Cross-Reacting Antibodies Enhance Dengue Virus Infection in Humans

Dangerous Dengue Provocation One problem with dengue virus is that one infection does not protect against a subsequent infection; secondary infections can result in the severe immunopathology of dengue hemorrhagic fever. Dejnirattisai et al. (p. 745) derived a panel of monoclonal antibodies specific for dengue viruses. These antibodies were mainly directed against the dengue virus precursor membrane protein (prM), and most cross-reacted with all four dengue serotypes. The antibodies were not capable of fully neutralizing the virus, but instead promoted immune responses over a wide range of concentrations. During virus production and virion assembly, maturation of prm is often incomplete, and, consequently, a major part of the host's natural antibody response recognizes a component that is present in variable numbers on the virion. Thus, rather than resulting in complete neutralization, the antibody response promotes virus infection of cells that carry receptors for antibodies. Variable maturation of a dengue viral antigen results in incomplete neutralization and promotes secondary pathology. Dengue virus co-circulates as four serotypes, and sequential infections with more than one serotype are common. One hypothesis for the increased severity seen in secondary infections is antibody-dependent enhancement (ADE) leading to increased replication in Fc receptor–bearing cells. In this study, we have generated a panel of human monoclonal antibodies to dengue virus. Antibodies to the structural precursor-membrane protein (prM) form a major component of the response. These antibodies are highly cross-reactive among the dengue virus serotypes and, even at high concentrations, do not neutralize infection but potently promote ADE. We propose that the partial cleavage of prM from the viral surface reduces the density of antigen available for viral neutralization, leaving dengue viruses susceptible to ADE by antibody to prM, a finding that has implications for future vaccine design.