Lethal Antibody Enhancement of Dengue Disease in Mice Is Prevented by Fc Modification

• DOI: 10.1371/journal.ppat.1000790
• Publication Date: 2010-02-11T19:50:26Z
• Authors: Scott J. Balsitis; Katherine L. Will...; Ruben Lachica; Diana Flores; Jennifer L. Kyle; Erin Mehlhop; Syd Johnson; Michael S. Diamond; P. Robert Beatty; Eva Harris
• Keywords: Antibody-dependent enhancement; Viremia; Dengue vaccine; Polyclonal antibodies

Immunity to one of the four dengue virus (DV) serotypes can increase disease severity in humans upon subsequent infection with another DV serotype. Serotype cross-reactive antibodies facilitate myeloid cells vitro by promoting entry via Fcgamma receptors (FcgammaR), a process known as antibody-dependent enhancement (ADE). However, despite decades investigation, no vivo model for antibody has been described. Analogous human infants who receive anti-DV transplacental transfer and develop severe during primary infection, we show here that passive administration is sufficient enhance mice using both mouse-adapted clinical isolates. Antibody-enhanced lethal featured many hallmarks humans, including thrombocytopenia, vascular leakage, elevated serum cytokine levels, increased systemic viral burden tissue phagocytes. Passive high dose serotype-specific eliminated viremia, but lower doses these or polyclonal monoclonal all enhanced even when levels were neutralizing vitro. In contrast, genetically engineered variant (E60-N297Q) cannot bind FcgammaR exhibited prophylactic therapeutic efficacy against ADE-induced challenge. These observations provide insight into pathogenesis antibody-enhanced identify novel strategy design dengue.