HPV L1 virus-like particles (VLPs) have recently emerged as a promising preventive HPV vaccine. However, immunization with VLPs does not generate therapeutic effects for established or breakthrough HPV infections that have escaped antibody-mediated neutralization. The control of these established infections most likely requires cell mediated immunity. To address this issue, a chimeric VLP which includes early viral proteins, E2 and ET, fused to the L2 minor capsid protein has been designed (L1/L2-E2-E7 cVLP). In a preclinical animal model, vaccination with L1/L2-E2-E7 cVLP has been shown to be capable of generating both protective antibodies and HPV-specific T cell-mediated therapeutic immune responses, leading to regression of E7-expressing tumors. These encouraging results have led to the initiation of a phase I trial sponsored by the NCI. Currently, GMP-grade L1/L2-E2-E7 cVLP has been generated by Novavax and Dr. Clayton Harro will perform the National Cancer Institute-sponsored phase I trial at the Johns Hopkins Center for Immunization Research. We hypothesize that vaccination of L1/L2-E2-E7 cVLP in humans will generate protective neutralizing antibodies in serum and cervical secretion as well as E2- and E7-specific CTL activity. The clinical material generated from this trial represents a unique opportunity to address our hypothesis. HPV infection is limited to the genital mucosa and protective antibody must neutralize the inoculum locally. This clinical trial also allows us to determine whether neutralizing antibodies are present in cervical secretions throughout the menstrual cycle after cVLP immunization. Specifically, we plan in the current proposal to:
Specific Aim 1 : Collect serum and cervical secretions across the menstrual cycle of cVLP vaccines and determine neutralizing titer, avidity and isotype for antibody in these specimens;
Specific Aim 2 : Assay the E7 and E2-specific CD8+ T-lymphocytes in the peripheral blood of patients vaccinated with cVLP. We anticipate that the characterization of human immunological responses in cVLP vaccinees will demonstrate that this vaccine is capable of generating humoral immunity to prevent new infection as well as clearance of pre-existing infection via early viral protein-specific, cell-mediated immunity, making it more efficacious than L1 VLP vaccination.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
1P50CA098252-01
Application #
6824972
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2003-09-30
Project End
2008-08-31
Budget Start
Budget End
Support Year
1
Fiscal Year
2003
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Boitano, Teresa K L; Smith, Haller J; Rushton, Tullia et al. (2018) Impact of enhanced recovery after surgery (ERAS) protocol on gastrointestinal function in gynecologic oncology patients undergoing laparotomy. Gynecol Oncol 151:282-286
Anchoori, Ravi K; Jiang, Rosie; Peng, Shiwen et al. (2018) Covalent Rpn13-Binding Inhibitors for the Treatment of Ovarian Cancer. ACS Omega 3:11917-11929
Ooki, Akira; Dinalankara, Wikum; Marchionni, Luigi et al. (2018) Epigenetically regulated PAX6 drives cancer cells toward a stem-like state via GLI-SOX2 signaling axis in lung adenocarcinoma. Oncogene 37:5967-5981
Ahn, Julie; Bishop, Justin A; Roden, Richard B S et al. (2018) The PD-1 and PD-L1 pathway in recurrent respiratory papillomatosis. Laryngoscope 128:E27-E32
Silver, Michelle I; Rositch, Anne F; Phelan-Emrick, Darcy F et al. (2018) Uptake of HPV testing and extended cervical cancer screening intervals following cytology alone and Pap/HPV cotesting in women aged 30-65 years. Cancer Causes Control 29:43-50
Yang, J-Ming; Bhattacharya, Sayak; West-Foyle, Hoku et al. (2018) Integrating chemical and mechanical signals through dynamic coupling between cellular protrusions and pulsed ERK activation. Nat Commun 9:4673
Xing, Deyin; Zheng, Gang; Schoolmeester, John Kenneth et al. (2018) Next-generation Sequencing Reveals Recurrent Somatic Mutations in Small Cell Neuroendocrine Carcinoma of the Uterine Cervix. Am J Surg Pathol 42:750-760
Qiu, Jin; Peng, Shiwen; Ma, Ying et al. (2018) Epithelial boost enhances antigen expression by vaccinia virus for the generation of potent CD8+ T cell-mediated antitumor immunity following DNA priming vaccination. Virology 525:205-215
Ooki, Akira; Begum, Asma; Marchionni, Luigi et al. (2018) Arsenic promotes the COX2/PGE2-SOX2 axis to increase the malignant stemness properties of urothelial cells. Int J Cancer 143:113-126
Leath 3rd, Charles A; Monk, Bradley J (2018) Twenty-first century cervical cancer management: A historical perspective of the gynecologic oncology group/NRG oncology over the past twenty years. Gynecol Oncol 150:391-397

Showing the most recent 10 out of 291 publications