A Phase I Study to Evaluate the Safety and Immunogenicity of HPV 16 L2 11-200

评估 HPV 16 L2 11-200 安全性和免疫原性的 I 期研究

基本信息

批准号：
7693774
负责人：
WARNER KING HUH
金额：
$ 35.52万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-29 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7693774
关键词：
Address Adjuvant Animal Model Anogenital venereal warts Antibodies Antigens Area Bacteria Benign Blood Circulation Bovine Papillomavirus Cattle Clinical Clinical Research Clinical Trials Cottontail Rabbit Papillomavirus Cutaneous Developed Countries Developing Countries Development Disease Distant Dose Drug Formulations Epidemiologic Studies Epidermodysplasia Verruciformis Epithelium Escherichia coli Future Genes Genital system Genotype Goals HPV-High Risk Human Human Papilloma Virus Vaccine Human Papillomavirus Human papilloma virus infection Human papillomavirus 16 Immune Sera Immunoglobulin G Immunoglobulin M Infection L1 viral capsid protein Laboratory Research Left Lesion Malignant Neoplasms Malignant neoplasm of cervix uteri Mediating Molecular Mus Oncogenic Oral Oryctolagus cuniculus Pan Genus Papillomavirus Patients Phase I Clinical Trials Preventive Intervention Resources Risk Safety Screening procedure Serum Soft Palate Testing Time United States United States Food and Drug Administration Vaccinated Vaccination Vaccines Vagina Viremia Virus Virus-like particle Woman base cancer prevention clinically significant cost immunogenic immunogenicity meetings neutralizing antibody novel polypeptide programs public health relevance therapy development transmission process vaccine development vaccine evaluation

项目摘要

DESCRIPTION (provided by applicant): Several epidemiologic studies have identified infection with oncogenic type human papillomavirus (HPV) as a necessary cause of cervical cancer. More than 99% of cervical cancers contain genes of "high risk" HPVs, of which there are at least 15 different types. Our goal is to eliminate HPV-related cancer through the development of a single vaccine that is protective against all oncogenic HPV types. The two HPV capsid proteins, L1 and L2, are both 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. Broad protection may require an expensive highly multivalent L1 VLP vaccine, but current commercial clinical studies utilize VLPs from only two oncogenic types. We propose L2 as a single conserved protective antigen. Protection in animal models is mediated by L2 neutralizing antibodies which also cross-neutralize diverse HPV genotypes. Vaccination of cattle with bovine papillomavirus type 4 (BPV4) L2 11-200 protects against BPV4 challenge on the soft palate. Furthermore, vaccination of rabbits with HPV16 L2 11-200 protects against both cutaneous infection with cottontail rabbit papillomavirus (CRPV) and mucosal challenge with rabbit oral papillomavirus (ROPV). Thus, vaccination with L2 11-200 produced in bacteria protects against both the homologous virus type as well as evolutionarily distant heterologous types supporting the possibility of an L2-based pan-oncogenic HPV vaccine. Unlike currently available L1 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 HPV 16 L2 11-200 for this proposed clinical trial. HYPOTHESIS 1: Vaccination of patients with HPV16 L2 11-200 polypeptide is safe with or without adjuvant. Specific Aim #1: To evaluate whether vaccination using GMP grade HPV16 L2 11-200 with and without adjuvant is safe in healthy women. HYPOTHESIS 2: The HPV16 L2 11-200 polypeptide is immunogenic in patients and formulation with adjuvant enhances its immunogenicity. Specific Aim #2: To determine which formulation and minimal dose of GMP grade HPV16 11-200 polypeptide with adjuvant induces the maximal titers of neutralizing antibody and also the spectrum of HPV types neutralized by sera of patients vaccinated with the optimal formulation of GMP grade HPV16 11-200 polypeptide. 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 L2-specific human IgG or IgM will confer protection from vaginal challenge of mice with HPV pseudovirion and determine the minimal neutralizing antibody titer for protection. PUBLIC HEALTH RELEVANCE: Several clinical and molecular epidemiologic studies have identified infection with oncogenic type human papillomavirus (HPV) as a necessary cause of cervical cancer. Unlike currently available L1 VLP vaccines, vaccination with L2 11-200 produced in bacteria protects against both the homologous virus type as well as evolutionarily distant heterologous types, supporting the possibility of an L2-based pan-oncogenic HPV vaccine. Furthermore, it is known that HPV type distribution is markedly different throughout the world and a pan-oncogenic L2 HPV vaccine, that is substantially cheaper to produce in E. coli, may have a substantial global impact, particularly in developing nations and low resource settings where 80% of cervical cancer occurs.

