Time-varying, serotype-specific force of infection of dengue virus

Abstract

Infectious disease models play a key role in public health planning. These models rely on accurate estimates of key transmission parameters such as the force of infection (FoI), which is the per-capita risk of a susceptible person being infected. The FoI captures the fundamental dynamics of transmission and is crucial for gauging control efforts, such as identifying vaccination targets. Dengue virus (DENV) is a mosquito-borne, multiserotype pathogen that currently infects ∼390 million people a year. Existing estimates of the DENV FoI are inaccurate because they rely on the unrealistic assumption that risk is constant over time. Dengue models are thus unreliable for designing vaccine deployment strategies. Here, we present to our knowledge the first time-varying (daily), serotype-specific estimates of DENV FoIs using a spline-based fitting procedure designed to examine a 12-y, longitudinal DENV serological dataset from Iquitos, Peru (11,703 individuals, 38,416 samples, and 22,301 serotype-specific DENV infections from 1999 to 2010). The yearly DENV FoI varied markedly across time and serotypes (0-0.33), as did daily basic reproductive numbers (0.49-4.72). During specific time periods, the FoI fluctuations correlated across serotypes, indicating that different DENV serotypes shared common transmission drivers. The marked variation in transmission intensity that we detected indicates that intervention targets based on one-time estimates of the FoI could underestimate the level of effort needed to prevent disease. Our description of dengue virus transmission dynamics is unprecedented in detail, providing a basis for understanding the persistence of this rapidly emerging pathogen and improving disease prevention programs.

Keywords: arthropod-borne virus; disease ecology; emerging infections.

Fig. 1.

Summary of participants and interval-censored infections. The top panel shows the total number of active participants across cohort studies from 1999 to 2010. The absence of a cohort study from late 2005 to mid-2006 is indicated by the gray shaded region. Remaining panels: After applying the seroconversion identification algorithm to the raw data the number of interval censored infections are plotted against time. For all, the midpoint of the interval over which the infection was censored is used to time infections.

Fig. 2.

Number and order of interval censored infections by serotype. For each serotype the number of interval-censored infections are plotted against year. Note that for comparison purposes the scale of the y axis is not the same in each panel. Per individual, these infections are broken down by which infection they constitute (primary, secondary, tertiary, or quaternary). Because both DENV-1 and DENV-2 cocirculated before the beginning of the study period, the majority of individuals were already exposed to at least one of these serotypes and thus most interval-censored infections were not primary infections. For this same reason (the cocirculation of DENV-1 and DENV-2 before 1999), there are considerably fewer DENV-1 and DENV-2 interval-censored infections than DENV-3 and DENV-4 interval-censored infections.

Fig. 3.

Daily estimates of FoI. For each serotype, daily estimates of FoI as well as the 90% BCI are plotted against time. The absence of a cohort study from late 2005 to mid-2006 is indicated by the gray shaded region.

Fig. 4.

Yearly estimates of FoI. For each serotype yearly estimates of FoI as well as the 90% BCI are plotted against time. The absence of a cohort study from late 2005 to mid-2006 does not preclude the estimation of yearly FoI estimates for either 2005 or 2006, as evidenced by nonzero FoI estimates for the circulating serotypes for both of those years.

Fig. 5.

Daily estimates of ${\mathrm{ℛ}}_0$. For each serotype daily estimates of ${\mathrm{ℛ}}_0$ as well as the 50% BCI are plotted against time. The absence of a cohort study from late 2005 to mid-2006 is indicated by the gray shaded region. The estimates for both DENV-3 and DENV-4 are truncated, excluding estimation before their respective introductions.