Respiratory syncytial virus (RSV) is a major cause of lower respiratory infections in infants and the elderly. Bronchiolitis and pneumonia caused by RSV are the primary reasons for the hospitalization of infants under 6 months of age. The initial infection often occurs in the presence of maternal antibodies and reinfections occur throughout life. To date, efforts to develop a safe and effective vaccine have failed. Progress in RSV vaccine development has been hampered by the legacy of enhanced, even fatal, illness in vaccinated children during trials of a formalin- inactivated, alum-precipitated whole virus vaccine in the mid 1960s. The lack of a clear understanding of vaccine-augmented RSV disease still stands in the way of clinical trials of new vaccines in RSV naive infants. Our laboratory has demonstrated enhanced RSV and influenza disease in strains of knockout mice that are unable to respond to IFN-alpha/beta (IFN-alpha/beta Receptor-/-) or IFN-alpha/beta and IFN-gamma (Stat1-/- ). The pathology of primary virus infection in these mutant animals resembles that seen following RSV challenge of mice previously immunized with the formalin-inactivated whole virus vaccine (FI-RSV) with exacerbated, eosinophilic inflammation and a Th-2-like cytokine pattern. In this proposal we will test our hypothesis: that poor IFN- alpha/beta induction by RSV may help to explain the induction of Th-2 biased immunity by the FI-RSV vaccine preparation.
The specific aims of this proposal are: 1) Characterization of exacerbated disease in response to RSV infection in Stat1-/- mice. 2) Analysis of T cell lines derived from RSV immune WT and mutant animals. 3) Alteration of RSV pathology by priming in the presence of IFN- alpha/beta. 4) Development of a vaccine strategy promoting strong induction of IFN- alpha/beta.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047226-02
Application #
6511246
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Rubin, Fran A
Project Start
2001-03-01
Project End
2005-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
2
Fiscal Year
2002
Total Cost
$343,125
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
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