Development of a Pan-Oncogenic HPV Preventive Vaccine

点击翻译按钮获取中文摘要

The two HPV capsid proteins, L1 and L2, are botin independent protective antigens. Vaccination with) HPV L1 virus-like particles (VLP) Induces neutralizing antibodies and protection in patients with strong type restriction. Broad protection against the >15 known oncogenic HPVs is necessary for the eventual cessation of cytologic screening and eradication of cervical cancer. We propose L2 as a single conserved protective antigen. We have shown in rabbits and mice that vaccination with L2 11-200 produced in bacteria protects against both the homologous virus type as well as evolutionarily distant heterologous types (i.e. remarkably vaccination with HPVl 6 L2 11-200 protects against rabbit papillomavirus infection) supporting the possibility of an L2-based pan-oncogenic HPV vaccine. Furthermore, we have shown that vaccination with L2 induces cross-neutralizing antibodies in patients. Unlike current multivalent LI VLP vaccines, a single L2-based antigen produced in E. coli is inexpensive to produce. As such, a pan-oncogenic HPV type that is less costly to produce would have its greatest impact in underserved areas in the US and in developing nations. The Rapid Access to Preventive Intervention Development (RAPID, NCI) program is producing GMP-grade fusion protein comprising L2 11-200 of HPV6, 16 and 18 in tandem (L2 11-200x3) with alum adjuvant for this proposed clinical trial. HYPOTHESIS 1: Vaccination of patients with HPV L2 11-200x3 polypeptide in alum adjuvant is safe. Specific Aim #1: To perform a double-blinded, placebo-controlled, dose escalating Phase I trial to evaluate the safety HPV L2 11-200x3 polypeptide vaccination in healthy women. HYPOTHESIS 2: Vaccination of patients with HPV L2 11-200x3 polvpeptide in alum adjuvant induces high titers of broadly neutralizing antibodies. Specific Aim #2: To determine the dose ranging for HPV L2 11-200x3 in alum with respect to titers of neutralizing antibody and also the spectrum of HPV types neutralized in comparison to Gardasil¿. HPV infection is restricted to the epithelium and does not enter the bloodstream, yet passive transfer of neutralizing IgG into the bloodstream is protective. Where does the antibody meet and neutralize HPV? HYPOTHESIS 3: Transudation of L2-specific HPV neutralizing antibody into the genital tract is the relevant correlate of protection. Specific Aim #3: To determine whether passive transfer of mice with IgG or IgM from patients vaccinated with HPV L2 11-200x3, HPV16 LI capsomeres or Gardasil will confer protection from vaginal challenge of mice with HPV pseudovirion and compare the minimal neutralizing antibody titers required for protection. RELEVANCE (See instructions): Persistent infection with any of over 15 known oncogenic HPV types is a necessary cause of cervical cancer. Broad protection may require an expensive highly multivalent LI virus-like particle (VLP) vaccine, but commercial HPV vaccines currently utilize VLPs from only two oncogenic types (HPV16 and HPV18). Our goal is to eliminate HPV-related cancer through the development of a single vaccine that is protective against all oncogenic HPV types and is based upon the minor viral capsid antigen, L2.