Vaccination and Antiviral Treatment of Neglected Diseases Caused by Flaviviral Infections

K.      Schleich; C.      Nurnberger; A.      Sobanski; T.      Efferth

doi:10.2174/092986711794480168

Abstract

Flaviviral infections have a re-emerging impact on the health situation in developing countries with several billion of people living at risk. In the present review, we focus on three members of the genus Flavivirus belonging to the Flaviviridae family. They are transmitted to humans by mosquito bites, namely those viruses leading to Dengue Fever, Yellow Fever and mosquito-borne Japanese encephalitis. All three virus groups have a spherical structure with a diameter of approximately 50 nm. Although sharing a similar genomic structure and intracellular life cycle, they show different clinical manifestations. Infections are incurable, as there is no antiviral treatment available for either of the three viruses. Thus, prevention and vaccination are the best defenses. The most promising vaccines are live attenuated vaccines (LAVs), such as the YF17D strain against Yellow Fever or the SA-14-14-2 strain against Japanese encephalitis. Additionally, recombinant vaccines for Japanese encephalitis are in development. Although Dengue Fever is the most prevalent arthropode- borne flaviviral infection and a lot of research to develop a vaccine against all four Dengue Fever serotypes was undertaken, no vaccine is available on the market yet. Promising tetravalent vaccine candidates are currently undergoing clinical phase trials, including LAVs, recombinant and chimeric candidates as well as non-replicating vaccine approaches. Additionally, encouraging anti-flaviviral approaches target non-structural proteins, virus-specific proteases essential for cellular maturation of viral particles. Peptide inhibitors against the highly conserved NS2B and NS3 proteases are attractive as pan-flaviviral drug candidates.

Keywords: Flaviviral infections, Dengue Fever, Yellow fever, Japanese Encephalitis, live attenuated vaccines, recombinant vaccines, chimeras, viral peptide inhibitors, Vaccination, Flaviviridae family, open reading frame, capsid protein (C), membrane protein (prM/M), envelope protein (E), NS1, signal transduction, NS2A, NS2B, serine protease, helicase, NTPase, triphosphatase, tick-borne encephalitis, xodes ricinus, Ixodes persulcatus, Aedes aegypti, Aedes albopictus, hemorrhagic fever, crystalloid, colloid solutions, Viremia titers, World Health Organization, sylvatic cycles, Aedes mosquitoes, IMMUNE SYSTEM, antibodies, macrophages, monocytes, dendritic cells, antibody-dependent enhancement, DENGUE VACCINE, tetravalent vaccines, primary dog kidney (PDK), Recombinant LAVs, Chimeric LAVs, NON-REPLICATING VACCINES, Flaviviral methyltransferases, NS5 protein, cyclophilins, peptidyl-prolyl isomerases, favipiravir, pyrazine carboxamide derivatives, inosine monophosphate dehydrogenase (IMPDH), xanthosine monophosphate, Lippia alba, Lippia origanoides, Oreganum vulgare, Artemisia vulgaris, Culex tritaeniosphynchus, NITRIC OXIDE, ENDOPLASMATIC RETICU-LUM STRESS, JAK-STAT SIGNALING PATH-WAY