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

说明(申请人提供)：季节性流感病毒感染和流感大流行是全球高死亡率的原因，但目前通过接种疫苗进行的保护受到季节性变化和抗原漂移的限制。在这项提议中，我们的目标是通过在新的纳米平台上利用来自流感的保守的抗原蛋白(或蛋白片段)的受控呈现来开发通用流感疫苗。疫苗治疗在很大程度上是基于针对表面暴露的血凝素(HA)的中和抗体，这种抗体可以防止病毒进入细胞的结合或融合步骤。疫苗接种或流感感染也可以诱导流感特异性记忆CD8T细胞，这种细胞专用于内部流感病毒抗原，如核蛋白(NP)。因此，激发针对HA蛋白保守茎区(CSHA)的中和抗体，并诱导CD8T细胞对保守的NP产生选择性反应，可能是通用泛型流感疫苗的优秀组成部分。我们将开发一类病毒样颗粒(VLP)，具有模仿流感中HA和NP抗原片段呈现的纳米结构，以诱导特异性免疫反应，以开发通用流感疫苗。我们将建立在强大的初步结果的基础上，证明我们有能力通过在内部包裹NP来生物工程这些VLP，并且这些材料在感染高达100倍LD50流感的小鼠中诱导了强大的CD8 T细胞依赖恢复。我们将使用来源于噬菌体P22的VLP选择性地将NP片段(和/或CSHA)包裹在P22 VLP的内部，并在P22 VLP的外表面以高拷贝数展示CSHA(和/或NP片段)。这项提议的目标是将这两种抗原(CSHA和NP)与高度可工程的纳米平台相结合，以诱导保护性免疫反应，以努力开发通用流感疫苗。

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.