Development of a Pan-Oncogenic HPV Preventive Vaccine

泛癌基因HPV预防疫苗的研制

基本信息

批准号：
8379244
负责人：
WARNER KING HUH
金额：
$ 26.49万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8379244
关键词：
Address Amino Acids Anogenital venereal warts Antibodies Antigens Area Bacteria Benign Blood Circulation Capsid Cervarix Chimeric Proteins Clinical Research Clinical Trials Commit Cottontail Rabbit Papillomavirus Developing Countries Development Disease Distant Dose Double-Blind Method Epidermodysplasia Verruciformis Epithelium Escherichia coli Gardasil Genital system Genotype Goals Human Papilloma Virus Vaccine Human Papillomavirus Human papilloma virus infection Human papillomavirus 16 Human papillomavirus 18 Human papillomavirus 6 Immune Sera Immunoglobulin G Immunoglobulin M Infection Instruction L1 viral capsid protein Laboratory Research Lesion Letters Malignant Neoplasms Malignant neoplasm of cervix uteri Minor Mus Oncogenic Oryctolagus cuniculus Papillomavirus Infections Patients Phase I Clinical Trials Placebo Control Preventive Preventive Intervention Resources Risk Safety Screening procedure Testing Time United States United States Food and Drug Administration Vaccinated Vaccination Vaccines Vagina Viral Virus Virus-like particle Woman aluminum sulfate base clinically significant cost meetings neutralizing antibody novel polypeptide programs therapy development transmission process vaccine development vaccine evaluation

项目摘要

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.

HPV蛋白质L1和L2是植物学独立的保护剂。我们建议L2作为一个保守保护者。抗原。支持基于L2的PAN-CONIC HPV疫苗的可能性。与当前的LI VLP疫苗相比，跨性别的抗体是在美国产生的，泛型HPV的影响最大。预防干预开发（Rapid，NCI） - 级 HPV6，16和18的融合蛋白组成（L2 11-200x3）与该拟议的HPV L2 L2 11-200x3多肽在校友辅助患者中的辅助辅助剂（11-200x3）是安全的执行双盲，安慰剂对照，剂量升级的I期试验，以评估健康女性的安全性HPV L2 11-200x3多肽。明矾中HPV L2 11-200x3 polvpeptide患者的疫苗接种确定校友中HPV L2 11-200x3的剂量在中和的滴度方面，以及与Gardasil相比的HPV类型的剂量。。 HPV？L2特异性HPV的假设是生殖道的相关性。用HPV伪文化对小鼠的挑战，并比较保护所需的最小中和质滴度。