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)可在强型限制性患者中诱导中和抗体和保护。对于已知的致癌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。我们认为L2是一种单一的守恒保护 抗原。我们已经在兔和小鼠身上证明，在细菌中产生的L211-200疫苗既可以保护同源病毒类型，也可以保护进化上遥远的异源类型(即，显著地接种HPV16L211-200可以预防兔乳头状瘤病毒感染)，支持基于L2的泛致癌HPV疫苗的可能性。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，在大肠杆菌中生产的单一L2抗原生产成本较低。因此，一种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影响。快速获取预防干预发展(RAPID，NCI)计划正在产生GMP级 融合蛋白包括HPV6、16和18的L2 11-200与明矾佐剂串联(L2 11-200x3)，用于这项拟议的临床试验。假设1：在明胶佐剂中接种HPVL211-200x3多肽是安全的。具体目标#1：进行一项双盲、安慰剂对照、剂量递增的I期试验，以评估健康女性接种HPVL211-200x3多肽疫苗的安全性。假设2： 在明胶佐剂中接种HPVL211-200x3多肽可诱导高滴度的广谱中和抗体。具体目标#2：根据中和抗体滴度确定明矾中HPVL211-200x3的剂量范围，并与Gardasil进行比较，确定中和HPV型谱。HPV感染仅限于上皮细胞，不会进入血液，但被动地将中和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与保护相关。具体目的#3：确定被动转移来自HPVL211-200x3、HPV16LI胶囊或Gardasil患者的Ig G或Ig M的小鼠是否对HPV假病毒粒子小鼠的阴道攻击具有保护作用，并比较保护所需的最低中和抗体效价。

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.