Date Published: February 14, 2013
Publisher: Public Library of Science
Author(s): Katherine L. Williams, Soila Sukupolvi-Petty, Martina Beltramello, Syd Johnson, Federica Sallusto, Antonio Lanzavecchia, Michael S. Diamond, Eva Harris, Ana Fernandez-Sesma.
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 serotypes of dengue virus (DENV) are transmitted by Aedes aegypti and Ae. albopictus mosquitoes and are endemic predominantly in tropical and sub-tropical regions of the world , . Syndromes associated with DENV infection range from inapparent infection to classic dengue fever (DF), a debilitating self-limited disease, to life-threatening dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), characterized by vascular permeability and hypotensive shock . Due to several factors, including geographic expansion of the DENV mosquito vectors and increased global urbanization, trade, and travel , , there has been a substantial increase in both the incidence of dengue epidemics and co-circulation of the four DENV serotypes in the same region . This has resulted in an increased number of severe cases in dengue-endemic regions previously known for epidemics of only mild disease , –. While several tetravalent dengue vaccines are currently in various stages of clinical evaluation –, no vaccine or therapy has been licensed to prevent or treat DENV-induced disease.
In this report, we analyzed a panel of eight MAbs that bind to several epitopes on the dengue virion, including the fusion loop and dimer interface on EDII and the A strand and C-C′ loop on EDIII. We determined that differences exist between the ability of modified MAbs lacking the capacity to engage FcγR and C1q to act therapeutically following a virus-only lethal infection and an antibody-enhanced lethal infection. Analysis of MAb characteristics such as binding avidity and neutralization potency did not clearly define an in vitro correlate of in vivo efficacy across different epitopes, but were more predictive when studying MAbs targeting a specific class, such as those binding the fusion loop epitope. Further analysis suggested that modified, fusion loop- and A-strand-specific MAbs act therapeutically by competing against enhancing antibodies in polyvalent serum that recognize the same or proximal epitopes. By studying these relationships, for the first time, we established a novel in vitro suppression-of-enhancement assay with polyclonal mouse and human anti-DENV immune serum that appears to predict the ability of modified MAbs to act therapeutically against ADE in vivo. Thus, we provide in vivo data that support in vitro observations about the mechanism of ADE as well as a means to suppress ADE in vivo.