Wolbachia to Eliminate Dengue (AWED) cluster-randomised trial was conducted in Yogyakarta, Indonesia in 2018–2020 and provided pivotal evidence for the efficacy of w Mel- Ae. aegypti mosquito population replacement in significantly reducing the incidence of virologically-confirmed dengue (VCD) across all four dengue virus (DENV) serotypes. Here, we sequenced the DENV genomes from 318 dengue cases detected in the AWED trial, with the aim of characterising DENV genetic diversity, measuring genotype-specific intervention effects, and inferring DENV transmission dynamics in w Mel-treated and untreated areas of Yogyakarta. Phylogenomic analysis of all DENV sequences revealed the co-circulation of five endemic DENV genotypes: DENV-1 genotype I (12.5%) and IV (4.7%), DENV-2 Cosmopolitan (47%), DENV-3 genotype I (8.5%), and DENV-4 genotype II (25.7%), and one recently imported genotype, DENV-4 genotype I (1.6%). The diversity of genotypes detected among AWED trial participants enabled estimation of the genotype-specific protective efficacies of w Mel, which were similar (± 10%) to the point estimates of the respective serotype-specific efficacies reported previously. This indicates that w Mel afforded protection to all of the six genotypes detected in Yogyakarta. We show that within this substantial overall viral diversity, there was a strong spatial and temporal structure to the DENV genomic relationships, consistent with highly focal DENV transmission around the home in w Mel-untreated areas and a near-total disruption of transmission by w Mel. These findings can inform long-term monitoring of DENV transmission dynamics in Wolbachia -treated areas including Yogyakarta.