Content area
Full Text
Introduction
Dengue virus (DENV), of the genus Flavivirus, family Flaviviridae, can be grouped into four antigenically distinct serotypes (DENV 1-4). DENV is transmitted to humans through the bite of DENV-infected Aedes aegypti and Aedes albopictus. Natural DENV infections are thought to induce lifelong protection against the infecting homologous serotype and short-term cross protection against heterologous serotypes. Recent estimates indicate that up to 390 million infections occur annually worldwide, with approximately 96 million symptomatic cases [1] .
DENV infections generally present with a wide range of clinical symptoms, varying from asymptomatic infection, to undifferentiated dengue fever (DF), to dengue hemorrhagic fever (DHF), dengue shock syndrome [2] , or other severe forms of dengue [2] . The mechanisms underlying severe dengue disease are believed to be related to pathogenic manifestations of the immune response, including antibody cross-reactivity to the vascular endothelium, disease-enhancing antibodies, complement proteins and byproducts, and soluble mediators such as cytokines and chemokines [3] . How each of these elements contributes to disease pathology is not clear. DHF and DSS occur in secondary heterologous DENV infection at a 15-80 fold higher frequency than in primary infection. These levels underscore the significance of preexisting anti-DENV antibodies, which may enhance infections by heterologous DENV serotypes. There is no DENV-specific treatment available, increasing the need for an effective vaccine that can provide simultaneous protection against all four serotypes with minimal reactogenicity. Currently, there are no licensed dengue vaccines. However, there are several vaccine candidates under development, all using different strategies to provide protection. These include live-attenuated vaccines [4-6] , purified inactivated vaccines [7,8] , recombinant vaccines [9] , chimeric vaccines [10] , virus-like particles vaccines [11,12] and subunit vaccines [13,14] . Many of these are in preclinical and clinical trials. Vaccine development is hampered by the complexity of the immune responses, the potential for interference when all four DENV serotypes are delivered simultaneously, and the theoretical safety risk of vaccine-related immune enhancement.
Subunit and recombinant protein vaccines are thought to be safer than live-attenuated vaccines since their composition is devoid of replicative forms of the virus, usually associated with reactogenicity. However, subunit and recombinant vaccines can fail to elicit robust cell-mediated immune responses and are also easily degraded by lysosomal enzymes [15,16] . The dengue/yellow fever chimeric...