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Received Feb 1, 2018; Accepted Apr 26, 2018
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1. Introduction
Venezuelan equine encephalitis virus (VEEV), western equine encephalitis virus (WEEV), and eastern equine encephalitis virus (EEEV) are nonsegmented, positive-sense RNA viruses of the genus Alphavirus in the family Togaviridae [1]. Naturally transmitted by mosquitoes through rodent or bird hosts, VEEV, WEEV, and EEEV are highly pathogenic for equines and humans and have caused periodic epizootics throughout North, Central, and South America [2]. Human infection with these New World alphaviruses typically results in an acute, incapacitating disease characterized by fever, headache, nausea, myalgia, and malaise [3]. Severe neurological disease, including fatal encephalitis, can also result from VEEV, WEEV, and EEEV infection of humans. Although the human case-fatality rates associated with natural infection are estimated to be low for VEEV (≤1%) and intermediate for WEEV (3–15%), EEEV is the most severe of the arboviral encephalitides with a human case-fatality rate estimated to be from 33% to as high as 75% [4–7]. Moreover, numerous documented laboratory accidents and the results of animal studies have demonstrated that VEEV, WEEV, and EEEV are also highly infectious in aerosols, and infection with aerosolized virus could potentially result in higher human mortality than that observed with natural infection [8–10]. In addition to producing incapacitating or lethal infections and being infectious in aerosols, these encephalitic alphaviruses are also easily grown to high titers in inexpensive and unsophisticated cell culture systems and are considerably stable [4]. Consequently, VEEV, WEEV, and EEEV represent significant biological defense threats and are classified as Category B priority pathogens by both the Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases.
Although there are no licensed human vaccines for the encephalitic alphaviruses, live-attenuated and formalin-inactivated vaccines are currently utilized under US Food and Drug Administration Investigational New Drug (IND) status to protect laboratory workers and other at-risk personnel. The live-attenuated VEEV IND vaccine, TC-83, provides long-lasting immunity and protection from both subcutaneous and aerosol VEEV challenges; however, it causes significant adverse reactions in approximately 25% of recipients, and approximately 20% of recipients fail...