Therapeutic Efficacy of Antibodies Lacking FcγR against Lethal Dengue Virus Infection Is Due to Neutralizing Potency and Blocking of Enhancing Antibodies

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Abstract
Dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) are life-threatening complications following infection with one of the four serotypes of dengue virus (DENV). At present, no vaccine or antiviral therapies are available against dengue. Here, we characterized a panel of eight human or mouse-human chimeric monoclonal antibodies (MAbs) and their modified variants lacking effector function and dissected the mechanism by which some protect against antibody-enhanced lethal DENV infection. We found that neutralizing modified MAbs that recognize the fusion loop or the A strand epitopes on domains II and III of the envelope protein, respectively, act therapeutically by competing with and/or displacing enhancing antibodies. By analyzing these relationships, we developed a novel in vitro suppression-of-enhancement assay that predicts the ability of modified MAbs to act therapeutically against antibody-enhanced disease in vivo. These studies provide new insight into the biology of DENV pathogenesis and the requirements for antibodies to treat lethal DENV disease. The four dengue virus serotypes (DENV1-4) cause the most prevalent mosquito-transmitted viral disease globally, infecting 50–100 million people annually in tropical and sub-tropical regions worldwide, yet no vaccine or therapy has been licensed to prevent or treat dengue. The greatest risk factor for severe dengue disease is a previous infection with a different serotype, which is thought to be due in part to a phenomenon known as antibody-dependent enhancement (ADE) whereby anti-DENV antibodies from a prior infection augment DENV infection of target Fcg receptor (FcgR)-expressing cells. We previously developed a mouse model that demonstrates antibody-enhanced lethal DENV disease and showed that genetically-modified antibodies incapable of interacting with the FcgR eliminate ADE in vitro and in vivo. In this study, we studied a larger panel of modified MAbs that recognize different regions of the DENV envelope protein. While all modified MAbs acted therapeutically to prevent a lethal, virus-only DENV infection, only certain MAbs effectively protected mice following an antibody-enhanced lethal infection. We determined that therapeutically effective MAbs following an ADE infection worked by competing for binding of enhancing antibodies on the DENV virion. Based on this, we designed an in vitro suppression-of-enhancement assay that predicted the ability of modified MAbs to act therapeutically in vivo.