Thermostable RG1-VLPs, a candidate broadly protective HPV vaccine for the prevention of cervical cancer

热稳定性 RG1-VLP，一种用于预防宫颈癌的广泛保护性 HPV 候选疫苗

基本信息

批准号：
10005175
负责人：
WARNER KING HUH
金额：
$ 34.99万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10005175
关键词：
Address Adjuvant African American Aluminum Hydroxide Animals Antibodies Antibody Response Antibody titer measurement Antigens Award B-Lymphocyte Epitopes Baculoviruses Baltimore Biological Assay Cells Cervical Chimeric Proteins Clinical Research Cold Chains Country Crystallization Data Developing Countries Dose Dysplasia Economic Development Electron Microscope Enzyme-Linked Immunosorbent Assay Epitopes Female Formulation Freeze Drying Funding Geographic Locations Glass Goals Hispanics Human Papilloma Virus Vaccination Human Papilloma Virus Vaccine Human Papilloma Virus-Related Malignant Neoplasm Human Papillomavirus Human papilloma virus infection Human papillomavirus 16 Human papillomavirus 18 Human papillomavirus 6 Ice Immune Sera Immune response In Vitro Income Insecta L2 viral capsid protein Legal patent Location Malignant Neoplasms Malignant neoplasm of cervix uteri Measures Medical Care Costs Minor Monoclonal Antibodies Mucous Membrane Mus Oncogenic Oryctolagus cuniculus Patients Phylogenetic Analysis Pilot Projects Population Positioning Attribute Powder dose form Primary Prevention Process Property Proteins Protocols documentation Race Recombinant Proteins Recombinants Research Design Risk Safety Serum Shipping Spodoptera frugiperda Surface Technology Temperature Testing Toxicology Transition Temperature Vaccinated Vaccination Vaccine Antigen Vaccines Vagina Virus-like particle Woman arm base carcinogenicity cervical cancer prevention head-to-head comparison high risk immunogenic immunogenicity improved in vivo innovation meetings mouse model neutralizing antibody paragon particle phase 1 study phase I trial pre-clinical preclinical study prevent programs prophylactic protective efficacy response scaffold screening thermostability transmission process vaccine development virtual volunteer

项目摘要

Project Summary/Abstract: HPV is a necessary cause of 10% of all cancers of women globally, including 99% of cervical cancers. Rates of cervical cancer vary markedly by geographic region and level of economic development, with >85% occurring in developing countries. Successful prophylactic vaccination against hrHPV types can prevent dysplasia and thus cervical cancer. Global estimates of HPV vaccination delivery and cervical screening by region and income level show virtually no significant delivery to many poorer populations of women worldwide. There are 13 hrHPV types plus a group of 11 possibly carcinogenic types. Licensed HPV vaccines all target HPV16 and HPV18, and one also targets the next five most common types in cervical cancer. Since they do not target all cancer-associated HPV types, screening must be maintained even in vaccinated women, adding to medical costs. In addition, the stringent cold-chain requirements of HPV vaccines provide a serious impediment to their delivery in developing countries. Our overall goal is to develop an affordable HPV vaccine that both extends the breadth of protection to all cancer-associated HPV types, and is stable at ambient temperature. Here we address this goal with two innovations: 1) displaying an L2-based protective epitope (RG1) that is conserved for HPVs in a unique position on the surface of HPV16 L1 VLPs, producing a single antigen, broadly protective HPV vaccine technology, RG1-VLP, and 2) the RG1-VLP vaccine is formulated on alum and embedded in glassy organic matrices formed by adjusting lyophilization and formulation parameters in order to control ice crystal nucleation rates, glass transition temperatures, and other material properties and thereby protect against degradation during processing, shipping and storage. HYPOTHESIS 1: Cold chain storage properties are a significant barrier to the distribution of current HPV vaccines, and the development of a powdered RG1-VLP vaccine including adjuvant that is thermostable will address this need. Specific Aim 1: Develop a GLP freeze-dry protocol for a powder formulation of RG1-VLPs in alum and study its in vitro temperature stability, and in murine models its immunogenicity and protective efficacy in comparison to Gardasil9. HYPOTHESIS 2: RG1-VLP vaccination is safe and well tolerated. Specific Aim 2: To perform a Dose Escalation Phase I Trial of the Safety and Immunogenicity of thermostable RG1-VLP in 36 healthy female volunteers with the inclusion of a control Gardasil9 arm in the study. HYPOTHESIS 3: RG1-VLP vaccination of healthy women induces broadly protective serum antibody. Specific Aim 3: To analyze the levels of protective antibodies in the serum of patients from the phase I study induced by RG1-VLP vaccination or Gardasil9. We will utilize the passive transfer assay to measure protective responses, as well as L2 and L1 VLP ELISA and in vitro neutralization assays to quantify antigen-specific neutralizing antibody titers in serum.

项目摘要/摘要：HPV 是导致全球 10% 女性癌症的必要原因，其中包括 99% 的宫颈癌的发病率因地理区域和经济水平的不同而存在显着差异。发展中，超过 85% 发生在发展中国家。成功的 hrHPV 预防性疫苗接种 HPV 疫苗接种和宫颈癌的全球估计。按地区和收入水平进行的筛查显示，许多较贫困的妇女群体实际上没有获得显着的生育率全球有 13 种 hrHPV 类型以及一组 11 种可能致癌的 HPV 疫苗。所有都针对 HPV16 和 HPV18，其中一种还针对宫颈癌中接下来的五种最常见类型。它们并不针对所有与癌症相关的 HPV 类型，即使在接种疫苗的女性中也必须进行筛查，此外，HPV 疫苗严格的冷链要求也增加了医疗成本。我们的总体目标是开发一种负担得起的 HPV 疫苗。既扩大了对所有癌症相关 HPV 类型的保护范围，又在环境温度下保持稳定在这里，我们通过两项创新来实现这一目标：1）展示基于 L2 的保护表位 (RG1)。它在 HPV16 L1 VLP 表面的独特位置上为 HPV 保守，产生单一抗原，广泛保护性 HPV 疫苗技术、RG1-VLP，以及 2) RG1-VLP 疫苗采用明矾配制而成，并且嵌入通过调整冻干和配方参数形成的玻璃状有机基质中，以便控制冰晶成核速率、玻璃化转变温度和其他材料特性，从而防止在加工、运输和储存过程中降解。假设 1：冷链储存特性是当前 HPV 疫苗分销的重大障碍，包含热稳定佐剂的粉末状 RG1-VLP 疫苗的开发将解决这个问题具体目标 1：为明矾中的 RG1-VLP 粉末制剂制定 GLP 冻干方案。研究其体外温度稳定性，并在小鼠模型中研究其免疫原性和保护功效与 Gardasil9 的比较。假设 2：RG1-VLP 疫苗接种是安全且耐受性良好的具体目标 2：进行剂量递增。热稳定性 RG1-VLP 在 36 名健康女性志愿者中进行的安全性和免疫原性 I 期试验研究中纳入了 Gardasil9 对照臂。假设 3：健康女性接种 RG1-VLP 疫苗可诱导广泛的保护性血清抗体。目标3：分析I期研究患者血清中保护性抗体的水平 RG1-VLP 疫苗接种或 Gardasil9。我们将利用被动转移测定来测量保护性反应，以及 L2 和 L1 VLP ELISA 和体外中和测定，以量化抗原特异性中和血清中的抗体滴度。