This proposal's aim is to evaluate novel approaches for vaccination against herpes simplex virus (HSV). We hypothesize that immunization for the respiratory tract with DNA based vaccines or immunization enterically with replication incompetent recombinant HSV vectors can be tailored to produce different forms of immunity in the vaginal tract. If sufficient anti-HSV antibody of the appropriate type is induced, this may protect against viral invasion and so provide barrier immunity. However, clearance of virus from the invaded vaginal mucosa likely requires optimal CD4+ T cell function and perhaps CD8+ T cell responses. Vaccines will consist of combinations of plasmid DNA encoding the major glycoprotein gB along with DNA encoding one or more immunomodulatory molecules administered intranasally, or recombinant HSV vectors expressing immunomodulating proteins given enterically. The efficacy of vaccines at inducing various parameters of T cell and humoral immunity will be assessed. Animals will be challenged via the vaginal route HSV to measure protection and to establish the relationship of immunity to the activity of one or more immune components. In addition, vaccines will be tested for their ability to switch the pattern of immune responsiveness in animals primed to express CD4+ Th2 mediated responses and lacking CD8+ T cell reactivity. To achieve pattern shifting, DNA vaccines encoding viral protein along with oligonucleotides containing unmethylated CpG dinucleotides will be used. Our results should be applicable to the future design of vaccines against HSV and may have application to other situations that require immunomodulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI046462-01
Application #
6028139
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Beisel, Christopher E
Project Start
2000-03-01
Project End
2005-02-28
Budget Start
2000-03-01
Budget End
2001-03-01
Support Year
1
Fiscal Year
2000
Total Cost
$265,099
Indirect Cost
Name
University of Tennessee Knoxville
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
City
Knoxville
State
TN
Country
United States
Zip Code
37996
Kumaraguru, Udayasankar; Banerjee, Kaustuv; Rouse, Barry T (2005) In vivo rescue of defective memory CD8+ T cells by cognate helper T cells. J Leukoc Biol 78:879-87
Kumaraguru, Udayasankar; Suvas, Susmit; Biswas, Partha S et al. (2004) Concomitant helper response rescues otherwise low avidity CD8+ memory CTLs to become efficient effectors in vivo. J Immunol 172:3719-24
Toka, Felix N; Pack, Christopher D; Rouse, Barry T (2004) Molecular adjuvants for mucosal immunity. Immunol Rev 199:100-12
Toka, Felix N; Suvas, Susmit; Rouse, Barry T (2004) CD4+ CD25+ T cells regulate vaccine-generated primary and memory CD8+ T-cell responses against herpes simplex virus type 1. J Virol 78:13082-9
Lee, Sujin; Gierynska, Malgorzata; Eo, Seong Kug et al. (2003) Influence of DNA encoding cytokines on systemic and mucosal immunity following genetic vaccination against herpes simplex virus. Microbes Infect 5:571-8
Kumaraguru, Udayasankar; Pack, Christopher D; Rouse, Barry T (2003) Toll-like receptor ligand links innate and adaptive immune responses by the production of heat-shock proteins. J Leukoc Biol 73:574-83
Lee, Yunsang; Eo, Seong Kug; Rouse, Richard J D et al. (2003) Influence of CCR7 ligand DNA preexposure on the magnitude and duration of immunity. Virology 312:169-80
Kumaraguru, Udayasankar; Gouffon Jr, C A; Ivey 3rd, R A et al. (2003) Antigenic peptides complexed to phylogenically diverse Hsp70s induce differential immune responses. Cell Stress Chaperones 8:134-43
Suvas, Susmit; Kumaraguru, Uday; Pack, Christopher D et al. (2003) CD4+CD25+ T cells regulate virus-specific primary and memory CD8+ T cell responses. J Exp Med 198:889-901
Kumaraguru, Udayasankar; Gierynska, Malgorzata; Norman, Shanna et al. (2002) Immunization with chaperone-peptide complex induces low-avidity cytotoxic T lymphocytes providing transient protection against herpes simplex virus infection. J Virol 76:136-41

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