Flaviviruses and flavivirus vaccines.

Several human-pathogenic flaviviruses (including yellow fever, dengue, Japanese encephalitis, West Nile and tick-borne encephalitis viruses) have a significant public health impact in different parts of the world and the potential of emerging in previously non-endemic regions. For some viruses, the structure of the most important immunogen, the envelope protein E, has been determined to atomic resolution by X-ray crystallography, and the architecture of virus particles has been resolved by cryo-electron microscopy. Through the combination of structural and immunological investigations, we now have a detailed understanding of the mechanisms of virus neutralization and antibody-dependent enhancement (ADE) of infectivity at a molecular level. The latter phenomenon has been proposed to play an important role in the immunopathology of severe forms of dengue virus infections (hemorrhagic dengue fever and dengue shock syndrome) and is therefore of special relevance in the context of dengue vaccines. Effective human vaccines are in use for the prophylaxis of yellow fever (live attenuated), Japanese encephalitis (live attenuated and inactivated whole virus), and tick-borne encephalitis (inactivated whole virus). Although dengue is the most important flavivirus with respect to global disease incidence, the development and use of vaccines has been hampered so far by the theoretical risk of vaccine-related adverse events such as immune enhancement of infection and the requirement to induce a long-lasting protective immune response against all four dengue serotypes simultaneously. Currently, several kinds of dengue vaccines are in development, but only one of these candidates (a chimeric dengue-yellow fever live attenuated vaccine) has reached the stage of phase 3 clinical trials.