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

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Abstract
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. Dengue is the most common vector-borne viral disease of humans, with over 3 billion people at risk for infection and 50–100 million infections in tropical and subtropical regions each year. Dengue virus (DV) causes a spectrum of clinical disease ranging from an acute debilitating, self-limited febrile illness (DF) to a life-threatening vascular leakage syndrome, referred to as dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). There are four serotypes of DENV; infection with one serotype is thought to protect against re-infection with the same serotype, but may either protect against or enhance infection with one of the other three serotypes. Epidemiological and in vitro data has implicated anti-DENV antibodies in mediating pathogenesis of a second DENV infection. However, it is unclear which antibody conditions are protective and which exacerbate disease in vivo, in part because no animal model of antibody-enhanced dengue disease has been available. Here, we present the first animal model of antibody-enhanced severe DENV infection. Importantly, this model recapitulates many aspects of human disease, including vascular leakage, elevated serum cytokine levels, reduced platelet count, and disseminated infection of tissue phagocytes. Furthermore, we demonstrate the utility of this model by showing that a genetically modified anti-DENV antibody that fails to bind the Fcγ receptor has prophylactic and therapeutic efficacy against lethal DENV challenge in vivo.