The mosquito-borne members of the Flaviviridae family, contain a single-stranded positive-sense RNA genome and are the cause of yellow fever, dengue fever, Japanese encephalitis, and West Nile fever syndromes. In recent years, much of our laboratory effort was focused on the development and preclinical testing of dengue virus vaccine candidates suitable for inclusion in a live attenuated tetravalent vaccine. Clinical lots of each of these vaccine candidates were manufactured in prior years and have been evaluated individually in Phase I clinical trials, and several tetravalent vaccine admixtures have also recently been evaluated in human subjects. An optimal tetravalent admixture (TV005) has been selected and is now entering Phase II evaluation. Although the dengue virus vaccine program is predominantly in a clinical mode at this time, considerable effort is currently devoted to support a number of important functions, including, 1) manufacture, maintenance, and distribution of clinical lots of vaccines suitable for study in human subjects, 2) submission and laboratory support of IND applications for the clinical evaluation of tetravalent dengue vaccine formulations, 3) support of the five companies/foundations that have licensed our vaccine technology or virus products, which includes consultative visits and clinical trial planning, development of manufacturing processes, preparation and shipping of vaccine seed or clinical lot viruses, assistance with sequence analysis, and sharing of IND/clinical trial data, 4) support of collaborations with investigators interested in basic virology or immunology studies, 5) use of immune cells collected from our clinical studies to investigate the innate immune response to vaccination, and 6) preclinical development of potential second-generation vaccine candidates, such as the flavivirus pentavalent vaccine designed for control of dengue and Japanese encephalitis. Mosquito-borne Japanese encephalitis virus (JEV) causes the most important viral encephalitis in the AsiaPacific region, accounting for more than 20,000 reported cases and 6,000 deaths annually. The high fatality rate and frequent residual neuro-psychiatric sequelae in survivors make JEV infection a considerable health problem. Efforts to develop a JEV vaccine continue in our laboratory. It is envisioned that a suitable live attenuated JEV vaccine could be combined with our live attenuated DEN virus vaccine to create a second generation pentavalent vaccine for the control of these viruses in Southeast Asia. Toward this end, a fully virulent JEV isolate (India/78) was selected as the parent virus for vaccine development based on the pathogenicity of a number of wildtype JEV isolates tested in mice by intracerebral or peripheral inoculation. Genome sequencing of this virus provided the template for creating full-length recombinant cDNA clones of JEV and chimeric cDNA clones containing the JEV structural genes and the DEN4 nonstructural genes. The laboratory has recovered these engineered viruses and has evaluated their pathogenicity in mice. The recombinant rJEV virus remains fully virulent in mice and thus provides a background for the evaluation of attenuating mutations. The rJEV/DEN4 chimeric viruses appear to be over-attenuated in mice, indicating that chimerization is much more attenuating for JEV compared to the related West Nile virus. Sets of mutations derived from the attenuated SA14-14-2 vaccine virus produced in China have been introduced into the rJEV virus clone in order to evaluate the attenuating potential of mutations found in both the structural and non-structural genes. Following evaluation in mice, a number of these recombinant viruses look suitable for consideration as vaccine candidates.
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