Antibody-dependent Enhancement - in Dengue Virus Infection

In Dengue Virus Infection

Further information: Dengue fever and Dengue virus

The most widely known example of ADE occurs in the setting of infection with the dengue virus (DENV). DENV is a single-stranded positive-polarity RNA virus of the Flaviviridae family. It causes a disease of varying severity in humans, from dengue fever (DF), which is usually self-limited, to dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), either of which may be life-threatening. It is estimated that as many as 100 million individuals are infected with DENV annually.

The phenomenon of ADE may be observed when a person who has previously been infected with one serotype of DENV becomes infected many months or years later with a different serotype. In such cases, the clinical course of the disease is more severe, and these people have higher viremia compared with those in whom ADE has not occurred. This explains the observation that while primary (first) infections cause mostly minor disease (DF) in children, secondary infection (re-infection at a later date) is more likely to be associated with severe disease (DHF and/or DSS) in both children and adults.

There are four antigenically different serotypes of DENV (DENV-1 - DENV-4). Infection with DENV induces the production of neutralizing homotypic immunoglobulin G (IgG) antibodies which provide lifelong immunity against the infecting serotype. Infection with DENV also produces some degree of cross-protective immunity against the other three serotypes. Neutralizing heterotypic (cross-reactive) IgG antibodies are responsible for this cross-protective immunity, which typically persists for a period of several months to a few years. These heterotypic antibody titers decrease over long time periods (4 to 20 years). While heterotypic IgG antibody titers decrease, homotypic IgG antibody titers increase over long time periods. This could be due to the preferential survival of long-lived memory B cells producing homotypic antibodies.

In addition to inducing neutralizing heterotypic antibodies, infection with DENV can also induce heterotypic antibodies which neutralize the virus only partially or not at all. The production of such cross-reactive but non-neutralizing antibodies could be the reason for more severe secondary infections. It is thought that by binding to but not neutralizing the virus, these antibodies cause it to behave as a "trojan horse", where it is delivered into the wrong compartment of dendritic cells that have ingested the virus for destruction. Once inside the white blood cell, the virus replicates undetected, eventually generating very high virus titers which cause severe disease.

To illustrate the phenomenon of ADE, consider the following example: an epidemic of dengue fever occurred in Cuba, lasting from 1977–1979. The infecting serotype was DENV-1. This epidemic was followed by two more outbreaks of dengue fever—one in 1981 and one in 1997; DENV-2 was the infecting serotype in both of these later epidemics. 205 cases of DHF/DSS occurred during the 1997 outbreak, all in people older than 15 years. All but three of these cases were demonstrated to have been previously infected by the DENV-1 serotype during the epidemic of 1977–1979. Furthermore, people who had been infected with DENV-1 during the 1977-79 outbreak and secondarily infected with DENV-2 in 1997 had a 3-4 fold increased probability of developing severe disease than those secondarily infected with DENV-2 in 1981. This scenario can be explained by the presence of neutralizing heterotypic IgG antibodies in sufficient titers in 1981, the titers of which had decreased by 1997 to the point where they no longer provided significant cross-protective immunity.