Development of a Pan-Oncogenic HPV Preventive Vaccine

HPV衣壳蛋白L1和L2是Botin独立的保护性抗原。接种)HPV L1病毒样颗粒(VLP)诱导强直型患者产生中和抗体及其保护作用 限制。对于已知的致癌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。我们认为L2是一种单一的守恒保护 抗原。我们已经在兔子和小鼠身上表明，接种细菌中产生的L211-200疫苗可以保护 针对同源病毒类型以及进化上遥远的异源类型(即显著 接种HPV16L211-200可预防兔乳头瘤病毒感染)支持这种可能性 一种基于L2的泛致癌HPV疫苗。此外，我们已经证明，接种L2疫苗可以诱导 患者体内的交叉中和抗体。与目前的多价Li VLP疫苗不同，单一的L2为基础的疫苗 在大肠杆菌中生产的抗原生产成本不高。因此，一种成本较低的泛致癌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影响。这个 快速获取预防干预发展(RAPID，NCI)计划正在产生GMP级 由HPV6、16和18L211-200与明矾佐剂串联(L211-200x3)的融合蛋白 拟议的临床试验。假设1：患者接种明胶中HPVL211-200x3多肽 佐剂是安全的。具体目标1：实施双盲、安慰剂对照、剂量递增的I阶段 健康女性HPVL211-200x3多肽疫苗安全性评价试验假设2： 明胶佐剂中接种HPVL2 11-200x3多肽可诱导高滴度广谱 中和抗体。具体目标2：确定HPVL211-200x3在明矾中的剂量范围 关于中和抗体滴度以及中和HPV类型的谱与 加德西尔。HPV感染仅限于上皮细胞，不会进入血流，但仍是被动的 将中和的免疫球蛋白转移到血液中是有保护作用的。抗体在哪里相遇并中和？ 人类乳头瘤病毒?假设3：L2特异性HPV中和抗体渗入生殖道是 相关保护的关联性。具体目标#3：确定被动转移免疫球蛋白或 接种HPVL211-200x3、HPV16LI胶囊或Gardasil的患者的免疫球蛋白将提供 人乳头瘤病毒假病毒粒子对小鼠阴道攻击的保护作用及最小中和作用的比较 保护所需的抗体滴度。 相关性(请参阅说明)： 持续感染已知的15种致癌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度多价LI病毒样颗粒(VLP)疫苗，但 商业HPV疫苗目前仅使用来自两种致癌类型(HPV16和HPV18)的VLP。我们的 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 抗所有致癌的HPV类型，基于次要的病毒衣壳抗原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.