Adding proof to a longstanding but previously unconfirmed theory about severe dengue in humans, a new study in children from Nicaragua pinpoints a narrow but critical range of antibody level that enhances reaction to the disease the second time around. While lab results and animal studies to date have demonstrated that re-exposure to dengue given a preexisting level of dengue antibodies is linked to more severe disease upon re-infection, this phenomenon - known as antibody-dependent enhancement (ADE) - has yet to be directly observed in humans, even despite decades of research investigating it. This new study holds important implications for vaccine efforts against dengue, and for such efforts for related flaviviruses like Zika. Worldwide, millions of people are infected with dengue each year, with the most severe cases resulting in Hemorrhagic Fever/Dengue Shock Syndrome (DHF/DSS), which can cause blood vessels to leak and organs to fail. Between 2004 and 2016, Leah Katzelnick et al. studied the effects of dengue in more than 8,000 children with varying exposure to the virus, and corresponding varying levels of antibodies. Children with a specific range of antibody levels, or titers, had a more than seven-fold chance of developing DHF/DSS compared to unexposed children or those with very high antibody levels, the authors report. Therefore, a vaccine that induces antibody levels at, or near, the peak enhancement level may increase a person's risk of severe dengue compared to if they had never been vaccinated, the authors say. These findings may have implications for implementation of vaccine trials in vaccinees who were previously exposed to the virus.