Abstract

More than 99% of cervical cancers have been associated with human papillomaviruses (HPVs), particularly HPV-16. HPV-associated cervical malignancies might be prevented or treated by induction of the appropriate virus-specific immune responses in patients. HPV-associated cervical malignancies might be prevented or treated by induction of the appropriate virus-specific immune responses in patients. The overall objective of the multi-disciplinary research program is to identify relevant immunological mechanisms that mediate beneficial clinical outcomes of vaccination. The working hypotheses are that 1) testing a 'pipeline' of novel HPV vaccines will generate measurable clinical, pathological, and virological outcomes, and 2) immunological parameters that significantly correlate with thee outcomes can serve as predictors of vaccine effects and provide insight into relevant mechanisms of immunity. The HPV vaccine trials undergoing at the Johns Hopkins Hospital (JHH) provide a unique opportunity for us to identify the most potent HPV vaccine(s) and the immunological parameters that are most relevant to these vaccine effects. The sera, peripheral blood mononuclear cells, biopsy materials from these HPV vaccine trials at JHH are invaluable to the development and characterization of important immunological parameters. Dr. Roden (Project 1) will characterize protective humoral immune responses generated by patients vaccinated with HPV-16 virus-like particles (VLP) and HPV-16 chimeric HPV L1/L2-E2-E7 VLP. Dr. Wu (Project 2) and Dr. Pardoll (Project 3) will develop several new in vitro and in vivo HPV- specific cellular immunological assays and characterize the cell-mediated immune responses generated by multiple E7-specific HPV vaccines. The projects will cooperatively identify the relevant immunological assays that correlate with clinical, virological and pathological indicators in humans. A strong correlation between relevant immunological parameters and clinical/virological outcomes will provide insight into how the host develops and effects protective immune responses as a result of vaccination, help establish criteria for the evaluation of newer generations of vaccines, and provide a foundation for the rational development of new vaccines.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI048203-04
Application #
6606912
Study Section
Special Emphasis Panel (ZAI1-PTM-I (M1))
Program Officer
Nasseri, M Faraz
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2005-06-30
Support Year
4
Fiscal Year
2003
Total Cost
$759,441
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Pathology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Yang, Rongcun; Wheeler, Cosette M; Chen, Xiaojiang et al. (2005) Papillomavirus capsid mutation to escape dendritic cell-dependent innate immunity in cervical cancer. J Virol 79:6741-50
Yang, Rongcun; Murillo, Francisco Martinez; Delannoy, Michael J et al. (2005) B lymphocyte activation by human papillomavirus-like particles directly induces Ig class switch recombination via TLR4-MyD88. J Immunol 174:7912-9
Pinto, Ligia A; Castle, Philip E; Roden, Richard B et al. (2005) HPV-16 L1 VLP vaccine elicits a broad-spectrum of cytokine responses in whole blood. Vaccine 23:3555-64
Kim, Tae Woo; Lee, Jin Hyup; Hung, Chien-Fu et al. (2004) Generation and characterization of DNA vaccines targeting the nucleocapsid protein of severe acute respiratory syndrome coronavirus. J Virol 78:4638-45
Yang, Rongcun; Murillo, Francisco Martinez; Lin, Ken-Yu et al. (2004) Human papillomavirus type-16 virus-like particles activate complementary defense responses in key dendritic cell subpopulations. J Immunol 173:2624-31
Yang, Rongcun; Murillo, Francisco Martinez; Cui, Hengmi et al. (2004) Papillomavirus-like particles stimulate murine bone marrow-derived dendritic cells to produce alpha interferon and Th1 immune responses via MyD88. J Virol 78:11152-60
Peng, Shiwen; Ji, Hongxiu; Trimble, Cornelia et al. (2004) Development of a DNA vaccine targeting human papillomavirus type 16 oncoprotein E6. J Virol 78:8468-76
Cheng, W F; Hung, C F; Lin, K Y et al. (2003) CD8+ T cells, NK cells and IFN-gamma are important for control of tumor with downregulated MHC class I expression by DNA vaccination. Gene Ther 10:1311-20
Yang, Rongcun; Yutzy 4th, William H; Viscidi, Raphael P et al. (2003) Interaction of L2 with beta-actin directs intracellular transport of papillomavirus and infection. J Biol Chem 278:12546-53
Roden, R B; Day, P M; Bronzo, B K et al. (2001) Positively charged termini of the L2 minor capsid protein are necessary for papillomavirus infection. J Virol 75:10493-7