The Nicaraguan Pediatric Dengue Cohort Study: Incidence of Inapparent and Symptomatic Dengue Virus Infections, 2004–2010

Abstract

Dengue, caused by the four serotypes of dengue virus (DENV), is the most prevalent mosquito-borne viral disease of humans. To examine the incidence and transmission of dengue, the authors performed a prospective community-based cohort study in 5,545 children aged 2–14 years in Managua, Nicaragua, between 2004 and 2010. Children were provided with medical care through study physicians who systematically recorded medical consult data, and yearly blood samples were collected to evaluate DENV infection incidence. The incidence of dengue cases observed was 16.1 cases (range 3.4–43.5) per 1,000 person-years (95% CI: 14.5, 17.8), and a pattern of high dengue case incidence every other year was observed. The incidence of DENV infections was 90.2 infections (range 45.2–105.3) per 1,000 person-years (95% CI: 86.1, 94.5). The majority of DENV infections in young children (<6 years old) were primary (60%) and the majority of infections in older children (≥9 years of age) were secondary (82%), as expected. The incidence rate of second DENV infections (121.3 per 1,000 person-years; 95% CI: 102.7, 143.4) was significantly higher than the incidence rate of primary DENV infections (78.8 per 1,000 person-years; 95% CI: 73.2, 84.9). The rigorous analytic methodology used in this study, including incidence reporting in person-years, allows comparison across studies and across different infectious diseases. This study provides important information for understanding dengue epidemiology and informing dengue vaccine policy.

Asymptomatic humans transmit dengue virus to mosquitoes

“…Before the development of studies based on geographic cluster sampling around index cases (16,17), inapparent DENV infections could only be detected in very small numbers or retrospectively in cohort studies after the viremic period had ended (18,19). We overcame this obstacle by capturing DENV-infected people across the continuum of disease manifestations while they were viremic using a comprehensive catchment system combining passive, hospital-based surveillance and cluster investigations in and around the households of hospitalized index cases (Materials and Methods).…”

Human CD4 + T Cell Responses to an Attenuated Tetravalent Dengue Vaccine Parallel Those Induced by Natural Infection in Magnitude, HLA Restriction, and Antigen Specificity

“…Secondary T cell responses to conserved/cross-reactive regions may contribute to the heightened protection and lower disease severity observed for tertiary heterotypic DENV infections (6,29) and may thereby represent a desirable attribute of vaccine-induced cellular responses.…”

“…The development of broadly cross-reactive neutralizing antibodies follows secondary infections, but the antibodies resulting from a previous infection are generally not cross-neutralizing and can actually be linked to antibodydependent enhancement (ADE) of infection and disease (1,4). Cohort studies, human challenge studies, and phase III efficacy studies indicate that antibodies alone are not a perfect correlate of protection (5)(6)(7)(8). CD8 ϩ responses were previously regarded as a possible correlate of disease risk, but recent data suggest that they may instead be considered a potential correlate of protection, based on mouse model data showing decreased tissue viremia after challenge (9)(10)(11) and the association of certain HLA alleles with strong CD8 ϩ responses and decreased disease susceptibility (12).…”

The Human CD8 + T Cell Responses Induced by a Live Attenuated Tetravalent Dengue Vaccine Are Directed against Highly Conserved Epitopes

“…We previously reported a protective role for CD8 ϩ T cells focusing on conserved regions upon secondary heterologous infection (9). Although primary infection with one serotype induces mostly serotype specific T cell responses and only short-term cross-protection against other serotypes, the evolution of secondary T cell responses toward conserved regions likely contributes to the general protection against tertiary DENV infections (24,25).…”