While primary DENV infections are typically moderate or asymptomatic, secondary infections are associated with an increased risk of severe disease. antibody dependent enhancement Abstract Infants less than 1 y of Cisapride age experience high rates of dengue disease in dengue computer virus (DENV) endemic countries. This burden is commonly attributed to antibody-dependent enhancement (ADE), whereby concentrations of maternally derived DENV antibodies become subneutralizing, and infection-enhancing. Understanding antibody-related mechanisms of enhanced infant dengue disease risk represents a significant challenge due to the dynamic nature of antibodies and their imperfect measurement processes. Further, important uncertainties exist regarding the impact of long-term shifts in birth rates, population-level contamination risks, and maternal ages around the DENV immune scenery of newborns and their subsequent risks of severe dengue disease in infancy. Here, we analyze DENV antibody data from two infant cohorts (N = 142 infants with 605 blood draws) and 40 y of infant dengue hospitalization data from Thailand. We Cisapride use mathematical models to reconstruct maternally derived antibody dynamics, accounting for discretized measurement processes and limits of assay detection. We then explore possible antibody-related mechanisms of enhanced infant dengue disease risk and their ability to reconstruct the observed age distribution of hospitalized infant dengue cases. We find that ADE mechanisms are best able to reconstruct the observed data. Finally, we describe how the shifting epidemiology of dengue in Thailand, combined with declining birth rates, have decreased the absolute risk of infant dengue disease by 88% over a 40-y period while having minimal impact on the mean age of infant hospitalized dengue disease. Dengue computer virus (DENV) is usually a mosquito-borne flavivirus with four serotypes (DENV1-4). As in many tropical regions, DENV is usually hyperendemic throughout Cisapride South-East Asia. While main DENV infections are typically moderate or asymptomatic, secondary infections are associated with an increased risk of severe disease. Primary infections are believed to provide long-lasting protection against reinfection with that serotype and shorter-term protection against heterologous serotypes through the generation of cross-reactive antibodies (1). The increased disease risk associated with secondary infections is usually thought to be mediated by a mechanism known as antibody-dependent enhancement (ADE), whereby preexisting heterologous antibodies bind but do not neutralize infecting virions (2C4). Both antibody specificity and concentration are therefore thought to be important determinants of ADE and give rise to the idea of a titer-related windows of risk. The risk window is usually believed to arise when cross-reactive antibody titer concentrations become low enough that they cannot effectively neutralize virions but Cisapride high enough that they can enhance heterologous infections (3C5). Binding of nonneutralizing antibodies to the infecting serotype is usually believed to facilitate computer virus access into Fc-receptor-bearing cells and subsequently, increase viral burden in the host (2, 6, 7). ADE is also believed to occur in young infants when going through their primary contamination if maternally derived anti-DENV antibodies are present (8C12). The placental transfer of IgG antibodies from mother to infant is an important mechanism for protecting young infants from infectious pathogens while the neonatal immune system is still developing (13). These transplacentally acquired antibodies decay within the first 12 months of life, in the beginning providing protection against contamination, and subsequently waning over time to subneutralizing levels that have the potential to mediate ADE (illustrated in and and show model-reconstructed infant populace DENV titers for the Bangkok (and in panels show the same model fits using a log-linear level for antibody titers. Grey shaded regions represent titer values below the assay limits of detection. The mean titer of each serotype, relative to DENV1, by cohort and assay are shown in panel where the black points and lines show the observed mean and 95% CI, and colored points and lines represent the model median and 95% CrI estimates. A total of 1 1,434 infant dengue cases 12 mo of age were reported at Queen Sirikit National Institute of Child Health (QSNICH) in Bangkok between 1974 and 2014 and 84 cases at Kamphaeng Phet (KPP) hospital between 1994 and 2019 ((the monthly rate of decline in age-specific vulnerability to hospitalized disease), resulting in increasing estimates of imply risk titers (of 0.21 (0.19 to 0.22) per month (shows model estimates of DENV titer-related relative risks and risk thresholds for hospitalized infant dengue disease in each of the cohorts and assays. The pink lines and shaded ribbons show the Cisapride median and 95% CrI titer-risk Rabbit Polyclonal to DRP1 (phospho-Ser637) estimates from your model assuming a log-normal relationship between DENV titers and enhanced risk of hospitalized infant dengue disease upon contamination. The blue vertical lines and shaded ribbons show the median and 95% CrI protective titer threshold estimates from your threshold model, while the green vertical lines and ribbons.