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.
Showing the most recent 10 out of 291 publications