Regulation of humoral immunity to a virus-like particle vaccine candidate

类病毒颗粒疫苗候选物的体液免疫调节

• 批准号: 9387500
• 负责人: Madelyn Ruth Schmidt
• 金额: $ 25.13万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-16 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9387500
• 关键词: Adaptive Immune System; Address; Adjuvant; Adoptive Transfer; Affinity; Agonist; Antibody Affinity; Antibody Formation; Antibody Response; Antigens; B-Cell Activation; B-Lymphocytes; Bone Marrow; Cell surface; Cells; Cessation of life; Characteristics; Cotton Rats; Cytoplasmic Tail; Data; Dendritic Cells; Development; Elderly; Event; Future; G-substrate; GTP-Binding Proteins; Generations; Glycoproteins; Goals; Helper-Inducer T-Lymphocyte; Hospitalization; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunization; Immunize; Immunocompromised Host; In Vitro; Individual; Infant; Infection; Infectious Agent; Innate Immune System; Knockout Mice; Link; Lower Respiratory Tract Infection; Lung diseases; Membrane Proteins; Memory B-Lymphocyte; Mus; Mutant Strains Mice; Newcastle disease virus; Nucleoproteins; Plasma Cells; Plasmablast; Population; Preparation; Primary Cell Cultures; Production; Receptor Signaling; Regulation; Respiratory Failure; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Series; Signal Induction; Signal Pathway; Signal Transduction; Structure of germinal center of lymph node; Surface; System; T-Lymphocyte; Testing; Up-Regulation; Vaccines; Viral Proteins; Virus; Virus Replication; Virus-like particle; cytokine; design; experimental study; glycoprotein G; immune activation; in vivo; macrophage; mutant mouse model; neutralizing antibody; novel; novel vaccines; pathogen; receptor; research clinical testing; response; vaccine candidate

Project Summary and Relevance Human respiratory syncytial virus (RSV) is a major cause of serious lower respiratory tract infections and hospitalization in infants, the elderly and immunocompromised individuals. Natural infection does not induce durable protective immunity to the virus and multiple reinfections can occur even within the same year. To date, there is as yet no effective vaccine or treatment. We have developed novel RSV-virus-like particle (VLP) vaccine candidates composed of Newcastle Disease Virus nucleoprotein and membrane proteins that express RSV F and G glycoproteins ectodomains fused with NDV glycoprotein cytoplasmic domains. This VLP induces long-lived protective neutralizing antibody responses and memory B cells in mice when given once in the absence of adjuvant. Mice challenged with RSV post immunization clear the virus and do not display enhanced pulmonary disease. Because adjuvant is not required for this protective immune response, we propose that the VLP directly stimulates the innate immune system, such as TLRs or MAV. We will investigate this possibility by using mutant mouse models deficient in single components of the innate immune system and the impact on development of durable protective immunity. These studies will provide essential information for the future development of our vaccine candidate and define the most efficacious TLR agonists for clinical testing

项目摘要和相关性 人呼吸道合胞病毒（RSV）是严重下呼吸道感染的主要原因 和婴儿，老年人和免疫功能低下的个体的住院。自然感染没有 诱导对病毒的持久保护性免疫，即使在同年内也可能发生多次再感染。 迄今为止，目前尚无有效的疫苗或治疗。我们已经开发了新颖的RSV病毒样粒子 （VLP）由纽卡斯尔病毒病毒核蛋白和膜蛋白组成的疫苗候选物 与NDV糖蛋白细胞质结构域融合的Express RSV F和G糖蛋白外生素。这个VLP 当给予一度时，会诱导小鼠的长寿命保护性中和抗体反应和记忆B细胞 缺乏佐剂。通过RSV挑战的小鼠免疫验证了病毒，不显示病毒 增强的肺部疾病。由于这种保护性免疫反应不需要佐剂，我们 建议VLP直接刺激先天免疫系统，例如TLRS或MAV。我们将调查 通过使用缺乏先天免疫系统单个组件的突变小鼠模型和 对持久防护性免疫发展的影响。这些研究将为 候选疫苗的未来发展，并定义了临床最有效的TLR激动剂 测试