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Development, Production and Testing of VLP based Respiratory Syncytial Virus (RSV

基于VLP的呼吸道合胞病毒（RSV）的开发、生产和测试

基本信息

批准号：
8646582
负责人：
JOSE M. GALARZA
金额：
$ 50.96万
依托单位：
TECHNOVAX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8646582
关键词：
Acute Adult Age Animal Model Animals Antigens Asthma Centers for Disease Control and Prevention (U.S.)Cessation of life Child Childhood Cotton Rats Data Development Disease Dose Elderly Electron Microscopy Equilibrium Formalin Genetic Materials Goals Hospitalization Image Immune response Immune system Immunization Inactivated Vaccines Infant Infection Intervention Licensing Life Modeling Monoclonal Antibodies Morbidity - disease rate Mus Nature Palivizumab Particulate Phase Prevention Preventive Intervention Production Proteins Public Health Recurrence Respiratory Syncytial Virus Infections Respiratory Syncytial Virus Vaccines Respiratory Tract Infections Respiratory syncytial virus Risk Risk Factors Safety Small Business Innovation Research Grant Structure Supportive care Surface Surface Antigens Testing Vaccines Viral Antigens Virion Virus Virus Diseases Virus-like particle Wheezing base cost cost effective design high risk infant immunogenicity mouse model multiple myeloma M Protein particle pathogen prevent prophylactic protective efficacy public health relevance respiratory response stable cell line success vaccine candidate virus genetics

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to develop a safe and efficacious virus-like particle (VLP) based-respiratory syncytial virus (RSV) vaccine to prevent the disease caused by this pathogen. The respiratory illnesses provoked by RSV in infants, children and the elderly are of global economical and public health impact. A recent worldwide estimate [5] indicates that over 33 million children under the age of five suffer RSV associated lower respiratory infections (ALRI) and at least 3 million are hospitalized and approximately 199,000 die of the disease each year. In the US, the CDC estimates that there are over 126,000 RSV associated pediatric hospitalizations at a cost of over $900 million per year. There is no vaccine currently licensed and treatments for the disease are limited; a prophylactic intervention relies on administering a neutralizing monoclonal (Synagis) to infants at risk of infection and to supportive care. A safe and effective vaccine would be the most desirable and cost effective preventive intervention. However, to date the creation of such a vaccine has not been attained and its development hindered by the enhancement of disease provoked by a formalin-inactivated vaccine produced in the 1960's. Other approaches have not proven successful and even dangerous. Here, we propose to develop and test a virus-like particle displaying RSV antigens as a strategy to create a safe and effective RSV vaccine. VLPs are mimics of wild type virus particles but do not contain viral genetic material making them unable to replicate or cause infection. The particulate nature and redundant array of native antigen on the surface of the VLP incites a greater recognition by the immune system. We have successfully produced native RSV-VLPs that display surface spikes and resemble wild type virus. Our RSV based VLP candidate vaccines are created by co-expressing the proteins M, F and SH or M, F or M, F and G as well as additional combinations. The type and magnitude of the immune response they induce as well as the efficacy afforded by the RSV-VLP candidate vaccines will be assessed in animal models. To fulfill these goals, we have designed three specific aims: Specific aim I: Produce and characterize virus-like particles (VLPs) displaying respiratory syncytial virus surface antigens.in alternative compositions F, F+SH, F+G and F+SH+G Specific aim II: Evaluate the immunogenicity (quality and magnitude of the immune response) elicited by the RSV-VLP vaccine and establish safety profile as well as the protective efficacy afforded by alternative compositions of RSV-VLP vaccines in a mouse model of respiratory syncytial virus infection. Selected candidates will be reevaluated by escalating doses of vaccine in mice. Also, initiate development of stable cell lines for the continuous production of the preferred VLP vaccine. Specific aim III: The VLP composition demonstrating efficacy, potency and safety will be retested in the cotton rat model of respiratory syncytial virus infection seeking probe of efficacy in two model of RSV infection. These studies will support a SBIR Phase II proposal and pursue an IND application with the FDA.

描述（由申请人提供）：本提案的目标是开发一种安全有效的基于病毒样颗粒（VLP）的呼吸道合胞病毒（RSV）疫苗，以预防由该病原体引起的疾病。 RSV 在婴儿、儿童和老年人中引起的呼吸道疾病对全球经济和公共卫生产生影响。最近的全球估计 [5] 表明，每年有超过 3300 万 5 岁以下儿童患有 RSV 相关下呼吸道感染 (ALRI)，至少有 300 万人住院，大约 199,000 人死于该病。据 CDC 估计，美国有超过 126,000 例与 RSV 相关的儿童住院治疗，每年的费用超过 9 亿美元。目前尚无获得许可的疫苗，该疾病的治疗方法也有限；预防性干预依赖于对有感染风险的婴儿施用中和单克隆抗体（Synagis）以及支持性护理。安全有效的疫苗将是最理想且最具成本效益的预防干预措施。然而，迄今为止，这种疫苗的研制尚未实现，并且由于 20 世纪 60 年代生产的福尔马林灭活疫苗引发的疾病加剧，其发展受到阻碍。其他方法尚未被证明是成功的，甚至是危险的。在这里，我们建议开发和测试一种显示 RSV 抗原的病毒样颗粒，作为创建安全有效的 RSV 疫苗的策略。 VLP 是野生型病毒颗粒的模拟物，但不包含病毒遗传物质，使其无法复制或引起感染。 VLP 表面天然抗原的颗粒性质和冗余阵列激发了免疫系统的更大识别。我们已成功生产出具有表面刺突且类似于野生型病毒的天然 RSV-VLP。我们基于 RSV 的 VLP 候选疫苗是通过共表达蛋白质 M、F 和 SH 或 M、F 或 M、F 和 G 以及其他组合而创建的。它们诱导的免疫反应的类型和程度以及 RSV-VLP 候选疫苗所提供的功效将在动物模型中进行评估。为了实现这些目标，我们设计了三个具体目标：具体目标 I：生产和表征显示呼吸道合胞病毒表面抗原的病毒样颗粒 (VLP)。在替代组合物 F、F+SH、F+G 和 F+SH+G 中具体目标 II：评估 RSV-VLP 疫苗引起的免疫原性（免疫反应的质量和程度）并建立安全性和保护性 RSV-VLP 疫苗的替代组合物在呼吸道合胞病毒感染的小鼠模型中提供的功效。选定的候选者将通过增加小鼠疫苗剂量来重新评估。此外，启动稳定细胞系的开发，以连续生产首选的 VLP 疫苗。具体目标III：将在呼吸道合胞病毒感染的棉鼠模型中重新测试显示功效、效力和安全性的VLP组合物，以探索在两种RSV感染模型中的功效。这些研究将支持 SBIR II 期提案，并向 FDA 申请 IND 申请。