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

• 批准号: 8810290
• 负责人: Trevor Douglas
• 金额: $ 26.26万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-20 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8810290
• 关键词: Engineered; virus; like; nanoparticles; targeting

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 universal influenza vaccine by exploiting the controlled presentation of conserved antigenic proteins (or protein fragments) from influenza on a novel nano-platform. 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). 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 excellent components of a universal pan 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 that these materials 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，我们的目标是通过利用流感中的保守抗原蛋白（或蛋白质片段）在新型的纳米平台上开发普遍的流感疫苗。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可以诱导流感 - 特异性记忆CD8 T细胞，该细胞针对内部流感病毒抗原（如核蛋白蛋白（NP））。因此，引发中和抗体的中和抗体，特异性对于HA蛋白（CSHA）的保守茎区（CSHA）以及选择性CD8 T细胞对保守的NP的响应可能是普遍PAN流感疫苗的极好组成部分。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，这既表明我们通过在内部封装NP来生物工程VLP的能力，并且这些材料引起了强大的CD8 T细胞依赖的恢复，而小鼠受到高达100倍LD50流感质疑的小鼠。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相结合，以引起保护性免疫反应，以旨在开发普遍的流感疫苗。