描述（由申请人提供）：几项流行病学研究已将致癌型人乳头瘤病毒（HPV）的感染确定为宫颈癌的必要原因。超过99％的子宫颈癌包含“高风险” HPV的基因，其中至少有15种不同的类型。我们的目标是通过开发一种针对所有致癌HPV类型的单一疫苗来消除与HPV相关的癌症。两个HPV衣壳蛋白L1和L2都是独立的保护抗原。用HPV L1病毒样颗粒（VLP）疫苗接种可诱导强型限制患者中和抗体和保护。对> 15个已知的致癌HPV的广泛保护对于最终停止细胞学筛查和消除宫颈癌是必要的。广泛的保护可能需要昂贵的高度多价L1 VLP疫苗，但是当前的商业临床研究仅利用两种致癌类型的VLP。我们建议L2作为单个保守的保护抗原。动物模型中的保护是通过中和抗体介导的，这些抗体也使多样化的HPV基因型跨性别化。用牛乳头瘤病毒4型（BPV4）L2 11-200疫苗接种牛，可预防软口感上的BPV4挑战。此外，用HPV16 L2 11-200疫苗接种兔子可以防止用棉铃兔乳头瘤病毒（CRPV）（CRPV）和兔口腔乳头瘤病毒（ROPV）的粘膜挑战。因此，在细菌中产生的L2 11-200的疫苗接种可预防同源病毒类型以及进化远处的异源类型，这些类型支持基于L2的基于L2的泛氧化HPV疫苗的可能性。与当前可用的L1 VLP疫苗不同，大肠杆菌中产生的单个基于L2的抗原的生产价格便宜。因此，生产成本较低的泛氧HPV类型对美国和发展中国家的影响不足的影响最大。该建议的临床试验的快速进入预防干预开发（Rapid，NCI）计划正在生产GMP级HPV 16 L2 11-200。假设1：HPV16 L2 11-200多肽患者的疫苗接种是安全的。具体目的＃1：评估使用有或没有辅助剂的GMP级HPV16 L2 11-200的疫苗接种在健康女性中是否安全。假设2：HPV16 L2 11-200多肽在患者中具有免疫原性，并具有辅助配方增强其免疫原性。具体目的＃2：确定GMP级HPV16 11-200多肽的配方和最小剂量与辅助诱导中和抗体的最大滴度以及由GMP HPV16 11-200 Polypeptypolypypypledepy的最佳成型的患者疫苗接种的患者血清中和的HPV类型的光谱。假设3：L2特异性HPV中和抗体进入生殖道是保护的相关相关性。特定目的＃3：确定用L2特异性人IgG或IgM的小鼠被动转移是否会赋予用HPV伪循环的小鼠的阴道挑战的保护，并确定最小的中和抗体滴度以保护。公共卫生相关性：几项临床和分子流行病学研究已将致癌型人乳头瘤病毒（HPV）的感染确定为宫颈癌的必要原因。与当前可用的L1 VLP疫苗不同，在细菌中产生的L2 11-200疫苗可以预防同源病毒类型以及进化上远距离异源类型，从而支持基于L2的基于L2的泛氧化HPV疫苗。此外，众所周知，HPV类型的分布在世界范围内截然不同，并且在大肠杆菌中生产的泛氧化L2 L2 HPV疫苗可能会产生实质性的全球影响，尤其是在发展中国家和低资源环境中，其中80％的宫颈癌发生。