ZIA BC 009052 (ZIA) | |||
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Title | Papillomavirus Virion Proteins and Vaccines | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Schiller, John | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $1,477,480 | Project Dates | 01/01/1989 - 00/00/0000 |
Fiscal Year | 2015 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Digestive Diseases (5.0%) |
Anus (5.0%) Cervical Cancer (70.0%) Head and Neck (5.0%) Ovarian Cancer (4.0%) Penis (8.0%) Vaginal (5.0%) |
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Research Type | |||
Exogenous Factors in the Origin and Cause of Cancer Vaccines |
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Abstract | |||
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, anal and oropharyngeal lesions and certain human papillomavirus (HPV) types, most frequently HPV 16. Our research is primarily concerned with development of vaccines and other infection inhibition strategies against HPV and the elucidation of the HPV life cycle. We have developed a simple and efficient strategy for generating high titers of infectious papillomavirus particles that transduce encapsidated marker plasmids, i.e. pseudovirions. We have exploited this technology in our basic virologic and translational research efforts. We have used our pseudovirus technology to develop the first cervicovaginal challenge model for HPVs. We have used this assay to define the molecular mechanism used by HPV to infect its target tissue and to determine how the antibodies induced L1- and L2-based prophylactic vaccines prevent infection. Key to the process is an obligatory binding to the basement membrane of a disrupted epithelium. This binding induces a conformational change required for subsequent steps in infection. The in vitro neutralizing assays we previously developed for L1 VLP vaccine analysis have proven to be relatively insensitive measures of protective L2 antibodies. Based on our understanding of the in vivo infectious process, we have recently developed a novel in vitro neutralizing assay that is 1000-fold more sensitive measure of L2 antibody activity. This assay will be critical in the further clinical development of L2-based vaccines, which we previously discovered to induce antibodies that, unlike L1 VLP vaccines, broadly cross-neutralize divergent mucosal and cutaneous HPV types. Our development of a method to induce efficient HPV pseudovirus infection of the female genital tract after transient disruption with the over-the-counter spermicide nonoxonol-9 has proven to be the key to our recent development of an effective, and we believe practical, intravaginal vaccination strategy. We have found that intravaginal pseudovirus vaccination of N-9 treated mice induces strong systemic and mucosal T and B cell responses to target antigens transduced by the pseudovirions. Systemic responses rival those induced by previously optimized Ad5 vectors. Intravaginal responses are remarkably strong, with up to 80% of all intravaginal CD8 T cells staining tetramer positive for the targeted antigen. Most of the induced T appear to be intraepithelial, and high level of effector memory CD8 T cells are maintained in the vaginal tract 100 days after vaccination. Critically, CD8 IEL's were not induced after systemic vaccination with Ad5 vectors. Intravaginal pseudovirus vaccination is a promising approach for focusing immune responses to the female genital tract and so might increase the effectiveness of vaccines directed against HSV and HIV infections and against HPV induced neoplasia. This concept was tested in an SIV/rhesus macaque intravaginal challenge model in collaboration with Dr. Franchini. In collaboration with Dr. Jeff Cohen, vectors expressing HSV antigens are being tested in mouse and guinea pig HSV-2 challenge models. We have determined that intravaginal delivery of Adenovirus 5 vectors induce similar locals T cell responses as intravaginal delivery of HPV pseudovirions and are superior at inducing systemic T cell responses. In collaborated with Crucell/Johnson & Johnson, we have determine that Ad26 and Ad35 vectors behave similarly. Crucell has extensive expertise in GMP production of their adenovirus vectors, which should greatly facilitate translation of our findings into a clinical trial. To more generally evaluate the potential of HPV pseudoviruses as gene transfer vehicles, we have conducted a broad infection tropism survey. In patent pending studies, we demonstrated that intact murine epithelium at |