Detailed analysis of T cell responses from individuals enrolled in vaccinia virus vaccine trials may dramatically improve our understanding of the effects of dilution on vaccine immunogenicity and on the relationship of cell-mediated immunity to protection from adverse events following immunization. Our experiments will begin to address the level of cell-mediated immunity elicited in naive adults following vaccination with the Aventis Pasteur smallpox vaccine. Furthermore, these studies will establish a paradigm in which researchers can begin to incorporate improved measures of cell-mediated immunity in clinical environments, generating data that will provide useful surrogate biomarkers of immune responses related to adverse events or protection. Specifically, we will test the hypothesis that the lack of a vigorous response of host T cells to immunodominant cytolytic T cell epitopes following primary immunization is associated with adverse events that are related to failure to clear virus shedding rapidly. Previous work examining cell-mediated immunity to vaccinia virus during clinical vaccine trials is very limited. Small studies have examined the effects of smallpox vaccination and identified that human CTL memory responses to vaccinia virus do occur. Much of the work performed to date examining CM1 responses in humans to specific antigens/viruses have been performed using bulk culture proliferation techniques and standard cytotoxicity assays. While these assay provide a measure of T cell responsiveness to specific antigens, they fail to delineate which of the subsets of T cells are involved in protective memory responses or are associated with adverse events. We will examine many of these questions by taking advantage of new technology that allows for examination of T cell responses at the single cell level, and in an immunodominant epitope specific manner. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI057661-04
Application #
7028880
Study Section
Special Emphasis Panel (ZRG1-SSS-J (05))
Program Officer
Rathbun, Gary
Project Start
2003-09-15
Project End
2008-02-28
Budget Start
2006-03-01
Budget End
2008-02-28
Support Year
4
Fiscal Year
2006
Total Cost
$284,256
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
McKinney, B A; Reif, D M; White, B C et al. (2007) Evaporative cooling feature selection for genotypic data involving interactions. Bioinformatics 23:2113-20
McKinney, B A; Crowe Jr, J E; Voss, H U et al. (2006) Hybrid grammar-based approach to nonlinear dynamical system identification from biological time series. Phys Rev E Stat Nonlin Soft Matter Phys 73:021912
McKinney, Brett A; Reif, David M; Ritchie, Marylyn D et al. (2006) Machine learning for detecting gene-gene interactions: a review. Appl Bioinformatics 5:77-88
Rock, Michael T; Yoder, Sandra M; Talbot, Thomas R et al. (2006) Cellular immune responses to diluted and undiluted aventis pasteur smallpox vaccine. J Infect Dis 194:435-43
Shaklee, Julia F; Talbot, Thomas R; Muldowney 3rd, James A S et al. (2005) Smallpox vaccination does not elevate systemic levels of prothrombotic proteins associated with ischemic cardiac events. J Infect Dis 191:724-30
Rock, Michael T; Yoder, Sandra M; Wright, Peter F et al. (2005) Differential regulation of granzyme and perforin in effector and memory T cells following smallpox immunization. J Immunol 174:3757-64
Talbot, Thomas R; Stapleton, Jack T; Brady, Rebecca C et al. (2004) Vaccination success rate and reaction profile with diluted and undiluted smallpox vaccine: a randomized controlled trial. JAMA 292:1205-12
Reif, David M; White, Bill C; Moore, Jason H (2004) Integrated analysis of genetic, genomic and proteomic data. Expert Rev Proteomics 1:67-75