Dengue hemorrhagic fever can occur in primary dengue virus (DENV) infection of infants. The decay of maternally derived DENV
immunoglobulin (Ig) G and the incidence of DENV infection were determined in a prospectively studied cohort of 1244 Vietnamese
infants. Higher concentrations of total IgG and DENV-reactive IgG were found in cord plasma relative to maternal plasma. Maternally
derived DENV-neutralizing and E protein–reactive IgG titers declined to below measurable levels in >90% of infants by 6 months
of age. In contrast, IgG reactive with whole DENV virions persisted until 12 months of age in 20% of infants. Serological
surveillance identified 10 infants with asymptomatic DENV infection for an incidence of 1.7 cases per 100 person-years. DENV-neutralizing
antibodies remained measurable for ⩾1 year after infection. These results suggest that whereas DENV infection in infants is
frequently subclinical, there is a window between 4 and 12 months of age where virion-binding but nonneutralizing IgG could
facilitate antibody-dependent enhancement
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"New-borns are assumed to be immunologically naïve to all serotypes and are born into the class of susceptibles (S). Although the presence of maternal antibodies is shown to affect the risk of infection, the impact on the overall dynamics is believed to be minimal and thus not taken into consideration  . Susceptibles become primarily infected by serotype i (I i ) at rate βSI i and α TRANS βSI ji proportional to the number of primarily and secondarily infectious individuals respectively. "
[Show abstract][Hide abstract]ABSTRACT: The epidemiology of dengue fever is characterized by highly seasonal, multi-annual fluctuations, and the irregular circulation of its four serotypes. It is believed that this behaviour arises from the interplay between environmental drivers and serotype interactions. The exact mechanism, however, is uncertain. Constraining mathematical models to patterns characteristic to dengue epidemiology offers a means for detecting such mechanisms. Here, we used a pattern-oriented modelling (POM) strategy to fit and assess a range of dengue models, driven by combinations of temporary cross protective-immunity, cross-enhancement, and seasonal forcing, on their ability to capture the main characteristics of dengue dynamics. We show that all proposed models reproduce the observed dengue patterns across some part of the parameter space. Which model best supports the dengue dynamics is determined by the level of seasonal forcing. Further, when tertiary and quaternary infections are allowed, the inclusion of temporary cross-immunity alone is strongly supported, but the addition of cross-enhancement markedly reduces the parameter range at which dengue dynamics are produced, irrespective of the strength of seasonal forcing. The implication of these structural uncertainties on predicted vulnerability to control is also discussed. With ever expanding spread of dengue, greater understanding of dengue dynamics and control efforts (e.g. a near-future vaccine introduction) has become critically important. This study highlights the capacity of multi-level pattern-matching modelling approaches to offer an analytic tool for deeper insights into dengue epidemiology and control.
"Epidemiological studies over the last few decades have indeed reported that most of the DHF/DSS cases occur upon secondary infection with a heterologous DENV serotype [5, 6]. Increased risk of DHF/DSS was also reported in infants at 5–9 months of age born to dengue immune mothers when maternally acquired antibodies wane to sub-neutralizing levels . These epidemiological observations were explained by the antibody-dependent enhancement (ADE) of infection hypothesis, whereby actively (during primary infection) or passively (through maternal transfer) acquired anti-DENV antibodies cross react but fail to neutralize a heterologous (or homologous) serotype of DENV . "
[Show abstract][Hide abstract]ABSTRACT: Epidemiological studies have reported that most of the severe dengue cases occur upon a secondary heterologous infection. Furthermore, babies born to dengue immune mothers are at greater risk of developing severe disease upon primary infection with a heterologous or homologous dengue virus (DENV) serotype when maternal antibodies reach sub-neutralizing concentrations. These observations have been explained by the antibody mediated disease enhancement (ADE) phenomenon whereby heterologous antibodies or sub-neutralizing homologous antibodies bind to but fail to neutralize DENV particles, allowing Fc-receptor mediated entry of the virus-antibody complexes into host cells. This eventually results in enhanced viral replication and heightened inflammatory responses. In an attempt to replicate this ADE phenomenon in a mouse model, we previously reported that upon DENV2 infection 5-week old type I and II interferon (IFN) receptors-deficient mice (AG129) born to DENV1-immune mothers displayed enhancement of disease severity characterized by increased virus titers and extensive vascular leakage which eventually led to the animals' death. However, as dengue occurs in immune competent individuals, we sought to reproduce this mouse model in a less immunocompromised background. Here, we report an ADE model that is mediated by maternal antibodies in type I IFN receptor-deficient A129 mice. We show that 5-week old A129 mice born to DENV1-immune mothers succumbed to a DENV2 infection within 4 days that was sub-lethal in mice born to naïve mothers. Clinical manifestations included extensive hepatocyte vacuolation, moderate vascular leakage, lymphopenia, and thrombocytopenia. Anti-TNFα therapy totally protected the mice and correlated with healthy hepatocytes. In contrast, blocking IL-6 did not impact the virus titers or disease outcome. This A129 mouse model of ADE may help dissecting the mechanisms involved in dengue pathogenesis and evaluate the efficacy of vaccine and therapeutic candidates.
"Clinical evidence for a role of antibodies in dengue pathogenesis comes from observations of the increased risk of DHF/DSS in 5– 9 month-old infants, when maternal antibodies against DENV have waned to sub-neutralizing levels (Chau et al., 2009Chau et al., , 2008 Duangchinda et al., 2010; Kliks et al., 1988; Simmons et al., 2007). While infection with a heterologous DENV serotype in young children or adults would trigger anamnestic, cross-reactive responses from both B and T cells (Chau et al., 2008; Duangchinda et al., 2010 ), only maternal antibodies cross the placenta to the infant. "