New Opportunities Projects
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Development of Novel Pseudoinfectious Flavivirus Vaccines
Institution: University of Texas Medical Branch at Galveston (UTMB), Galveston, TX Principal Investigator: Peter Mason, Ph.D. Consultant: Ilya V. Frolov, Ph.D. – UTMB, Galveston, TX Expected Product: Genetically engineered vaccines for Yellow fever virus and West Nile virus. Description: There are numerous NIAID Category A, B, and C Priority Pathogens in the family Flaviviridae. These agents are arthropod-borne members of the Flavivirus genus, which can cause encephalitis or hemorrhagic fever. Current approved vaccines for these diseases include a live-attenuated vaccine (LAV) for yellow fever (YF) and inactivated virus vaccines (INV) for Japanese encephalitis (JE) and tick-borne encephalitis (TBE). The methods used to produce these vaccines have not yet yielded approved vaccines to prevent dengue fever/hemorrhagic fever or encephalitis caused by West Nile virus (WNV). Currently, LAVs for dengue are being developed based on the effective LAV for YF (17D strain). However, the 17D vaccine has recently been associated with several cases of disease in healthy adults, including the death of a 22-year-old, and this LAV is not acceptable for use in the immunocompromised (including pregnant women and infants). INV products, on the other hand, are expensive to produce, due to the large amounts of antigen needed to immunize vaccinees. Interestingly, the Japanese government has recently withdrawn its recommendation for universal vaccination with its JE vaccine due to concerns about residual mouse brain antigen present in this INV. To address the need for new and better vaccines for flavivirus diseases we have developed a method to produce genetically engineered, “pseudo-infectious” flaviviruses (PIFV) that offer great promise as vaccine candidates. These PIFVs consist of viruses that contain large deletions in the essential capsid (C) protein, and are thus non-infectious in animals, man, or traditional cell cultures. PIFVs can be propagated in cells expressing C; in cells lacking the C protein (e.g., cells in vaccinated hosts) PIFV undergo a limited replication cycle, producing large amounts of a highly immunogenic subviral immunogen. We have shown that a WNV PIFV does not cause disease in animals, and that animals inoculated with this PIFV produce high titers of WNV-neutralizing antibodies. Thus, PIFVs are ideal safe and effective vaccine candidates. The goal of this project is to take our proof-of principle studies on PIFV generation to the next step, by developing methods for large-scale production of PIFV, and demonstrating that they can be used to safely immunize animals against challenge with flaviviruses. To achieve this goal we have developed the following specific aims: 1. Develop a replication-defective PIFV vaccine candidate for YF and WNE. 2. Develop methods to produce high yields of the YFV and WNV PIFV in certified cell lines.
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