Pathogenesis of Eastern Equine Encephalitis Virus in Mice and Development of a Second Generation Vaccine

Abstract : Eastern equine encephalitis virus (EEEV), an Alphavirus in the family Togaviridae, is an important human and veterinary pathogen, and is considered the most deadly of the mosquito-borne alphaviruses due to the high case fatality rate associated with clinical infections, reaching as high as 75% in humans and 90% in horses. In patients that survive, the neurologic sequelae are often devastating. Although natural infections are acquired by mosquito bite, EEEV is also highly infectious by aerosol. This fact, along with the relative ease of production and stability of this virus, has led it to being identified as a potential agent of bioterrorism. Characterizing the early events in the pathogenesis of EEEV (FL93-939) by various routes of infection is an important first step in developing a vaccine to prevent disease. We hypothesize that when mice are challenged with EEEV either intranasally or via aerosol that the virus will enter the brain rapidly using the olfactory system, which will have important implications for therapeutic and vaccine development. The goal of vaccine development is to produce a product that closely mimics natural infection; thereby stimulating an appropriate and effective immune response. However, new EEEV vaccine candidates should protect against both subcutaneous and aerosol exposure to virulent virus, which can be challenging. Formalin, INA, and gamma irradiation have been used to inactivate viruses and have recently been used to inactivate V3526. Inactivating an attenuated-live virus provides an additional layer of safety in the formulation of the vaccine candidate. We hypothesize that formalin, INA, and gamma-irradiation will inactivate a genetically modified strain of EEEV (CVEV1219) but will maintain its antigenic epitopes, thereby creating a valid vaccine candidate that will result in protective immune responses in mice when challenged by the parental virus (EEEVFL93-939).