Role of F Protein Conformation in RSV Vaccine Efficacy

F 蛋白构象在 RSV 疫苗功效中的作用

基本信息

批准号：
9173380
负责人：
Trudy G. Morrison
金额：
$ 63.4万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-07 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9173380
关键词：
1 year old Acute Address Adjuvant Adoptive Transfer Adult Animals Antibodies Antibody Affinity Antibody Avidity Antibody Response B-Lymphocytes Binding Binding Proteins Bone Marrow Cells Child Cotton Rats Cytoplasmic Tail Data Disease Effectiveness Elderly Exposure to Failure Formalin Generations Glycoproteins Goals Health Human Immune Immune response Immunization Immunocompromised Host Inactivated Vaccines Infant Infection Laboratories Life Lung diseases Membrane Proteins Memory Memory B-Lymphocyte Methods Modeling Molecular Conformation Monoclonal Antibodies Morbidity - disease rate Mus Newcastle disease virus Nucleocapsid Proteins Paramyxovirus Plasma Cells Population Property Protein Conformation Proteins Publishing Pulmonary Pathology Rat virus 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 Role Safety Serum Spleen Target Populations Testing Vaccines Viral Viral Antigens Virus Virus-like particle base burden of illness experience glycoprotein G glycoprotein structure glycosylation human disease insight murine antibody neutralizing antibody novel virus particle pathogen polyclonal antibody prevent research study response stem vaccine candidate vaccine development vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): Most acute viral respiratory disease in infants and young children is due to respiratory syncytial virus (RSV). This virus also causes serious disease in elderly and immunocompromised populations and is a significant cause of morbidity in healthy adult populations. Despite the substantial disease burden due to this virus worldwide, there are no vaccines available. Several problems have impeded RSV vaccine development. First is safety. An early formalin-inactivated vaccine (FI-RSV), which stimulated weak and unbalanced immune responses, predisposed infants to more severe disease upon natural exposure to live virus. A second problem is the failure of many vaccine candidates to stimulate protective immune responses. A third problem is the failure of natural infection as well as vaccine candidates to stimulate long-lived, protective memory responses. All these problems are ultimately due to a lack of understanding of mechanisms involved in stimulation of protective as well as durable anti-RSV immune responses. This proposal will test the hypothesis that different conformational forms of RSV F protein impact the properties of anti-RSV immune responses. The goal is to define conformations of RSV F protein, expressed on virus-like particles, that stimulate high titer neutralizing antibodies and protective, long-lived and memory immune responses and to understand the mechanisms responsible for generation of these responses. To test the hypothesis, four aims are proposed. Specific Aim 1: to characterize the RSV F protein binding properties of antibodies stimulated in mice and in cotton rats by VLPs containing stabilized pre-fusion or stabilized post-fusion F protein. Specific Aim 2: to clarify th role of anti-G antibodies in the neutralization titers induced in mice and cotton rats by VLPs containing the pre-fusion form of the RSV F protein and VLPs containing the post-fusion form. Specific Aim 3: to characterize immune responses to VLPs containing pre- and post-fusion forms of F in RSV experienced mice and cotton rats as models for maternal immunization. Specific Aim 4: to determine if VLPs containing the pre-fusion and the post-fusion F proteins induce RSV F protein specific long-lived bone marrow associated plasma cells (LLPC) and memory B cells in both mice and cotton rats.

描述（由申请人提供）：婴儿和幼儿中大多数急性病毒性呼吸道疾病是由呼吸道合胞病毒（RSV）引起的，这种病毒也会在老年人和免疫功能低下人群中引起严重疾病，并且是健康成年人发病的重要原因。尽管这种病毒在世界范围内造成了巨大的疾病负担，但尚无可用的疫苗，这阻碍了 RSV 疫苗的开发。首先是安全性问题。和不平衡的免疫反应，使婴儿在自然接触活病毒后容易患上更严重的疾病。第二个问题是许多候选疫苗未能刺激保护性免疫反应。第三个问题是自然感染以及候选疫苗均未能刺激。所有这些问题最终都是由于缺乏对刺激保护性以及持久的抗 RSV 免疫反应的机制的了解。该提案将检验 RSV F 蛋白的不同构象形式的假设。影响抗 RSV 的特性目标是定义在病毒样颗粒上表达的 RSV F 蛋白的构象，该蛋白可刺激高滴度中和抗体和保护性、长寿命和记忆性免疫反应，并了解产生这些反应的机制。检验假设，提出了四个目标具体目标 1：表征含有稳定融合前或稳定融合后 F 蛋白的 VLP 在小鼠和棉鼠中刺激的抗体的 RSV F 蛋白结合特性。澄清一下抗 G 抗体在含有 RSV F 蛋白融合前形式的 VLP 和含有融合后形式的 VLP 诱导的小鼠和棉鼠中和滴度中的作用具体目标 3：表征对含有预融合形式的 VLP 的免疫反应。 - RSV 小鼠和棉鼠中的 F 和融合后形式作为母体免疫模型具体目标 4：确定含有融合前和融合后 F 蛋白的 VLP 是否诱导 RSV F 蛋白特异性。小鼠和棉鼠体内的长寿骨髓相关浆细胞 (LLPC) 和记忆 B 细胞。