Cross-Reacting Antibodies Enhance Dengue Virus Infection in Humans

Abstract

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.

Dengue: a continuing global threat

“…The available data suggest that neutralizing antibodies are the major contributors to protective immunity 124,125 , however the role of the cellular immune response requires further study 123 . In this context, clinical trials are crucial for vaccine development owing to the unique information they provide on immune responses and reactogenicity.…”

The pathogenesis of dengue

“…This research has demonstrated that antibodies to dengue structural precursormembrane protein (prM), a component of the humoral response to infection, are highly cross-reactive between DEN virus serotypes. 46 In vitro studies indicate that even when anti-prM antibodies are at high concentrations, they are non-neutralising but potently mediate ADE in Fc receptor bearing cells. 46,47 The proposed basis for prM-mediated ADE is that on a proportion of virus particles prM is only partially cleaved from the virus surface during the virus maturation process.…”

“…46 In vitro studies indicate that even when anti-prM antibodies are at high concentrations, they are non-neutralising but potently mediate ADE in Fc receptor bearing cells. 46,47 The proposed basis for prM-mediated ADE is that on a proportion of virus particles prM is only partially cleaved from the virus surface during the virus maturation process. In this scenario, such "immature" virus particles that would otherwise be non-or less-infectious, are rendered infectious in an environment where anti-prM antibodies can mediate ADE.…”

“…In this scenario, such "immature" virus particles that would otherwise be non-or less-infectious, are rendered infectious in an environment where anti-prM antibodies can mediate ADE. 46 These in vitro observations have led to the suggestion that a vaccine candidate should be designed in a way that would minimise the anti-prM response. 46 A second epidemiological setting that implicates a role for ADE is primary infection of infants born to dengue-immune mothers.…”

“…46 These in vitro observations have led to the suggestion that a vaccine candidate should be designed in a way that would minimise the anti-prM response. 46 A second epidemiological setting that implicates a role for ADE is primary infection of infants born to dengue-immune mothers. Primary infections in infants aged between 4-12 months of age can result in severe dengue, an outcome that is epidemiologically less common in younger infants and children aged between 1-2yrs of age.…”