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 virus presents a growing threat to public health in the developing world. Four major serotypes of dengue virus have been characterized, and epidemiological evidence shows that dengue hemorrhagic fever (DHF), the more serious manifestation of the disease, occurs more frequently upon reinfection with a second serotype. We have studied dengue virus-specific T-cell responses in Thai children. During acute infection, few dengue-responsive CD8+ T cells were recovered; most of those present showed an activated phenotype and were undergoing programmed cell death. Many dengue-specific T cells were of low affinity for the infecting virus and showed higher affinity for other, probably previously encountered strains. Profound T-cell activation and death may contribute to the systemic disturbances leading to DHF, and original antigenic sin in the T-cell responses may suppress or delay viral elimination, leading to higher viral loads and increased immunopathology.

Complement activation mediated by NS1 leads to local and systemic generation of anaphylatoxins and SC5b-9, which may contribute to the pathogenesis of the vascular leakage that occurs in patients with DHF/DSS.

The evolution of dengue viruses has resulted in four antigenically similar yet distinct serotypes. Infection with one serotype likely elicits lifelong immunity to that serotype, but generally not against the other three. Secondary or sequential infections are common, as multiple viral serotypes frequently cocirculate. Dengue infection, although frequently mild, can lead to dengue hemorrhagic fever (DHF) which can be life threatening. DHF is more common in secondary dengue infections, implying a role for the adaptive immune response in the disease. There is currently much effort toward the design and implementation of a dengue vaccine but these efforts are made more difficult by the challenge of inducing durable neutralizing immunity to all four viruses. Domain 3 of the dengue virus envelope protein (ED3) has been suggested as one such candidate because it contains neutralizing epitopes and it was originally thought that relatively few cross-reactive antibodies are directed to this domain. In this study, we performed a detailed analysis of the anti-ED3 response in a cohort of patients suffering either primary or secondary dengue infections. The results show dramatic evidence of original antigenic sin in secondary infections both in terms of binding and enhancement activity. This has important implications for dengue vaccine design because heterologous boosting is likely to maintain the immunological footprint of the first vaccination. On the basis of these findings, we propose a simple in vitro enzyme-linked immunosorbent assay (ELISA) to diagnose the original dengue infection in secondary dengue cases.Dengue virus is an insect-borne flavivirus transmitted to humans by the bite of an infected mosquito, usually Aedes aegypti (20). There are four circulating serotypes of dengue (dengue serotype 1 [Den1] to Den4) that show up to 70% sequence homology across their genomes (4, 17), and it is common for multiple viral serotypes to cocirculate in countries where dengue is endemic. Most dengue infections are either asymptomatic or lead to uncomplicated dengue fever (DF). However, in 1 to 5% of cases, symptoms can be more severe with the development of plasma leakage and hemorrhage. Such dengue hemorrhagic fever (DHF) can lead to circulatory collapse, resulting in a mortality rate of around 20% if left untreated.The more frequent occurrence of DHF in secondary dengue infections in children and adults suggests a role for the acquired immune system in disease pathogenesis, and there has been considerable research into both the B-and T-cell responses. Antibody-dependent enhancement (ADE) of infection, proposed by Halstead in 1977 (24, 25), is one hypothesis for this increase in severity in secondary infections (23,36). During a primary infection, antibodies that cross-react with the remaining 3 serotypes are induced. After a few months, when heterologous protection is no longer observed (54), it is hypothesized that these cross-reactive antibodies decline to subneutralizing levels, meaning that a heterologous infecting serot...