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：
7727551
负责人：
WARNER KING HUH
金额：
$ 31.27万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7727551
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 Developed Countries 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 papillomavirus 16 Human papillomavirus 18 Human papillomavirus 6 Immune Sera Immunoglobulin G Immunoglobulin M Infection Instruction L1 viral capsid protein Laboratory Research Left Lesion Letters Malignant Neoplasms Malignant neoplasm of cervix uteri Minor Mus Oncogenic Oryctolagus cuniculus Pan Genus Papillomavirus Infections Patients Phase I Clinical Trials Placebo Control Preventive Preventive Intervention Reproduction spores Research Personnel 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. 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.

两种 HPV 衣壳蛋白 L1 和 L2 是 HPV 疫苗独立的保护性抗原。 L1 病毒样颗粒 (VLP) 诱导强型患者中和抗体并提供保护对于最终停止使用，需要针对 >15 种已知致癌 HPV 提供广泛的保护。我们建议 L2 作为单一保守的保护性手段。我们已经在兔子和小鼠身上证明，接种细菌产生的 L2 11-200 可以起到保护作用。针对同源病毒类型以及进化上遥远的异源类型（即）接种 HPV1 6 L2 11-200 可预防兔乳头瘤病毒感染）支持了这种可能性基于 L2 的全致癌 HPV 疫苗的研究此外，我们已经证明，接种 L2 疫苗可诱导感染。与目前的多价 LI VLP 疫苗不同，基于单一 L2 的疫苗。大肠杆菌产生的抗原的生产成本较低，因此，全致癌 HPV 类型的成本较低。生产将对美国和发展中国家服务欠缺的地区产生最大的影响。快速获得预防性干预开发（RAPID、NCI）计划正在生产 GMP 级产品融合蛋白，包含 HPV6、16 和 18 的 L2 11-200 串联 (L2 11-200x3)，并为此使用明矾佐剂拟议的临床试验。假设 1：用明矾中的 HPV L2 11-200x3 多肽对患者进行疫苗接种。佐剂是安全的。具体目标#1：进行双盲、安慰剂对照、剂量递增的第一阶段。评估健康女性 HPV L2 11-200x3 多肽疫苗接种安全性的试验假设 2：使用明矾佐剂对 HPV L2 11-200x3 多肽患者进行疫苗接种可诱导广泛的高滴度具体目标#2：确定明矾中 HPV L2 11-200x3 的剂量范围。与中和抗体的滴度以及中和的 HPV 类型谱相比加德西 (Gardasil) HPV感染仅限于上皮细胞，不进入血液，呈被动性中和 IgG 转移到血液中具有保护作用，抗体在哪里相遇并中和。假设 3：L2 特异性 HPV 中和抗体渗出到生殖道是具体目标#3：确定小鼠是否被动转移 IgG 或来自 HPV L2 11-200x3、HPV16 LI 壳粒或 Gardasil 患者的 IgM 将赋予保护小鼠免受 HPV 假病毒粒子的阴道攻击并比较最小中和保护所需的抗体滴度。相关性（参见说明）：持续感染超过 15 种已知致癌 HPV 类型中的任何一种是宫颈癌的必要原因。广泛的保护可能需要昂贵的高多价 LI 病毒样颗粒 (VLP) 疫苗，但是商业 HPV 疫苗目前仅使用两种致癌类型（HPV16 和 HPV18）的 VLP。目标是通过开发单一的保护性疫苗来消除 HPV 相关癌症针对所有致癌 HPV 类型，基于次要病毒衣壳抗原 L2。