Dengue and Japanese encephalitis viruses are important causes of human disease on a global scale and vaccine development against both viruses remains a public health priority. Based on the efficacy of the live- attenuated viral vaccine against yellow fever virus, the potential of expressing the structural proteins of Dengue and Japanese encephalitis viruses in the context of chimeric yellow fiver viruses is being investigated.
Aim 1 will determine whether an engineered chimeric virus can provide protective immunity against challenge with neuropathogenic Japanese encephalitis virus in adult mice, and to compare relative immunogenicity and protection with available Japanese encephalitis vaccine products.
Aim 2 will fully characterize a chimeric yellow fever virus expressing the envelope protein of a dengue type 2 strain, and determine whether this novel virus can elicit protection in the mouse model.
Aim 3 will use the chimeric yellow fever virus system to define the genetic determinants within the Japanese encephalitis virus envelope protein, which differentiate a highly neurovirulent clone from a nonvirulent clone.
Aim 4 will determine whether a profound attenuation of the YS/JE-SA, 4-14-2 chimeric virus by investigating the effects of the envelope protein on different stages of viral replication. The overall goal of this proposal is to evaluate whether this chimeric virus technology warrants further consideration for development of human live- attenuated vaccines for dengue, Japanese encephalitis, and perhaps other medically important flaviviruses and to provide better knowledge of the molecular pathogenesis of these viruses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043512-05
Application #
6510870
Study Section
Virology Study Section (VR)
Program Officer
Meegan, James M
Project Start
1998-07-01
Project End
2005-06-30
Budget Start
2002-07-01
Budget End
2005-06-30
Support Year
5
Fiscal Year
2002
Total Cost
$306,265
Indirect Cost
Name
Saint Louis University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Chambers, Thomas J; Droll, Deborah A; Jiang, Xiaoshan et al. (2007) JE Nakayama/JE SA14-14-2 virus structural region intertypic viruses: biological properties in the mouse model of neuroinvasive disease. Virology 366:51-61
Chambers, Thomas J; Jiang, Xiaoshan; Droll, Deborah A et al. (2006) Chimeric Japanese encephalitis virus/dengue 2 virus infectious clone: biological properties, immunogenicity and protection against dengue encephalitis in mice. J Gen Virol 87:3131-40
Vlaycheva, Leonssia; Nickells, Michael; Droll, Deborah A et al. (2005) Neuroblastoma cell-adapted yellow fever virus: mutagenesis of the E protein locus involved in persistent infection and its effects on virus penetration and spread. J Gen Virol 86:413-21
Vlaycheva, Leonssia; Nickells, Michael; Droll, Deborah A et al. (2004) Yellow fever 17D virus: pseudo-revertant suppression of defective virus penetration and spread by mutations in domains II and III of the E protein. Virology 327:41-9
Chambers, Thomas J; Liang, Yan; Droll, Deborah A et al. (2003) Yellow fever virus/dengue-2 virus and yellow fever virus/dengue-4 virus chimeras: biological characterization, immunogenicity, and protection against dengue encephalitis in the mouse model. J Virol 77:3655-68
Vlaycheva, Leonsia A; Chambers, Thomas J (2002) Neuroblastoma cell-adapted yellow fever 17D virus: characterization of a viral variant associated with persistent infection and decreased virus spread. J Virol 76:6172-84
Arroyo, J; Guirakhoo, F; Fenner, S et al. (2001) Molecular basis for attenuation of neurovirulence of a yellow fever Virus/Japanese encephalitis virus chimera vaccine (ChimeriVax-JE). J Virol 75:934-42