After a person is infected with dengue, they develop an immune response to that dengue subtype. The immune response produced specific antibodies to that subtype specific surface proteins that prevents the virus from binding to macrophage cells (the target cell that dengue viruses infect) and gaining entry. However, if another subtype of dengue virus infects the individual, the virus will activate the immune system to attack it as if it was the first subtype. The immune system is tricked because the four subtypes have very similar surface antigens. The antibodies bind to the surface proteins but do not inactivate the virus. The immune response attracts numerous macrophages, which the virus proceeds to infect because it has not been inactivated. This situation is referred to as Antibody-Dependent Enhancement (ADE) of a viral infection. This makes the viral infection much more acute. The body releases cytokines that cause the endothelial tissue to become permeable which results in Dengue Haemorrhagic Fever (DHF) and fluid loss from the blood vessels.
There are several possibilities to explain the phenomenon:
1. A viral surface protein laced with antibodies against a virus of one serotype binds to a similar virus with a different serotype. The binding is meant to neutralize the virus surface protein from attaching to the cell, but the antibody bound to virus also binds to the receptor of the cell, the Fc-region antibody receptor FcγR. This brings the virus into close proximity to the virus-specific receptor, and the cell endocytoses the virus through the normal infection route.
2. A virus surface protein may be attached to antibodies of a different serotype, activating the classical pathway of the complement system. The complement cascade system instead binds C1q attached to the virus surface protein via the antibodies, which in turn bind C1q receptor found on cells, bringing the virus and the cell close enough for a specific virus receptor to bind the virus, beginning infection. This mechanism as not been shown specifically for the dengue virus infection, but is supposed to occur with Ebola virus infection in vitro.
3. When an antibody to a virus is present for a different serotype, it is unable to neutralize the virus, which is then ingested into the cell as a sub-neutralized virus particle. These viruses are phagocytosed as antigen-antibody complexes, and degraded by macrophages. Upon ingestion the antibodies no longer even sub-neutralize the body due to the denaturing condition at the step for acidification of phagosome before fusion with lysosome. The virus becomes active and begins its proliferation within the cell.
In 1997, 205 cases of DHF/DSS occurred in Cuba, all in people older than 15 years, after an infection with DENV-2 serotype. All but three cases were shown to have been previously infected by DENV-1 virus, during the epidemic of 1977–1979. Two outbreaks of the disease occurred after the first epidemic in 1977-1979, one in 1981 and one in 1997. People who had been infected with DENV-1 during the 1977-79 outbreak and secondarily infected with DENV-2 in 1997 had 3 to 4 more chances to develop a severe disease than those secondarily infected with DENV-2 in 1981. While heterotypic antibody titers decrease, homotypic antibody titers increase during long time periods (4 to 20 years). This could be due to the preferential survival of long-lived B memory cells producing homotypic antibodies, thanks to their bigger affinity. This cross-reactive protection does not persist more than 3 months. The decrease of cross-reactive neutralizing antibodies titers in the serum could be the reason for more severe secondarily infections.