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

描述（由申请人提供）：一些流行病学研究已经确定致癌型人乳头瘤病毒（HPV）感染是宫颈癌的必要原因。超过99%的子宫颈癌含有“高风险”人乳头瘤病毒基因，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型HPV的单一疫苗来消除HPV相关的癌症。两种HPV衣壳蛋白L1和L2都是独立的保护性抗原。疫苗接种HPV L1病毒样颗粒（VLP）诱导中和抗体和保护强型限制患者。对于最终停止细胞学筛查和根除宫颈癌来说，广泛预防bbbb15已知的致癌hpv是必要的。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。我们认为L2是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，L2中和抗体也可以交叉中和多种HPV基因型。接种牛乳头瘤病毒4型（BPV4） L2 11-200疫苗可以防止BPV4对软腭的攻击。此外，接种HPV16 L2 11-200疫苗的家兔对棉尾兔乳头瘤病毒（CRPV）的皮肤感染和兔口腔乳头瘤病毒（ROPV）的粘膜攻击均有保护作用。因此，接种细菌中产生的L2 11-200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的泛致癌HPV疫苗的可能性。与目前可用的L1 VLP疫苗不同，在大肠杆菌中生产的单一基于l2的抗原生产成本低廉。因此，一种生产成本较低的泛致癌型HPV将在美国和发展中国家的服务不足地区产生最大的影响。快速获取预防干预开发（Rapid， NCI）项目正在为这项拟议的临床试验生产gmp级HPV 16 L2 11-200。假设1：接种HPV16 L2 11-200多肽的患者在有无佐剂的情况下是安全的。具体目标1：评估在健康女性中接种GMP级HPV16 L2 11-200疫苗是否安全。假设2:HPV16 L2 11-200多肽在患者体内具有免疫原性，加入佐剂可增强其免疫原性。特定目的2：确定哪种配方和最小剂量的GMP级HPV16 11-200多肽加佐剂可诱导中和抗体的最大滴度，以及接种最佳配方GMP级HPV16 11-200多肽的患者血清中和的HPV类型谱。假设3:l2特异性HPV中和抗体进入生殖道与保护相关。特异性目的#3：确定l2特异性人IgG或IgM小鼠的被动转移是否会保护小鼠免受HPV假病毒粒子的阴道攻击，并确定保护的最小中和抗体滴度。

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.