Dengue is a mosquito-borne viral disease posing a significant threat to public health. Dengue virus (DENV) evolution is often characterized by lineage turnover, which, along with ecological and immunological factors, has been linked to changes in dengue phenotype affecting epidemic dynamics. Utilizing epidemiologic and virologic data from long-term population-based studies (the Nicaraguan Pediatric Dengue Cohort Study and Nicaraguan Dengue Hospital-based Study), we describe a lineage turnover of DENV serotype 2 (DENV-2) prior to a large dengue epidemic in 2019. Our phylogenetic analyses confirmed that all Nicaraguan DENV-2 isolates from 2018 and 2019 formed their own clade within the Nicaraguan lineage of the Asian/American genotype. The emergence of the new DENV-2 lineage reflects a replacement of the formerly dominant clade presiding from 2005 to 2009, a lineage turnover marked by several shared derived amino acid substitutions throughout the genome. To elucidate evolutionary drivers of lineage turnover, we performed selection pressure analysis and reconstructed the demographic history of DENV-2. We found evidence of adaptive evolution by natural selection at the codon level as well as in branch formation. The timing of its emergence, along with a statistical signal of adaptive evolution and distinctive amino acid substitutions, the latest in the NS5 gene, suggest that this lineage may have increased fitness relative to the prior dominant DENV-2 strains. This may have contributed to the intensity of the 2019 DENV-2 epidemic, in addition to previously identified immunological factors associated with pre-existing Zika virus immunity.
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