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：
10251096
负责人：
WARNER KING HUH
金额：
$ 20.86万
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/10251096
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 Preventative vaccination 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 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是全球所有癌症中10％的10％的必要原因，包括 99％的宫颈癌。宫颈癌的发生率与地理区域和经济水平明显不同发展，> 85％的发展中国家。成功针对HRHPV的预防性疫苗类型可以预防发育不良，从而预防宫颈癌。 HPV疫苗接种和宫颈的全球估计按地区和入学水平进行筛查几乎没有向许多较贫穷的女性群体分娩全世界。有13种HRHPV类型以及11种积极的致癌类型。许可的HPV疫苗所有目标HPV16和HPV18，也针对宫颈癌的接下来最常见类型。自从它们并不针对所有与癌症相关类型的HPV类型，即使在接种疫苗的妇女中也必须保持筛查，增加医疗费用。此外，HPV疫苗的严格冷链要求非常严重障碍在发展中国家交付。我们的总体目标是开发负担得起的HPV疫苗这两者都将保护广度扩展到所有与癌症相关的HPV类型，并且在环境下稳定温度。在这里，我们通过两项创新来解决这个目标：1）显示基于L2的保护表位（RG1）对于在HPV16 L1 VLP表面的独特位置的HPV中，这是保守的，产生了单个抗原，广泛的保护性HPV疫苗技术，RG1-VLP和2）RG1-VLP疫苗是在明矾和通过调节冻干和制定参数形成的玻璃状有机矩阵中嵌入控制冰晶核速率，玻璃过渡温度和其他材料特性，从而在处理，运输和存储期间防止降解。假设1：冷链存储特性是当前HPV疫苗分布的重要障碍，即并开发粉末状的RG1-VLP疫苗，包括可调的可调式疫苗将解决此问题需要。特定目标1：为校友的RG1-VLP粉末公式制定GLP冷冻干燥方案研究其体外温度稳定性，并在鼠类中模拟其免疫原性和保护性效率与Gardasil9进行比较。假设2：RG1-VLP疫苗接种是安全且耐受性良好的。特定目标2：执行剂量升级在36位健康的女性志愿者中，对热稳定RG1-VLP的安全性和免疫原性的I期试验在研究中包含对照gardasil9臂。假设3：健康女性的RG1-VLP疫苗接种可诱导广泛的保护性血清抗体。具体的目的3：分析I诱导的I期研究的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法来衡量保护性响应，以及L2和L1 VLP ELISA以及体外中和的主张，以量化抗原特异性中和血清中的抗体滴度。