New Opportunities Projects
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Alphavirus Vaccines for Biodefense
Institution: University of Texas Medical Branch at Galveston (UTMB), Galveston, TX Principal Investigator: Scott C. Weaver, Ph.D. Co-Investigators: Expected Product: Live-attenuated, chimeric and subunit vaccines against alphavirus (VEEV, EEEV, WEEV) infections. Description: Alphaviruses including Venezuelan (VEEV), eastern
(EEEV) and western equine encephalitis viruses (WEEV) are highly
developed agents of biological warfare and terrorism (BWT) and
important, naturally emerging zoonotic viruses. Current biodefense
against these viruses is inadequate, and widespread morbidity and
mortality could be inflicted upon exposure of civilians or military
personnel. Effective, licensed vaccines, critical first lines of
defense and important tools for biodefense research, are badly
needed. We will exploit recent advances in alphaviral genetics
and vaccine design, as well as the unique alphavirology expertise
within our regional group, to develop safe and effective vaccines
suitable for licensure. We will generate a set of vaccine candidates
against VEEV, EEEV and WEEV using 3 different strategies: 1) live-
attenuated, chimeric Sindbis-based viruses expressing VEEV, EEEV
and WEEV structural proteins; 2) replication-defective viral particles,
based on the chimeric Sindbis-based genomes, that express heterologous
envelope glycoproteins in vivo; and 3) chimeric Sindbis-based replicons
that express in vivo the heterologous envelope glycoproteins, and
also produce in vivo, virus-like particles lacking RNA. A major
advantage of these chimeric systems, which have proved successful
for flaviviruses, is that none will have the potential to generate
or retain the encephalitic alphavirus parent virus or its complete
genome. We will also combine these vaccines with several different
adjuvants expressed from replicon systems to optimize the immune
response. These candidate alphavirus vaccines will be evaluated
in rodent models for safety, immunogenicity and protection against
challenge including aerosol and mosquito infection. The live-attenuated
and replicon-based alphaviruses developed in this project will
take advantage of the greater antigen presentation, cell-mediated
immunity and longer lasting antibody levels characteristic of exposure
to replicating viruses. In addition to protection of civilian and
military populations from an anticipated alphavirus BWT event and
protection of laboratory personnel doing critical BWT and public
health research, the methods we will develop can be exploited to
rapidly and efficiently develop new vaccines against newly recognized,
emerging alphaviruses or an engineered alphavirus weapon. They
will also be useful for protecting populations at risk of natural
exposure to these zoonotic agents in many parts in the New World.
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