Development of a Pan-Oncogenic HPV Preventive Vaccine

泛癌基因HPV预防疫苗的研制

• 批准号: 8326151
• 负责人: WARNER KING HUH
• 金额: $ 26.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8326151
• 关键词: Address; Amino Acids; Anogenital venereal warts; Antibodies; Antigens; Area; Bacteria; Benign; Blood Circulation; Capsid; Cervarix; Chimeric Proteins; Clinical Research; Clinical Trials; Commit; Cottontail Rabbit Papillomavirus; Developing Countries; Development; Disease; Distant; Dose; Double-Blind Method; Epidermodysplasia Verruciformis; Epithelium; Escherichia coli; Gardasil; Genital system; Genotype; Goals; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Human papillomavirus 18; Human papillomavirus 6; Immune Sera; Immunoglobulin G; Immunoglobulin M; Infection; Instruction; L1 viral capsid protein; Laboratory Research; Lesion; Letters; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Minor; Mus; Oncogenic; Oryctolagus cuniculus; Papillomavirus Infections; Patients; Phase I Clinical Trials; Placebo Control; Preventive; Preventive Intervention; Resources; Risk; Safety; Screening procedure; Testing; Time; United States; United States Food and Drug Administration; Vaccinated; Vaccination; Vaccines; Vagina; Viral; Virus; Virus-like particle; Woman; aluminum sulfate; base; clinically significant; cost; meetings; neutralizing antibody; novel; polypeptide; programs; therapy development; transmission process; vaccine development; vaccine evaluation

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.

两种HPV衣壳蛋白L1和L2是植物园独立的保护抗原。 HPV L1病毒样颗粒（VLP）的疫苗接种可诱导具有强类型限制的患者中和抗体和保护。对> 15个已知的致癌HPV的广泛保护对于宫颈癌的细胞学筛查和放射分配的事件是必要的。我们建议L2作为一个保守的保护 抗原。我们已经在兔子和小鼠中显示了在细菌中产生的L2 11-200的吸尘器，可以预防同源病毒类型以及进化上远距离的异源类型（即用HPVL 6 L2 11-200真空吸尘，可预防兔子毛皮乳头病毒感染），以避免兔子乳头状瘤感染），以支持L2基于L2的PANCINE的可能性。此外，我们已经表明，用L2吸尘会诱导 患者的跨中和抗体。与当前的多价LI VLP疫苗不同，大肠杆菌中产生的单个基于L2的抗原的生产价格便宜。因此，生产成本较低的泛氧HPV类型对美国和发展中国家的影响不足的影响最大。预防干预开发（Rapid，NCI）计划的快速访问正在生产GMP级 融合蛋白包含HPv6、16和18的L2 11-200（L2 11-200X3），并针对该提出的临床试验进行了校正调整。假设1：明矾调节中HPV L2 11-200x3多肽患者的疫苗接种是安全的。具体目标1：进行双盲，安慰剂对照，剂量不断升级的I期试验，以评估健康女性中安全HPV L2 11-200x3多肽疫苗接种。假设2： 校友中HPV L2 11-200x3 plevpeptide的疫苗接种可诱导高滴定的广泛中和抗体的滴度。具体目的＃2：在中和抗体的滴度以及与Gardasil¿HPV感染相比，中和类型中和HPV类型的光谱相比，HPV L2 11-200x3的剂量范围仅限于上皮细胞，并且不进入血液，并且不进入血液中，却不进入血液中，但中性地转移到中性igg中的中性igg to the Bloodsets carted tocled carted carted tocled carted carted carted。抗体在哪里相遇并中和 HPV？假设3：L2特异性HPV中和抗体进入生殖道是保护的相关相关性。具体目的3：确定用HPV L2 11-200x3接种的患者的IgG或IgM被动转移是否是否会赋予HPV Pseudovision的小鼠挑战的HPV16 Li Capsomeres或Gardasil的抗药性，并比较最小的中性抗体替代者所需的保护剂。