Engineered virus-like nanoparticles targeting immunity needed for pan flu vaccine

针对泛流感疫苗所需免疫力的工程病毒样纳米粒子

基本信息

批准号：
9279057
负责人：
Trevor Douglas
金额：
$ 46.16万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
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：
2014-02-20 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9279057
关键词：
Adjuvant Affect Agonist Antibodies Antibody Response Antigen Presentation Antigen-Presenting Cells Antigens Architecture Bacteriophage P22 Binding Biomedical Engineering Biomimetics CD8-Positive T-Lymphocytes Capsid Cells Development Diagnosis Disease Encapsulated Engineering Epitopes Event Exhibits Goals Hemagglutinin Immune Immune response Immunity Immunization Immunodominant Epitopes Infectious Disease Immunology Influenza Lethal Dose 50 Lipopolysaccharides Lung Mediating Memory Modification Molecular Mus Nature Nucleoproteins Peptides Protein Fragment Proteins Recovery Seasonal Variations Serotyping Surface System TNFRSF5 gene Testing Therapeutic Toll-like receptors Vaccination Vaccine Therapy Vaccines Viral Viral Antigens Viral Proteins Virus Virus Assembly Virus Diseases Virus-like particle Work base chemical genetics design experience gene product immunogenic improved in vivo influenza virus vaccine influenzavirus interest mortality nano nanoarchitecture nanomaterials nanomedicine nanoscale nanovaccine neutralizing antibody novel vaccines pandemic influenza prevent protective efficacy public health relevance receptor response seasonal influenza self assembly vaccine delivery vaccine development

项目摘要

DESCRIPTION (provided by applicant): Seasonal influenza virus infections and influenza pandemics are responsible for high global mortality but current protection through vaccination is limited by seasonal variation and antigenic drift. In this proposal our goal is to develop a novel vaccine nano-platform and then utilize that platform to produce a universal influenza vaccine by exploiting the controlled presentation of conserved antigenic proteins (or protein fragments) from influenza. Vaccine therapies are based heavily on neutralizing antibodies specific for surface exposed hemagglutinin (HA), which prevent either the binding or the fusion step involved in virus entry of the cell. Vaccination, or influenza infection, can also induce influenza specific memory CD8 T cells, specific for internal influenza virus antigens such as the nucleoprotein (NP), that aid in clearance of viral infected infected cells and overall recovery in the event that neutralizing antibodies are unable to provide complete protection. Thus, eliciting neutralizing antibodies, specific for the conserved stalk region of the HA protein (csHA) and induction of selective CD8 T cell responses to the conserved NP, could be an excellent strategy for a universal influenza vaccine. We will develop a class of virus-like particles (VLPs), having nano-architectures that mimic the presentation of HA and NP antigenic fragments in influenza, in order to elicit specific immune responses towards the development of a universal influenza vaccine. We will build on strong preliminary results demonstrating both our ability to bioengineer these VLPs by encapsulation of NP on the interior and the ability of these materials to elicit a strong CD8 T cell-dependent recovery in mice challenged with up to 100x LD50 influenza. We will use the VLP, derived from the bacteriophage P22, to encapsulate NP fragments (and/or csHA) selectively on the interior and display csHA (and/or NP fragments) on the exterior surface of the P22 VLP in high copy number. The goal of this proposal is to integrate these two antigens (csHA and NP) with a highly engineer-able nano- platform to elicit protective immune responses in an effort aimed at the development of a universal influenza vaccine.

描述（由申请人提供）：季节性流感病毒感染和流感大流行病负责全球死亡率，但通过疫苗接种的当前保护受到季节性变异和抗原漂移的限制。在此提案中，我们的目标是开发一种新型的疫苗纳米平台，然后利用该平台来通过从流感中利用保守的抗原蛋白（或蛋白质碎片）的受控呈现来产生普遍的流感疫苗。疫苗疗法大大基于中和对表面暴露的血凝素（HA）的抗体，该抗体可以防止细胞进入病毒进入的结合或融合步骤。疫苗接种或流感感染也会诱发流感特定的记忆CD8 T细胞，特异性是内部流感病毒抗原（如核蛋白（NP）），有助于清除病毒感染感染的细胞，并在中和抗体无法提供完全保护的情况下进行总体恢复。因此，引发中和抗体的中和抗体，特有的HA蛋白的保守茎区域（CSHA）以及选择性CD8 T细胞对保守NP的响应可能是通用流感疫苗的绝佳策略。我们将开发一类类似病毒的颗粒（VLP），其具有模仿流感中HA和NP抗原片段的纳米构造，以便引起对普遍流感疫苗发展的特定免疫反应。我们将基于强大的初步结果，这既证明了我们通过在内部封装NP的生物工程VLP的能力，以及这些材料在高达100倍LD50流感质疑的小鼠中引起强大CD8 T细胞依赖性恢复的能力。我们将使用源自噬菌体P22得出的VLP在内部选择性地封装NP片段（和/或CSHA），并在p22 VLP的外表上显示CSHA（和/或NP片段），以高拷贝数为单位。该提案的目的是将这两种抗原（CSHA和NP）与高度工程的纳米平台整合起来，以引起保护性免疫反应，以旨在开发普遍的流感疫苗。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Differential Type I Interferon Signaling Is a Master Regulator of Susceptibility to Postinfluenza Bacterial Superinfection.

DOI：
10.1128/mbio.00506-16
发表时间：
2016-05-03
期刊：
mBio
影响因子：
6.4
作者：
Shepardson KM;Larson K;Morton RV;Prigge JR;Schmidt EE;Huber VC;Rynda-Apple A
通讯作者：
Rynda-Apple A

Development of virus-like particles for diagnostic and prophylactic biomedical applications.