Basic principles that govern the ability of transfection-initiated immunizations to raise immune responses will be addressed using quantitative assays for activities of the cell mediated and humoral arms of the immune system. Studies will be carried out using a murine influenza virus model. Immunizations will be done using pCMV-H1, a DNA expression vector for the H1 influenza hemagglutinin glycoprotein. This glycoprotein has well defined epitopes for antibody, T-helper cell, and cytotoxic T-cell responses. Protection will be tested by lethal challenge via the nares with a mouse adapted form of the A/PR/8/34 (HINI) influenza virus. The first specific aim addresses hoe the form of a DNA- expressed antigen affects access to the immune system by testing the relative efficiency with which cell-associated and secreted forms of H1 raise antibody, cytotoxic T-cell, and protective responses. The second specific aim addresses how different routes of inoculation affect access to the immune system. Experiments in this specific aim will characterize transfection-initiated immune responses raised by intradermal, intranasal, and intravenous administration of DNA. The third specific aim addresses how co-transfected of H1 and lymphokines or a surface marked that costimulates antigen presentation affect the efficiency with which transfected cells access the immune system. These experiments should define basic principles for a novel and highly effective method of presenting antigens to the immune system: direct inoculation of DNA expression vectors. This approach to antigen delivery may also provide a new approach to vaccine development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI034946-02
Application #
2070237
Study Section
Virology Study Section (VR)
Project Start
1994-01-01
Project End
1996-12-31
Budget Start
1995-01-01
Budget End
1995-12-31
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Pathology
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Oran, Alp E; Robinson, Harriet L (2004) DNA vaccines: influenza virus challenge of a Th2/Tc2 immune response results in a Th2/Tc1 response in the lung. J Virol 78:4376-80
Bright, Rick A; Ross, Ted M; Subbarao, Kanta et al. (2003) Impact of glycosylation on the immunogenicity of a DNA-based influenza H5 HA vaccine. Virology 308:270-8
Oran, Alp E; Robinson, Harriet L (2003) DNA vaccines, combining form of antigen and method of delivery to raise a spectrum of IFN-gamma and IL-4-producing CD4+ and CD8+ T cells. J Immunol 171:1999-2005
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Sasaki, Shin; Amara, Rama Rao; Yeow, Wen-Shuz et al. (2002) Regulation of DNA-raised immune responses by cotransfected interferon regulatory factors. J Virol 76:6652-9
Sasaki, S; Amara, R R; Oran, A E et al. (2001) Apoptosis-mediated enhancement of DNA-raised immune responses by mutant caspases. Nat Biotechnol 19:543-7
Pertmer, T M; Oran, A E; Madorin, C A et al. (2001) Th1 genetic adjuvants modulate immune responses in neonates. Vaccine 19:1764-71
Pertmer, T M; Oran, A E; Moser, J M et al. (2000) DNA vaccines for influenza virus: differential effects of maternal antibody on immune responses to hemagglutinin and nucleoprotein. J Virol 74:7787-93
Boyle, C M; Robinson, H L (2000) Basic mechanisms of DNA-raised antibody responses to intramuscular and gene gun immunizations. DNA Cell Biol 19:157-65
Ross, T M; Xu, Y; Bright, R A et al. (2000) C3d enhancement of antibodies to hemagglutinin accelerates protection against influenza virus challenge. Nat Immunol 1:127-31

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