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

Abstract

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.

Seroprevalence of Neutralizing Antibodies Against Dengue Virus in Two Localities in the State of Morelos, Mexico

“…It is important to point out that 2.5% (95% CI = 0.06-13.2) of the seroprevalence against DENV-4 was associated with a short-term multitypic neutralizing immune response, because the subjects were individuals recently infected by DENV who may not have been exposed to DENV-4 according to the viral surveillance of the region 6 ( Figure 2). However, viral surveillance in the studied area by local health authorities, although passive, is particularly robust compared with other areas within Mexico, but we cannot exclude the undetected circulation of any other serotype, which Montoya and others 14 reported previously. In the second age group (n = 27), a seroprevalence higher than 60% was observed, except for DENV-4 (42.9%, 95% CI = 24.5-62.8), whereas for the third age group (n = 70), the seroprevalence was higher than 65% for all four serotypes.…”

“…Nevertheless, recent evidence shows that, in endemic communities, heterotypic secondary immune response is associated with low risk of clinical infection depending on the time that separates the first and the second infections. [13][14][15][16] Few studies of immunity against DENV have been carried out in Mexico. In Veracruz, the reported seroprevalence was 79.6%, similar to the seroprevalence reported in Matamoros.…”

Evaluation of Commercially Available Assays for Diagnosis of Acute Dengue in Schoolchildren During an Epidemic Period in Medellin, Colombia

“…19,20 In a recent study, samples collected from a Sri Lankan pediatric dengue cohort (799 children) were used to investigate antibody responses in children with clinically unapparent and clinically apparent DENV infections. 19 It was reported that children with repeated unapparent infections had a greater number of broadly preexisting neutralizing antibodies against DENV serotypes than children with apparent infections.…”

Analysis of the evidence about the efficacy and safety of the CYD-TDV dengue vaccine and its potential licensing and implementation within the Mexican Universal Vaccination Program

“…[21][22][23][24] In the face of the increased risk of hospitalization due to cases of virologically confirmed dengue within the group of vaccinated children aged nine years or less, the follow-up periods after vaccination must be extended.…”