Climate, demography, immunology, and virology combine to drive two decades of dengue virus dynamics in Cambodia
Authors: Brook Cara E. , Rozins Carly , Bohl Jennifer A. , Ahyong Vida , Chea Sophana , Fahsbender Liz , Huy Rekol , Lay Sreyngim , Leang Rithea , Li Yimei , Lon Chanthap , Man Somnang , Oum Mengheng , Northrup Graham R. , Oliveira Fabiano , Pacheco Andrea R. , Parker Daniel M. , Young Katherine , Boots Michael , Tato Cristina M. , DeRisi Joseph L. , Yek Christina , Manning Jessica E. 
Published: June 2022

ABSTRACTThe incidence of dengue virus disease has increased globally across the past half-century, with highest number of cases ever reported in 2019. We analyzed climatological, epidemiological, and phylogenomic data to investigate drivers of two decades of dengue in Cambodia, an understudied endemic setting. Using epidemiological models fit to a 19-year dataset, we first demonstrate that climate-driven transmission alone is insufficient to explain three epidemics across the time series. We then use wavelet decomposition to highlight enhanced annual and multiannual synchronicity in dengue cycles between provinces in epidemic years, suggesting a role for climate in homogenizing dynamics across space and time. Assuming reported cases correspond to symptomatic secondary infections, we next use an age-structured catalytic model to estimate a declining force of infection for dengue through time, which elevates the mean age of reported cases in Cambodia. Reported cases in >70 year-old individuals in the most recent 2019 epidemic are best explained when also allowing for waning multitypic immunity and repeat symptomatic infections in older patients. We support this work with phylogenetic analysis of 192 dengue virus (DENV) genomes that we sequenced between 2019-2022, which document emergence of DENV-2 Cosmopolitan Genotype-II into Cambodia. This lineage demonstrates phylogenetic homogeneity across wide geographic areas, consistent with invasion behavior and in contrast to high phylogenetic diversity exhibited by endemic DENV-1. Finally, we simulate an age-structured, mechanistic model of dengue dynamics to demonstrate how expansion of an antigenically distinct lineage that evades preexisting multitypic immunity effectively reproduces the older-age infections witnessed in our data.CLINICAL TRIAL NUMBERSNCT04034264 andNCT03534245.SIGNIFICANCE STATEMENTThe year 2019 witnessed the highest number of dengue cases ever reported, including in Cambodia, a Southeast Asian country with endemic transmission. We analyzed 19 years of national dengue surveillance data for Cambodia to demonstrate how increasing temperature and precipitation enhance similarity in dengue incidence across space and time, particularly in epidemic years. We document how two decades of demographic transition has depressed the rate at which dengue infections are acquired, thus increasing the age of reported infection. In 2019, expansion of a genetically distinct DENV-2 lineage into Cambodia likely underpinned repeated symptomatic infections in older-age individuals to drive high caseloads. As climates warm, we anticipate more synchronized dynamics globally and a shifting burden of symptomatic disease into older cohorts.