A Novel Inactivated Trivalent Vaccine to Prevent Infection by Venezuelan, Eastern, and Western Equine Encephalitis Viruses
Abstract
Venezuelan (VEEV), Eastern (EEEV), and Western (WEEV) equine encephalitis viruses are mosquito-transmitted alphaviruses with the potential to cause fatal neuroinvasive disease in humans. These viruses also can be spread by the aerosol route and thus, have significant potential as bioterrorist agents. Currently, there are no antiviral agents approved for alphaviruses. The existing investigational live VEEV vaccine (TC-83) was generated >40 years ago, is highly reactogenic, poorly immunogenic, and causes disease in up to 20% of recipients. VEEV, EEEV, and WEEV are members of the Togaviridae family of positive-sense RNA alphaviruses, and cycle in nature between mosquitoes and birds (EEEV and WEEV), mosquitoes and rodents (VEEV enzootic cycle), or mosquitoes and horses (VEEV epizootic cycle). Together, VEEV, WEEV, and EEEV are widely distributed in North, Central, and South America. Human infection can progress rapidly to encephalitis with fatality rates of ~1% in VEEV and WEEV cases, and remarkably, 50 to 75% in EEEV cases. Despite the epidemic potential of VEEV and the high morbidity and/or case fatality rate of EEEV and WEEV, there are no approved vaccines or therapeutics for humans. Moreover, our understanding of the molecular basis of antibody-mediated neutralization and the nature of cross-protection of humoral responses within a virus subtype or across to the other encephalitic alphaviruses is virtually non-existent. For this application, we propose to develop a safe and effective trivalent vaccine against VEEV, EEEV, and WEEV using attenuated chimeric viruses for vaccine production and proprietary H2O2-treatment for inactivation. These will be adjuvanted and tested for immunogenicity and protection in mouse and non-human primate models of lethal infection and compared to a second platform, a DNA plasmid-based vaccine composed of structural proteins from the homologous target viruses. As part of these studies, we also will determine the potency of antibody neutralization, extent of cross-neutralization against VEEV, EEEV, and WEEV, including a range of subtypes, and location of key neutralizing epitopes. This innovative basic and translational project will elucidate the biology of encephalitic alphaviruses and generate an effective counter-measure against endemic or malicious infection.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- May 26, 2016
- Source ID
- HDTRA11510013
Entities
People
- Michael S. Diamond
Organizations
- Defense Threat Reduction Agency
- Washington University in St. Louis