Fc receptor-bearing cells such as monocytes, macrophages, and dendritic cells have been shown to be major targets of dengue virus infections in humans ,  and  and increased Fc receptor-mediated uptake of incompletely neutralized virus can lead to the phenomenon of antibody-dependent enhancement of infection (ADE). Cross-reactive non-neutralizing antibodies (such as those present
after infection with a heterologous serotype in sequential infections) but also neutralizing antibodies at sub-neutralizing concentrations (e.g. when maternal antibodies drop to sub-neutralizing levels several months after birth) can all contribute mTOR inhibitor to ADE ,  and . In addition, secondary infections have been shown to activate pre-existing cross-reactive T cells that possess higher affinity for the previously encountered
but lower affinity for the newly infecting virus . Because Selleck AZD5363 of these properties, it has been proposed that the activated T cells are less efficient in viral clearance but through the cytokines they release contribute to the development of severe disease . In current models of dengue immunopathogenesis, the increase in virus load caused by ADE combined with strong anamnestic cross-reactive T cell responses are believed to result in a ‘cytokine storm’ that finally causes capillary leakage and the symptoms of DHF/DSS , ,  and . The risk of inducing
an immunological condition in vaccinees that not only does not protect but may even lead to enhanced disease was the major obstacle for the development and use of a dengue vaccine so far. The two most important points of concern are the need to induce an equally protective immunity against all 4 serotypes simultaneously, and the risk of waning immunity associated with the potential of immunological enhancement years after vaccination. An ideal dengue vaccine should therefore induce life-long immunity against all 4 serotypes and have an excellent profile of tolerability, also in children. Olopatadine Despite these hurdles, a number of approaches were pursued for the development of several different types of dengue vaccines , ,  and . These include conventionally attenuated live vaccines, genetically engineered chimeric dengue–dengue and dengue-yellow fever live vaccines, inactivated whole virus vaccines, recombinant E protein subunit vaccines, DNA vaccines, and viral vector vaccines expressing either E or only DIII. Ongoing human clinical trials with tetravalent candidate dengue vaccines are listed in Table 1. Currently, the most advanced of these developments is the chimeric dengue-yellow fever live vaccine (Chimerivax; Fig. 4) manufactured by Sanofi Pasteur .