Effects of infection history on dengue virus infection and pathogenicity

Abstract

The understanding of immunological interactions among the four dengue virus (DENV) serotypes and their epidemiological implications is often hampered by the lack of individual-level infection history. Using a statistical framework that infers full infection history, we analyze a prospective pediatric cohort in Nicaragua to characterize how infection history modulates the risks of DENV infection and subsequent clinical disease. After controlling for age, one prior infection is associated with 54% lower, while two or more are associated with 91% higher, risk of a new infection, compared to DENV-naive children. Children >8 years old have 55% and 120% higher risks of infection and subsequent disease, respectively, than their younger peers. Among children with ≥1 prior infection, intermediate antibody titers increase, whereas high titers lower, the risk of subsequent infection, compared with undetectable titers. Such complex dependency needs to be considered in the design of dengue vaccines and vaccination strategies.

Fig. 1

Estimated probabilities of infection and reported numbers of cases by serotype and year. Serotypes are colored in black for DENV-1, red for DENV-2, blue for DENV-3, and green for DENV-4. a The model-predicted serotype-specific probabilities of infection. Points and vertical bars indicate posterior medians and 95% credible intervals. b The number of surveillance-reported cases in Managua, Nicaragua, from 1995 to 2009. The year is defined as July of a year to June of the next year, to be consistent with the dengue season in the study region. Serotype-specific surveillance counts were imputed using information obtained from PAHO and literature (Supplementary Methods). Source data are provided as a Source Data file

Fig. 2

Estimated effects of risk factors for DENV infection. Associations with the risk of DENV infection are shown as posterior medians (points) and 95% credible intervals (horizontal bars) of odds ratios for age group, number (#) of prior infections, years since most recent infection, home ownership and number of electric fans. The reference (Ref) group is children aged 2–8 years, without any prior infection, with no household ownership and no fan in their household. Source data are provided as a Source Data file

Fig. 3

Estimated probabilities of disease given infection and effects of risk factors. Points and vertical bars indicate posterior medians and 95% credible intervals. a Serotype-specific probability of disease given infection. b Association of the risk of disease given infection with serostatus at entry, age group, and years since most recent infection. The reference group is children aged 2–8 years, without prior infection. Source data are provided as a Source Data file

Fig. 4

Posterior distribution of the time interval between consecutive infections. Results are colored in red for the time between inapparent infections and in blue for the time between an inapparent infection and a symptomatic infection. a Estimation is restricted to infections that occurred during the study. b Estimation is based on the proposed method combining the study period and the years before study entry. Source data are provided as a Source Data file