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Comparison of sera from children with DF, DHF, and controls showed significant elevation of soluble CD8 and IL-2 receptor, in those with DHF, evidence of a marked activation of CD8 T-cells and IL-2 receptor-bearing cells. Soluble CD4 was elevated to a lesser degree. Interferon-gamma was elevated in both DF and DHF.

Based on these results, researchers have mounted a prospective study of children recruited from a Thai outpatient clinic. Subjects had fever of 24 to 72 hours duration and no other source of infection. During the first year, 180 children were recruited; 60 were subsequently diagnosed with DF and showed dengue-positive antibody response, and 29 developed DHF. The study is not yet complete, but several interesting findings have emerged. One is that 100 percent of the children with dengue had viremia, while the literature suggests that the positive isolation rate would be 50 percent for DF and 25 percent for DHF. This finding actually makes more sense, in view of the theory that enhancing antibodies were contributing to the increased risk for severe disease. Researchers plan to titrate plasma to see whether the viral burden is greater in children with DHF.

Using T-cell clones from these children, researchers also plan to measure the cytokine production (particularly interferon-gamma) and the selective activation of T-cell receptors. The activation of specific T-cell receptors is of interest in regard to the pathogenesis of many infectious diseases. In previous studies, stimulating with dengue led to the preferential activation of V-beta-17-bearing T-cells, and the majority of dengue-specific T-cell clones also bear the V-beta-17 receptor. It is unclear whether this is an integral part of DHF, but it bears further investigation.

Vaccine Development. Classical studies by Sabin showed long-lived immunity to homologous virus serotype, so the concept of vaccination seems reasonable. The concern is to prevent DHF and not sensitize a population that might later be exposed to a different serotype and find itself at greater risk for more serious disease. For this reason, there is consensus that a successful vaccine must induce immunity to all four serotypes. From a public health point of view, it is also very important to immunize with one dose of a polyvalent vaccine, if at all possible.

A group in Thailand has performed Phase I immunogenicity studies in adults, using live attenuated strains of dengue-1 through 4. They believe that there is adequate immunogenicity in terms of neutralizing antibody response, although enhancing antibody response has not been measured. The group is now beginning studies with combination vaccines, but it is too early to say what the results will be. Polyvalent vaccination appears to be more difficult in children, possibly because of interference between serotypes, and a number of additional studies will be required. Lots of vaccines are being prepared for clinical trials, and there is an expectation that efficacy studies might be conducted by the end



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