Symptomatic Versus Inapparent Outcome in Repeat Dengue Virus Infections Is Influenced by the Time Interval between Infections and Study Year

Four dengue virus serotypes (DENV1-4) circulate globally, causing more human illness than any other arthropod-borne virus. Dengue can present as a range of clinical manifestations from undifferentiated fever to Dengue Fever to severe, life-threatening syndromes. However, most DENV infections are inapparent. Yet, little is known about determinants of inapparent versus symptomatic DENV infection outcome. Here, we analyzed over 2,000 DENV infections from 2004 to 2011 in a prospective pediatric cohort study in Managua, Nicaragua. Symptomatic cases were captured at the study health center, and paired healthy annual samples were examined on a yearly basis using serological methods to identify inapparent DENV infections. Overall, inapparent and symptomatic DENV infections were equally distributed by sex. The mean age of infection was 1.2 years higher for symptomatic DENV infections as compared to inapparent infections. Although inapparent versus symptomatic outcome did not differ by infection number (first, second or third/post-second DENV infections), substantial variation in the proportion of symptomatic DENV infections among all DENV infections was observed across study years. In participants with repeat DENV infections, the time interval between a first inapparent DENV infection and a second inapparent infection was significantly shorter than the interval between a first inapparent and a second symptomatic infection. This difference was not observed in subsequent infections. This result was confirmed using two different serological techniques that measure total anti-DENV antibodies and serotype-specific neutralizing antibodies, respectively. Taken together, these findings show that, in this study, age, study year and time interval between consecutive DENV infections influence inapparent versus symptomatic infection outcome, while sex and infection number had no significant effect. Moreover, these results suggest that the window of cross-protection induced by a first infection with DENV against a second symptomatic infection is approximately 2 years. These findings are important for modeling dengue epidemics and development of vaccines.Author Summary: The four serotypes of the mosquito-borne dengue virus (DENV) infect an estimated 100 million humans annually, resulting in tens of millions of dengue cases and hundreds of thousands of cases of severe disease. However, infection with DENV does not always lead to clinical signs, and a large proportion of DENV infections are inapparent. Here, we studied the factors that influence whether a DENV infection is inapparent or symptomatic. Data from over 2,000 DENV infections (∼1,600 inapparent and ∼400 symptomatic) were collected during 7 years from an ongoing prospective cohort study of children in Managua, Nicaragua. We show that whether a person is infected for the first, the second, or the third time with different DENV serotypes, the proportion of symptomatic infections is similar. However, the proportion of symptomatic infection varied substantially across study years, and symptomatic infections tended to happen in older children when compared to inapparent infections. We also show that if a second DENV infection happens within a period of ∼2 years after the first infection, the second infection is more likely to be inapparent. However, if the time interval between first and second DENV infections is longer, this protection wanes and the infection is likely to be symptomatic. These findings are important for the modeling of dengue epidemics and the development of new vaccines.