Dengue in Vietnamese Infants—Results of Infection‐Enhancement Assays Correlate with Age‐Related Disease Epidemiology, and Cellular Immune Responses Correlate with Disease Severity

Dengue is a well-documented public-health burden in many developing countries [1, 2]. Any of the 4 serotypes of dengue virus (DENV)—DENV1-DENV4—can cause a spectrum of outcomes in humans, ranging from asymptomatic infection to clinically significant disease. Severe disease is called “dengue hemorrhagic fever” (DHF) and is characterized by systemic capillary leakage, thrombocytopenia, and, in severe cases, hypovolemic shock. Substantial epidemiological evidence indicates that DHF in children and adults is typically associated with secondary infection caused by a DENV serotype distinct from that present when an individual is first exposed to DENV [3-6]. In contrast, DHF also occurs in primary DENV infections in infants born to dengue-immune mothers [7, 8]. A unifying hypothesis that explains the age-related epidemiology of DHF is a process called “antibody-dependent enhancement” (ADE) of disease [9]. The ADE model postulates that cross-reactive but subneutralizing levels of DENV-reactive IgG, acquired either passively or because of a previous infection, enhance DENV’s infectivity of Fc receptor-bearing cells. ADE could conceptually result in higher viral burdens in vivo and thereby precipitate some of the clinical events in dengue. Consistent with this model, children with secondary infections and DHF have higher initial plasma viral loads [10-12]. DHF in secondary infections is also associated with both significantly greater plasma concentrations of inflammatory cytokines [13-15] and increased frequencies of activated lymphocytes, compared with those in patients with milder disease [16, 17], presumably in response to higher viral burdens in DHF. Although much less is known about the pathogenesis of dengue in infants, previous studies by our group have suggested that, at least at the time of study enrollment, viral parameters are not associated with disease severity [8]. A critical challenge in dengue pathogenesis and vaccinology is to determine whether the biological character of ADE when measured in vitro can be correlated with disease outcomes and/or epidemiology. Previous prospective studies of children that have attempted to link the ADE phenomenon with disease outcomes in secondary infection but that have employed different methodologies have yielded conflicting results [18, 19]. Kliks et al. have described, in primary infections, a correlation between ADE activity in diluted maternal serum and the age at DHF onset in 13 Thai infants [20]. Against this backdrop, the aim of the present study was to correlate ADE with disease epidemiology in infants and to determine whether innate or acquired immune responses in infants with dengue, responses possibly triggered by ADE-mediated DENV infection, would correlate with disease severity. Our findings are consistent with the notion that infection-enhancing antibody plays a role in the pathogenesis of DHF in infants. Furthermore, we identified aspects of the infant innate and acquired immune response that are associated with disease severity.