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

描述（由申请人提供）：几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。超过99%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单一的疫苗来消除HPV相关的癌症，这种疫苗可以保护所有致癌的HPV类型。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，并在强型限患者中产生保护作用。对>15种已知致癌HPV的广泛保护对于最终停止细胞学筛查和根除宫颈癌是必要的。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利用两种致癌类型的VLP。我们建议L2作为一个单一的保守的保护性抗原。动物模型中的保护作用由L2中和抗体介导，L2中和抗体也交叉中和不同的HPV基因型。用牛乳头瘤病毒4型（BPV 4）L2 11-200接种牛可保护软腭免受BPV 4攻击。此外，用HPV 16 L2 11-200接种兔可防止棉尾兔乳头瘤病毒（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接种疫苗可保护抵抗同源病毒类型以及进化上远距离的异源类型，支持基于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E.大肠杆菌的生产成本低廉。因此，生产成本较低的泛致癌HPV类型将在美国和发展中国家服务不足的地区产生最大的影响。快速获得预防干预开发（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：用HPV 16 L2 11-200多肽接种患者在有或没有佐剂的情况下是安全的。具体目标#1：评价使用GMP级HPV 16 L2 11-200（含和不含佐剂）接种疫苗在健康女性中是否安全。假设2：HPV 16 L2 11-200多肽在患者中具有免疫原性，并且与佐剂一起配制增强其免疫原性。具体目标#2：确定GMP级HPV 16 11-200多肽与佐剂的哪种制剂和最小剂量诱导中和抗体的最大滴度，以及用GMP级HPV 16 11-200多肽的最佳制剂接种的患者的血清中和的HPV类型谱。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：确定小鼠被动转移L2特异性人IgG或IgM是否可保护小鼠免受HPV假病毒体阴道攻击，并确定保护的最小中和抗体滴度。 公共卫生相关性：一些临床和分子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。与目前可用的L1 VLP疫苗不同，用细菌中产生的L2 11-200接种疫苗可保护抵抗同源病毒类型以及进化上远距离的异源类型，支持基于L2的泛致癌HPV疫苗的可能性。此外，已知HPV类型分布在世界各地显著不同，并且在大肠杆菌中生产的全致癌L2 HPV疫苗便宜得多。大肠杆菌，可能会产生重大的全球影响，特别是在发展中国家和低资源环境中，80%的宫颈癌发生。

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.