Introduction:

　　 In the last 20 years, the epidemic patterns of dengue in Taiwan remained cycled with small-scale outbreaks occurring almost every three years and large-scale epidemics occurring nearly every ten year. Dengue (DEN) viruses type 1, 2, 3, and 4, a group of the family Flaviviridae, cause a severe public health problem throughout the tropical and subtropical areas of the world. To develop a safe and effective DEN vaccine becomes a high priority of the World Health Organization, health ministries in some affected countries, the US military, and some pharmaceutical companies.

　　 An immunopathological response following secondary infection of humans with a heterologous serotype of dengue virus can be a risk factor for the more severe forms of the disease. These observations could have implications for the development of a dengue vaccine because they suggest that a safe vaccine should be polyvalent to avoid inducing monotype-enhancing immune responses that may lead to severe manifestations of the disease.

　　 No effective vaccine is available. Research into dengue vaccines focuses on the use of live attenuated or inactivated vaccines, infectious clone-derived vaccines, immunogens vectored by various recombinant systems, subunit immunogens, and DNA vaccines.

Tetravalent live attenuated vaccine:

　　 The most advanced live attenuated tetravalent vaccine was developed in Mahidol University, Thailand, with the support of WHO's South-East Asia Regional Office. Attenuated viruses of all four serotypes were developed by serial passage of wild-type viruses in primary dog kidney (PDK) cells or other cell types. The vaccine underwent clinical trials in Thailand in mono-, di-, tri- and tetravalent formats, which proved safe and immunogenic in adults and children. After two doses, seroconversion to all four serotypes was demonstrated in most vaccinated volunteers and antiviral activity remained quite stable for at least a year.

　　 Tetravalent formulations were prepared and evaluated in a monkey model. Challenge studies in rhesus monkeys demonstrated that most animals seroconverted after two doses of the vaccine. After virus challenge, viremia was measurable in 4 of 20 monkeys. In pilot studies in humans, three doses of tetravalent vaccine induced 50% and higher seroconversion to all four dengue serotypes. The next stages of the clinical trials are in progress.

Chimeric vaccine

　　 The ChimeriVaxTM system, originally developed to construct JE( japan encephalitis) vaccine, has now been applied to dengue viruses by Acambis in the USA. A chimeric YF( yellow fever)-dengue type 2 virus (D2) was prepared, using a recombinant cDNA infectious clone of a YF vaccine strain (YF17D) as a backbone, into which the premembrane (PRM) and envelope (E) genes of dengue 2 virus were inserted. All monkeys vaccinated with ChimeriVax-D2 virus developed neutralizing antibodies and were protected against challenge with a wild-type dengue-2 virus. YF/dengue viruses for three other serotypes have been constructed and are undergoing laboratory analysis and evaluation in animal models.

DNA vaccines

　　 Since the phenomenon of antibody-dependent enhancement of infection by antivirion antibodies has been implicated in the development of severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), NS1 has been considered as a potential candidate for DEN vaccine. It has been reported that injection of DNA vaccine containing gene(s) for an antigenic portion of a virus induces a broad range of antigen-specific immune responses, including antibodies, CD4 helper T cells, CD8 cytotoxic T cells, and protective immunity against subsequent viral challenge. The laboratory of professor SYTWU previously demonstrated DNA immunization with DEN2 virus NS1 elicited protective immunity in C3H mice against subsequent viral challenge (Wu et al., 1999). Intravenously challenged with lethal DEN2, mice vaccinated with NS1 DNA exhibited a delay onset of paralysis, a marked decrease of morbidity, and a significant enhancement of survival. In contrast to humoral immune response, DNA immunization elicits strong cellular immune response, an NS1-specific T cell proliferation. The issues, which have to be addressed in designing a safe vaccine against dengue, are raised and the problems of designing subunit as well as whole virus vaccines are pointed out, particularly with regard to the phenomenon of antibody dependent enhancement and, more generally, the problem of immune potentiation of disease.Since the phenomenon of antibody-dependent enhancement of infection by antivirion antibodies has been implicated in the development of severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), NS1 has been evaluated as a potential candidate for DEN vaccine It has been reported that the efficacy of a DNA vaccine can be greatly improved by simultaneous expression of interleukin 2 (IL-2) or other cytokines. The immune responses and protective efficacy elicited by these immunomodulatory DNA vaccines will be further evaluated.

　　 A candidate DNA vaccine expressing dengue virus type 1 PrM and E proteins was developed and used for the immunization of different kinds of monkeys. The candidate vaccine induced the production of virus-neutralizing antibodies and gave partial protection against challenge with homologous dengue virus. Intramuscular immunization of rhesus macaques was more immunogenic than intradermal immunization. Another study focused on the construction of a dengue vaccine containing PrM and E genes of the Guinea C strain of dengue type 2 virus. In immunized mice the candidate vaccine induced neutralizing antibody production and strong anamnestic responses to challenge. Further extensive preclinical and clinical trials are required before a decision can be made on the acceptability of DNA vaccine for practical use.

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