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

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

Flaviviruses: Dengue

Dengue is the world\u27s most important human arboviral disease with indigenous and endemic transmission in more than 100 tropical and subtropical countries. There are numerous other locales that experience non-sustained epidemic transmission with cases in returning travelers or military personnel. More than half the population of the world is at risk of being infected with a dengue virus (DENV). Despite its importance dengue is under-recognized and underreported with current literature estimating 400 million infections each year with 100 million being clinically apparent. The human, community, country, and regional cost of dengue in terms of mortality, morbidity, and health care resource utilization is significant and growing in scope. There are numerous factors that are believed to contribute to the increase in dengue burden, which include (1) rising number of susceptible hosts (population growth), (2) expanding Aedes mosquito vector populations (ineffective vector control, increasing breeding sites, changing ecology), (3) increasing DENV distribution (travel), and (4) the convergence of the these three: urbanization, poverty, and decaying infrastructur