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Limitations of Existing Vaccines

Numerous dengue vaccines have been produced and tested in small numbers of human beings, but vaccines have not yet been made for all four dengue virus types. Early live attenuated vaccines against dengue were made in suckling mouse brain (Hotta, 1957; Sabin and Schlesinger, 1945; Schlesinger et al., 1956; Wisseman et al., 1963), a substrate no longer considered acceptable for human use. Recently, dengue 1, 2, and 4 attenuated viruses, grown in tissue cultures and produced under U.S. Army sponsorship, have been tested in humans. None have all of the attributes thought to be necessary for an acceptable vaccine, and large-scale production is not contemplated. Attenuated dengue 1, 2, 3, and 4 virus strains have been selected at the dengue laboratory, Ramathibodi Hospital, Bangkok. To date, dengue 2 has been tested in 10 human volunteers; the results apparently were successful. All volunteers responded and none developed dengue-like symptoms (Halstead, personal communication, 1985).

PATHOGEN DESCRIPTION

Dengue viruses are togaviruses of the genus flavivirus and are transmitted by the mosquito vector Aedes aegypti. They are enveloped, single-stranded RNA viruses. There are four distinct antigenic types, dengue types 1, 2, 3, and 4, and several antigenic and biologic subtypes. All dengue serotypes produce the dengue fever syndrome; dengue 2 and possibly dengue 3 and 4 have been implicated as the proximal causes of DHF/DSS (Halstead, 1981b).

HOST IMMUNE RESPONSE

Infection with a dengue serotype results in life-long immunity to that type. From a single infection, short-lived cross protection against disease produced by a different virus type may persist for 6 to 12 weeks. DHF/DSS may be regarded as a complication of the immune response; certain individuals who experience an initial dengue infection are at risk of developing severe disease following infection with a different virus serotype (Halstead, 1981b). This phenomenon has been documented prospectively; dengue types 1, 3, or 4 infections followed by dengue type 2 produces DSS.

The underlying mechanism in DHF/DSS is thought to be as follows. Dengue virus appears to replicate in mononuclear phagocytes. Antibody to one dengue serotype reacts with a second serotype producing immune complexes that attach to and infect mononuclear phagocytes, a phenomenon known as antibody-dependent infection enhancement (Halstead, 1980a). This infection causes the cells to release proteolytic enzymes, thromboplastin, and vascular permeability factors, which in turn lead to hemorrhage and vascular collapse (Halstead, 1983).



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