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, Zika, 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. Optimal tetravalent admixtures have been selected and have now entered Phase II and III 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, replacement, maintenance, stability/sterility analysis, and distribution of clinical lots of vaccines suitable for study in human subjects, 2) basic research on virus stabilization and lyophilization processes, 3) submission and laboratory support of IND applications for the clinical evaluation of tetravalent dengue vaccine formulations, 4) support of the seven companies/institutions 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, 5) support of collaborations with investigators interested in basic virology or immunology studies, 6) use of immune cells collected from our clinical studies to investigate the innate immune response to vaccination, 7) development of antigenic cartography methods for the analysis of antibody responses to dengue virus, and 8) characterization of epitopes recognized following dengue or Zika virus infection. With the emergence of Zika virus in the Western hemisphere and the recent public health emergency, our attention has been strongly focused on the development of live attenuated vaccine candidates that would be compatible for co-formulation with our tetravalent dengue vaccine. Recombinant chimeric viruses expressing the prM and E proteins of Zika virus on either the DENV-2 or DENV-4 background have been generated and evaluated successfully in rhesus monkeys. Manufacture of these vaccine candidates to create clinical lot materials is underway at Charles River Laboratories. In addition, serum from Zika patients in Latin America has been received and used to isolate Zika virus strains for use in developing the human challenge model. A strain from Nicaragua and a strain from Brazil have been fully sequenced, safely evaluated in rhesus monkeys, and have been produced and released as clinical trial materials. Mosquito-borne Japanese encephalitis virus (JEV) causes the most important viral encephalitis in the Asia Pacific region, accounting for more than 20,000 reported cases and 6,000 deaths annually. Efforts to develop a JEV vaccine continue in our laboratory and 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. The laboratory has recovered numerous engineered viruses and has evaluated their pathogenicity in mice. The recombinant rJEV virus remains fully virulent in mice and provides a background for the evaluation of attenuating mutations. 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 evaluation in non-human primates and consideration as vaccine candidates.
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