Ll capsomeres as a next generation preventive HPV vaccine

Ll 壳粒作为下一代预防性 HPV 疫苗

• 批准号: 7727548
• 负责人: Robert L Garcea
• 金额: $ 31.33万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727548
• 关键词: Adjuvant; Adverse effects; Animal Experiments; Antibodies; Antigens; Award; Canis familiaris; Capsid; Cell Culture Techniques; Cells; Chimeric Proteins; Clinical; Clinical Trials; Cold Chains; Country; Cytotoxic T-Lymphocytes; Development; Dose; Drug Formulations; Escherichia coli; Gardasil; Generations; Genital Human Papilloma Virus Infection; Goals; HPV-High Risk; Human; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papillomavirus 16; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunization; Immunology; Infection; Inferior; Instruction; Knowledge; L1 viral capsid protein; Laboratory Study; Life; Link; Malignant neoplasm of cervix uteri; Medicine; Modeling; Mus; Patients; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Placebos; Preparation; Preventive; Production; Property; Proteins; Receptor Activation; Recombinants; Refrigeration; Reproduction spores; Research Personnel; Scheme; Specimen; Structure; Temperature; Testing; Time; Toll-like receptors; Toxic effect; Toxicology; Vaccinated; Vaccination; Vaccines; Vagina; Virus-like particle; Woman; Women' s Health; aluminum sulfate; base; cost; crosslink; immunogenic; immunogenicity; mouse model; neutralizing antibody; next generation; preclinical study; prevent; programs; prophylactic; recombinant virus; response; success

The recent development of prophylactic vaccines protective against "high risk" human papillomaviruses (HPV) is a landmark in medicine. The current vaccine is composed of recombinant virus-like particles (VLPs) of the major capsid protein, L1, including the high risk HPV types 16 and 18. Phase ll/lll clinical trials have shown >95% efficacy of these VLP preparations in preventing HPV 16, 18 infection, and thus hopefully preventing the eventual development of about 70% of cervical cancers associated with these types. Despite this success the VLP vaccines have the adverse attributes of high cost ($360 for the initial three immunizations In the USA) and a requirement for refrigeration {i.e., cold chain). We have previously characterized the immunogenic properties of VLP subunits, pentameric L1 capsomeres, and compared these "subunits" to VLPs in a canine infection model. In this model capsomeres appeared near equivalent to VLPs in inducing protection against infection. Capsomeres are purified after recombinant expression of L1 in E. coli as a GST-fusion protein, at levels suggesting a significant reduction in manufacturing expense. The protein is readily purified, and can be precipitated, resuspended, and stored at room temperature without loss of immunogenicity. In the context of an ongoing NCI RAPID award GST-L1 capsomeres have been proposed as a "next generation" HPV vaccine that might be ideally suited for production and use in underdeveloped countries of the world where cervical cancer is particularly prevalent. We propose to use the GST-L1 protein that has been GMP produced (by Shantha Biotechnica), vialed, and toxicology screened under the auspices of a RAPID award for study in a phase I human trial. In aims 1 and 2 we propose a dose escalation scheme of 15 subjects at each of three dose levels (10, 50, 500 micrograms and placebo), repeated three times, with concomitant analysis of toxicity, development of neutralizing antibodies, cytotoxic T-cell responses, and possible adverse effects of GST antibody development. In the third aim, laboratory studies with clinical specimens and animal experiments will test new adjuvant strategies including Toll-like receptor activation, and evaluate the effects on humoral immunity of antigen spacing and linking by comparing capsomeres, cross-linked capsomeres, and VLPs. Knowledge of L1 capsomere structure and interaction with the innate immune system will be utilized to generate longer-lived and broader immunity with lower and fewer doses. The results of this project will determine whether the GST-LI preparation can proceed to further phase II testing. RELEVANCE (See instructions): Persistent infection with high risk HPV is a necessary cause of cervical cancer. Our goal is the development of a next generation, non-inferior HPV preventive vaccine that is economically feasible for production for use in the underdeveloped world where the impact of cervical cancer on women's health is greatest.

预防高危人乳头瘤病毒疫苗的研究进展 人乳头瘤病毒(HPV)是医学界的里程碑。目前的疫苗是由重组病毒样颗粒组成的 主要衣壳蛋白L1的VLP，包括高危HPV 16和18型。11/11期临床试验 已经证明这些VLP制剂在预防HPV16、18型感染方面有95%的疗效，因此有望 预防与这些类型相关的大约70%的宫颈癌的最终发展。尽管 这种成功的VLP疫苗具有成本高的不利属性(最初的三种疫苗为360美元 美国的疫苗接种)和对冷藏的要求(即冷链)。我们之前已经 表征VLP亚基、五聚体L1囊膜的免疫原性，并进行比较 在犬感染模型中，这些“亚单位”与VLP结合。在这个模型中，胶囊看起来几乎相当于 VLP在诱导抵抗感染方面的作用。L1基因重组表达后衣壳蛋白的纯化 在大肠杆菌中作为GST融合蛋白，其水平表明制造成本显著降低。 这种蛋白质很容易提纯，可以沉淀、再悬浮并在室温下储存。 而不会失去免疫原性。在NCI快速颁奖的背景下，GST-L1胶囊具有 被提议作为“下一代”HPV疫苗，这种疫苗可能非常适合在 世界上宫颈癌特别流行的欠发达国家。我们建议使用 GMP生产的GST-L1蛋白(由Shantha Biotech公司生产)，瓶装，毒理筛选 在第一阶段人体试验研究的快速奖的赞助下。在目标1和目标2中，我们提出了一种剂量 三个剂量水平(10、50、500微克和安慰剂)各15名受试者的升级方案， 重复三次，同时分析毒性、中和抗体、细胞毒性 T细胞反应，以及GST抗体发展可能产生的不良影响。第三个目标，实验室 临床标本研究和动物实验将测试新的佐剂策略，包括Toll样 受体激活，并评价抗原间隔和连接对体液免疫的影响 比较胶囊粒、交联型胶囊粒和VLP。了解L1胶囊的结构和 与先天免疫系统的相互作用将被用来产生更持久和更广泛的免疫力 越来越少的剂量。该项目的结果将决定GST-Li制剂是否可以 继续进行第二阶段的进一步测试。 相关性(请参阅说明)： 持续感染高危HPV是宫颈癌的必然原因。我们的目标是发展 一种经济上可行的生产使用的下一代非劣质HPV预防性疫苗 在不发达的世界，宫颈癌对妇女健康的影响最大。