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Dynamics and determinants of the force of infection of dengue virus from 1994 to 2015 in Managua, Nicaragua

Significance A recently licensed dengue vaccine requires pre-vaccination screening for dengue virus (DENV)-specific antibodies and was initially recommended for use only in areas with high DENV transmission. However, DENV transmission intensity is not static. We show that the age at which children acquired DENV-specific immunity more than doubled during the observational period (2004–2015) of a pediatric cohort study in Managua, Nicaragua. A high force of infection of DENV in the 1990s could be explained by the introduction of a novel DENV serotype, while a gradual decline in force of infection could be explained by a long-term population demographic transition. Such dynamics make DENV transmission intensity a problematic metric for designing, implementing, and evaluating interventions and for selecting target age groups/sites. Dengue virus (DENV) is the most prevalent human vector-borne viral disease. The force of infection (FoI), the rate at which susceptible individuals are infected in a population, is an important metric for infectious disease modeling. Understanding how and why the FoI of DENV changes over time is critical for developing immunization and vector control policies. We used age-stratified seroprevalence data from 12 years of the Pediatric Dengue Cohort Study in Nicaragua to estimate the annual FoI of DENV from 1994 to 2015. Seroprevalence data revealed a change in the rate at which children acquire DENV-specific immunity: in 2004, 50% of children age >4 years were seropositive, but by 2015, 50% seropositivity was reached only by age 11 years. We estimated a spike in the FoI in 1997–1998 and 1998–1999 and a gradual decline thereafter, and children age <4 years experienced a lower FoI. Two hypotheses to explain the change in the FoI were tested: (i) a transition from introduction of specific DENV serotypes to their endemic transmission and (ii) a population demographic transition due to declining birth rates and increasing life expectancy. We used mathematical models to simulate these hypotheses. We show that the initial high FoI can be explained by the introduction of DENV-3 in 1994–1998, and that the overall gradual decline in the FoI can be attributed to demographic shifts. Changes in immunity and demographics strongly impacted DENV transmission in Nicaragua. Population-level measures of transmission intensity are dynamic and thus challenging to use to guide vaccine implementation locally and globally.