Antibody-dependent enhancement of severe dengue disease in humans

TLDR

For dengue viruses 1–4, a specific antibody titer range enhances viral replication in vitro and severe disease in animal models, yet this antibody‑dependent enhancement has not been shown in humans. Using multiple statistical approaches on a long‑term pediatric cohort in Nicaragua, we demonstrate that the risk of severe dengue disease peaks within a narrow range of preexisting anti‑DENV antibody titers. High antibody titers protect against all symptomatic dengue, whereas only a narrow titer range confers risk of severe disease, indicating that correlates of severe dengue differ from those of protection and raising concerns for vaccine design.

Abstract

For dengue viruses 1 to 4 (DENV1-4), a specific range of antibody titer has been shown to enhance viral replication in vitro and severe disease in animal models. Although suspected, such antibody-dependent enhancement of severe disease has not been shown to occur in humans. Using multiple statistical approaches to study a long-term pediatric cohort in Nicaragua, we show that risk of severe dengue disease is highest within a narrow range of preexisting anti-DENV antibody titers. By contrast, we observe protection from all symptomatic dengue disease at high antibody titers. Thus, immune correlates of severe dengue must be evaluated separately from correlates of protection against symptomatic disease. These results have implications for studies of dengue pathogenesis and for vaccine development, because enhancement, not just lack of protection, is of concern.