Development of a Pan-Oncogenic HPV Preventive Vaccine

两种HPV衣壳蛋白L1和L2是不依赖于肉毒杆菌素的保护性抗原。接种疫苗）HPV L1病毒样颗粒（VLP）诱导中和抗体并保护强型患者 限制.对>15种已知致癌HPV的广泛保护对于最终停止是必要的 细胞学筛查和根除宫颈癌的重要性。我们建议L2作为一个单一的保守的保护 抗原的我们已经在兔子和小鼠中证明，用细菌中产生的L2 11-200疫苗接种可以保护 针对同源病毒类型以及进化上远缘的异源类型（即显著地 用HPV 16 L211 -200疫苗接种保护兔乳头瘤病毒感染）支持了以下可能性： 一种L2基因的泛致癌HPV疫苗此外，我们已经表明，接种L2诱导 患者体内的交叉中和抗体与目前的多价L1 VLP疫苗不同，单一的基于L2的VLP疫苗可用于免疫接种。 E.大肠杆菌的生产成本低廉。因此，成本较低的泛致癌HPV类型 生产将在美国和发展中国家服务不足的地区产生最大的影响。的 快速获得预防干预发展（RAPID，NCI）计划正在生产GMP级 包含HPV 6、16和18的串联的L2 11-200（L2 11- 200 × 3）的融合蛋白与明矾佐剂 拟进行临床试验。假设1：用明矾中的HPV L2 11- 200 x3多肽接种患者 佐剂是安全的。具体目标#1：进行一项双盲、安慰剂对照、剂量递增的I期研究 在健康女性中评估HPV L2 11- 200 x3多肽疫苗接种安全性的试验。假设2： 用明矾佐剂中的HPV L2 11- 200 x3多肽对患者进行疫苗接种诱导了广泛的HPV L2 11- 200 x3多肽的高滴度。 中和抗体具体目标#2：确定HPV L2 11- 200 x3在明矾中的剂量范围， 关于中和抗体的滴度以及中和的HPV类型的谱， 加德西HPV感染仅限于上皮，不会进入血液，但呈被动感染 中和IgG转移到血流中是保护性的。抗体在哪里相遇并中和 人乳头瘤病毒？假设3：L2特异性HPV中和抗体渗出到生殖道是HPV感染的主要原因。 相关保护。具体目标#3：确定是否被动转移小鼠IgG或 来自接种HPV L2 11- 200 x3、HPV 16 LI衣壳或Gardasil的患者的IgM将赋予 保护小鼠免受HPV假病毒体的阴道攻击，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种已知的致癌HPV类型是宫颈癌的必要原因。 广泛的保护可能需要昂贵的高度多价的L1病毒样颗粒（VLP）疫苗，但 商业HPV疫苗目前仅利用来自两种致癌类型（HPV 16和HPV 18）的VLP。我们 目标是通过开发一种具有保护性的单一疫苗来消除HPV相关癌症 针对所有致癌HPV类型，并且基于次要病毒衣壳抗原L2。

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.