Understanding Papillomavirus Virion Proteins and Vaccines

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

In HPV vaccine clinical trials, our five year 20,000 young women ESCUDDO trial is now complete and has formally established the non-inferiority of single vs two doses of two commercial HPV vaccines in preventing vaccine-type specific persistent infection. A manuscript reporting these finding has been submitted to NEJM, on which I am co-senior author. A follow up study to examine comparable efficacy to ten years is in the final planning stage. We also recently published the results of PRIMAVERA which evaluated the VLP antibody responses to a single dose of Cervarix in girls to three doses of Gardasil in young women. To further understand the exceptionally high potency of the HPV vaccines, we investigated the ability of vaccine-induced antibodies to prevent in vitro infection even after the virions have bound the cell surface. Surprisingly, sera from almost all vaccinated women completely prevent infection even if added at a 1/250 dilution six hours after virion attachment to the cell surface. Unexpectedly, three distinct mechanism of post-attachment neutralization were discovered, release of virions from the cell surface, retention on the cells surface and rapid virion degradation after endocytosis. A manuscript reporting these findings has been submitted for publication. We are now examining if the antibodies from women with rare breakthrough infections lack this activity, since these presumptive vaccine failures have not correlated with VLP antibody levels in simple binding assays. With Aura, our industry collaborators, we are currently in a phase 3 study of ocular melanoma and phase 1 trial of bladder cancer using VLP-infrared activated dye conjugates. We are observing encouraging preliminary results in the bladder cancer trial, including complete remissions in non-muscle invasive cancers after a single dose. These trials are based on preclinical proof-of-concepts studies conducted by the lab. We are currently evaluating the efficacy of this treatment strategy in other mouse tumor models, including breast and glioblastoma. We have filled a patent application with Hisataka Kobayashi and Peter Choyke in CCRs Molecular Imaging Program on alternative cytotoxic dyes to conjugate to the VLPs. In basic cancer biology studies, we have completed a study to understand why most why most types of cancer cells evolve to express cell surface proteoglycans that mimic those normal restricted to the basement membrane that serve as the initial HPV virion attachment factors. In brief, the specific HPSG modification that are recognized by the HPV capsids are markers for am intermediate epithelial to mesenchymal transition to a dedifferentiated state. Encouragingly, we have preliminary evidence that these determinants are on the surface of cancer stem cells.