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

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.

Structural basis of potent Zika–dengue virus antibody cross-neutralization

“…One surface exposed by this 'breathing' is the fusionloop epitope (FLE), which is a dominant cross-reactive antigenic site 9 . Although antibodies to this site can protect by complement-mediated mechanisms, as shown in a mouse model for West Nile virus 10 , they are poorly neutralizing and lead to antibody-dependent enhancement [11][12][13][14][15] , thereby aggravating Flavivirus pathogenesis and complicating the development of safe and effective vaccines.…”

Environmental influences on antibody-enhanced dengue disease outcomes

“…However, the passive administration of anti-DENV antibodies against one DENV serotype followed 24 h later by inoculation of another serotype of DENV was sufficient to enhance DENV infection and disease in AG129 mice. This was the first model of AED lethal in vivo (Balsitis et al 2010). …”

“…Delayed but not early glucocorticoid treatment has also been shown to protects the host, increase survival and decrease cerebral damage during experimental herpes simplex virus encephalitis in mice (Sergerie et al 2007). Because delayed administration of glucocorticoids reduced death and disease severity after serial AED it is reasonable to suggest that the cytokine storm previously observed in secondary DENV infection (Rothman 2009, Guabiraba et al 2010, Tan et al 2010 and AED (Balsitis et al 2010) may be inhibited by corticoids (Sergerie et al 2007).…”

18F-FDG as an inflammation biomarker for imaging dengue virus infection and treatment response

“…A comprehensive review comparing preclinical animal models used in dengue pathogenesis research has been recently compiled (15). The AG129 mouse model, which is deficient in IFN-α, -β, and -γ, has been used extensively to recapitulate some of the salient features of lethal human diseases, such as high viremia level, elevated cytokine levels, vascular leakage, and thrombocytopenia (16)(17)(18)(19). We recently showed that the infection of AG129 mice with mouse-adapted S221 DENV2/anti-DENV envelope glycoprotein monoclonal antibody immune complexes resulted in a tissueDevelopment of antiviral therapy against acute viral diseases, such as dengue virus (DENV), suffers from the narrow window of viral load detection in serum during onset and clearance of infection and fever.…”