Development of VPL Vaccine for RSV

RSV VPL 疫苗的开发

• 批准号: 8645890
• 负责人: JORGE C BLANCO
• 金额: $ 22.5万
• 依托单位: SIGMOVIR BIOSYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645890
• 关键词: Acute; Address; Adjuvant; Animal Model; Antibody Formation; Biological Models; Child; Collaborations; Cotton Rats; Cytoplasmic Tail; Development; Disease; Dose; Effectiveness; Elderly; Exposure to; Failure; Formalin; Generations; Glycoproteins; Goals; Grant; Human; Human respiratory syncytial virus; Immune response; Immunization; Immunocompromised Host; Inactivated Vaccines; Individual; Infant; Infection; Licensing; Life; Lung; Lung diseases; Massachusetts; Measures; Membrane Proteins; Memory; Molecular Conformation; Mus; Newcastle disease virus; Nucleocapsid Proteins; Pathology; Phase; Population; Property; Proteins; Publishing; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory System; Respiratory Tract Infections; Respiratory syncytial virus; Respiratory syncytial virus RSV F glycoprotein; Respiratory syncytial virus RSV F proteins; Respiratory tract structure; Risk; Safety; Small Business Technology Transfer Research; Staging; System; Testing; Universities; Vaccines; Viral; Virus; Virus Diseases; Virus Replication; Virus-like particle; base; burden of illness; design; efficacy testing; glycoprotein G; human disease; immunopathology; improved; insight; medical schools; neutralizing antibody; novel strategies; novel vaccines; novel virus; particle; pathogen; phase 1 study; phase 2 study; prevent; public health relevance; response; vaccine candidate; vaccine development

Project Summary Human respiratory syncytial virus (RSV) is recognized as the single most important viral cause of acute respiratory disease in infants and young children worldwide. Elderly populations and immunocompromised individuals are also at significant risk for serious RSV disease. Despite this very substantial disease burden imposed by RSV worldwide, there are no vaccines available. Several problems have impeded RSV vaccine development. First is safety. An early formalin-inactivated vaccine (FI-RSV) predisposed infants to more severe disease upon natural exposure to live virus resulting in concerns about the safety of all subsequently developed RSV vaccines, particularly nonreplicating vaccines. A second problem is a lack of understanding of requirements for stimulation protective responses making efficacy of new vaccine candidates difficult to predict. A third problem is the failure of RSV infections as well as many vaccine candidates to stimulate long-term, protective immune responses. This proposal is designed to test the hypothesis that novel virus-like particle (VLP) RSV vaccine candidates, unlike any previously tested, may be developed into an RSV vaccine. Published results indicate that Newcastle disease VLPs expressing RSV glycoproteins are very effective and safe vaccines that stimulate very durable protective responses in a murine system. This project will further develop these VLPs as RSV vaccine candidates. This project will test the hypothesis that different conformational forms of RSV F protein impact the properties of anti-RSV immune responses. The goal is to identify the conformation of RSV F protein, expressed on VLPs, that stimulate high titer neutralizing antibodies and protective, long-lived and memory immune responses and to test the efficacy and safety of selected vaccine candidates in cotton rats. Specific Aim 1: to determine neutralizing antibody titers and levels of protection from RSV challenge stimulated in mice by three different second generation VLP vaccine candidates. Specific Aim 2: to assess the safety afforded by selected VLPs after immunization of mice. Specific Aim 3: to assess the safety and protection afforded by a selected VLPs after immunization of cotton rats.

项目摘要 人呼吸道合胞病毒（RSV）被认为是急性呼吸道感染的单一最重要的病毒原因。 呼吸道疾病的婴儿和幼儿在世界各地。老年人群和免疫功能低下 个体也处于严重RSV疾病的显著风险中。尽管疾病负担很重 由于RSV在世界范围内的流行，没有可用的疫苗。几个问题阻碍了RSV疫苗 发展首先是安全。早期的福尔马林灭活疫苗（FI-RSV）使婴儿更容易感染 在自然暴露于活病毒后会导致严重疾病，导致对所有随后 研发了RSV疫苗，特别是非复制型疫苗。第二个问题是缺乏对 刺激保护性反应的要求使得新候选疫苗的功效难以预测。 第三个问题是RSV感染以及许多候选疫苗未能刺激长期， 保护性免疫反应 该提议旨在验证新的病毒样颗粒（VLP）RSV疫苗 与任何先前测试的候选物不同，候选物可被开发成RSV疫苗。公布的结果表明， 表达RSV糖蛋白的纽卡斯尔病VLP是非常有效和安全的疫苗， 非常持久的保护性反应。该项目将进一步开发这些VLP作为RSV 候选疫苗本项目将检验RSV F蛋白的不同构象形式 影响抗RSV免疫应答的性质。目的是鉴定RSV F的构象， 蛋白质，在VLP上表达，刺激高滴度中和抗体和保护性、长寿命和 记忆免疫应答，并在棉鼠中测试所选候选疫苗的有效性和安全性。 具体目标1：确定RSV攻毒的中和抗体滴度和保护水平 在小鼠中通过三种不同的第二代VLP疫苗候选物刺激。 具体目标2：评估所选VLP在小鼠免疫后提供的安全性。 具体目标3：评估棉花免疫后所选VLP提供的安全性和保护性 大鼠