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）：多项流行病学研究已确定致癌型人乳头瘤病毒（HPV）感染是宫颈癌的必要原因。 99%以上的宫颈癌含有“高危”HPV基因，其中至少有15种不同类型。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 HPV 相关癌症。两种 HPV 衣壳蛋白 L1 和 L2 都是独立的保护性抗原。 HPV L1 病毒样颗粒 (VLP) 疫苗接种可诱导中和抗体，对类型限制性强的患者提供保护。为了最终停止细胞学筛查和根除宫颈癌，有必要针对 >15 种已知致癌 HPV 提供广泛的保护。广泛的保护可能需要昂贵的高多价 L1 VLP 疫苗，但目前的商业临床研究仅使用来自两种致癌类型的 VLP。我们建议 L2 作为单一保守的保护性抗原。动物模型中的保护作用是由 L2 中和抗体介导的，该抗体也可以交叉中和不同的 HPV 基因型。给牛接种 4 型牛乳头瘤病毒 (BPV4) L2 11-200 疫苗可以保护软腭免受 BPV4 攻击。此外，给兔子接种 HPV16 L2 11-200 疫苗可以预防棉尾兔乳头瘤病毒 (CRPV) 的皮肤感染和兔口腔乳头瘤病毒 (ROPV) 的粘膜攻击。因此，用细菌中产生的 L2 11-200 进行疫苗接种可以预防同源病毒类型以及进化上遥远的异源病毒类型，这支持了基于 L2 的泛癌基因 HPV 疫苗的可能性。与目前可用的 L1 VLP 疫苗不同，大肠杆菌生产的单一 L2 抗原的生产成本低廉。因此，生产成本较低的全致癌 HPV 类型将对美国和发展中国家服务不足的地区产生最大的影响。快速预防干预开发 (RAPID, NCI) 计划正在为这项拟议的临床试验生产 GMP 级 HPV 16 L2 11-200。假设 1：患者接种 HPV16 L2 11-200 多肽疫苗无论有或没有佐剂都是安全的。具体目标#1：评估使用 GMP 级 HPV16 L2 11-200 疫苗接种（含或不含佐剂）对健康女性是否安全。假设2：HPV16 L2 11-200 多肽在患者体内具有免疫原性，含有佐剂的制剂可增强其免疫原性。具体目标#2：确定 GMP 级 HPV16 11-200 多肽与佐剂的哪种配方和最小剂量可诱导中和抗体的最大滴度，以及用最佳配方的 GMP 级 HPV16 疫苗接种的患者血清中和的 HPV 类型谱11-200多肽。假设 3：L2 特异性 HPV 中和抗体渗出到生殖道是保护的相关因素。具体目标#3：确定被动转移具有 L2 特异性人 IgG 或 IgM 的小鼠是否会为具有 HPV 假病毒颗粒的小鼠提供免受阴道攻击的保护，并确定用于保护的最小中和抗体滴度。公共卫生相关性：多项临床和分子流行病学研究已确定致癌型人乳头瘤病毒 (HPV) 感染是宫颈癌的必要原因。与目前可用的 L1 VLP 疫苗不同，用细菌产生的 L2 11-200 进行疫苗接种可以预防同源病毒类型以及进化上遥远的异源病毒类型，支持基于 L2 的泛癌基因 HPV 疫苗的可能性。此外，众所周知，HPV 类型分布在世界各地明显不同，而用大肠杆菌生产的泛致癌 L2 HPV 疫苗的生产成本要低得多，可能会产生重大的全球影响，特别是在发展中国家和资源匮乏的地区80%的宫颈癌发生在这里。