Evaluate ferret as a new small animal model of aerosol exposure to encephalitic alphaviruses
Abstract
ABSTRACT. Inhalation of the encephalitic alphaviruses, Venezuelan equine encephalitis virus (VEEV) and eastern equine encephalitis virus (EEEV) can cause high morbidity and mortality. There remains considerable concern that these viruses could be used as biological weapons. There are no licensed medical countermeasures available. Licensure will require pivotal efficacy studies be done in animals under the FDA s Animal Rule. This proposal has two objectives: 1) evaluate the ferret as a model for inhalation of VEEV and EEEV; 2) evaluate the impact of aerosol particle size on VEEV and EEEV infectivity and pathogenesis. We propose three tasks to accomplish these objectives in the base period. First, we will develop the capabilities of generating large particle aerosols containing alphaviruses. Second, we will determine the median doses required to cause morbidity and mortality in ferrets after exposure to small or large particle aerosols containing VEEV or EEEV. Radiotelemetry will be used to assess the physiological response to infection. Penetration into the central nervous system will be assessed with ribbon scanning microscopy of intact ex-vivo brains and nanoluciferase-expressing viruses using an in vivo imaging system. Third, we will study the natural history in ferrets after inhalation of small or large particle aerosols containing VEEV or EEEV at a dose relevant to future efficacy studies. We also propose three optional tasks. First, we will assess whether monitoring intracranial pressure via continuous telemetry would be useful as a biomarker of CNS disease caused by VEEV/EEEV. Second, we will evaluate efficacy of a potential therapeutic intervention in the ferret model against aerosol challenge with VEEV and EEEV. Third, we will assess the persistence and infectivity of VEEV and EEEV in small and large particle aerosols and in the environment.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 28, 2020
- Source ID
- HDTRA11910039
Entities
People
- Douglas S. Reed
Organizations
- Defense Threat Reduction Agency
- University of Pittsburgh