Papillomaviruses (PVs) infect the epithelia of animals and man where they generally induce benign proliferation at the site of infection. However, there is a strong association between malignant progression of human genital lesions and certain HPV types, most frequently HPV 16. We have generated virus-like particles (VLPs) for HPV 16 and other PVs that consist of the L1 major capsid protein or L1 plus L2, the minor capsid protein. Parenteral injection of purifed VLPs induced high titers of neutralizing antibodies and protection from experimental challenge in animal models. Based upon these results, we have validated GMP grade VLPs and have recently completed a phase 1 clinical trial of an HPV16 VLP vaccine. Vaccinees, even those vaccinated in the absence of adjuvant, produced high titers of HPV16 psuedovirion neutralizing antibodies and reported only minor side effects. A phase 2 trial is currently in progress.We are also developing alternative vaccine candidates. To increase the therapeutic potential of a VLP-based vaccine, we have incorporated non-structural HPV proteins into the VLPs as L2 fusion proteins. Vaccination with an HPV16 E7 chimeric VLP generated a CD8 restricted T cell response that protected mice from tumor challenge using an E7 expressing tumor line and also induced regression of established tumors. To increase mucosal antibody responses, we have tested intranasal instillation of purified VLPs in mice. In contrast to parenteral inoculation of VLPs, this protocol elicited both secretory IgA and transudated IgG in the female genital tract. Neutralizing antibodies were detected throughout the estus cycle in intranasally vaccinated mice, but not in those vaccinated parenterally.To break B-cell tolerance and induce antibody responses to a self-protein, we replaced an immunodominant epitope of a VLP with a self polypeptide. Specifically, we engineered a L1 protein that displayed the first external loop of mouse CCR5 on the surface of particles. Mice vaccinated with these particles induced high titers of antibodies that bound cell surface CCR5 and blocked HIV infection of culutred cells. Macaques vaccinated with similar particles displaying macaque/human CCR5 peptide also produced anti-CCR5 IgG. These findings suggest a general method for inducing auto-antibodies, with many basic and applied reasearch applications. - Cancer Prevention, immune response, Papillomaviruses, vaccine design, Virus-Cell Interactions, AIDS, Antibody, autoantibodies, Cancer vaccines, CCR5, cervical cancer, cervical dysplasia, HIV, HPV, vaccine against human retroviruses, - Human Subjects & Human Tissues, Fluids, Cells, etc.
Showing the most recent 10 out of 37 publications
