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，我们的目标是开发一种新的疫苗纳米平台，然后利用该平台通过控制来自流感的保守抗原蛋白(或蛋白片段)的呈现来生产通用流感疫苗。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。接种疫苗或感染流感也会导致流感。 特异性记忆CD8 T细胞，针对内部流感病毒抗原，如核蛋白(NP)，帮助清除感染病毒的细胞，并在中和抗体无法提供完全保护的情况下全面恢复。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，可能是一种优秀的通用流感疫苗策略。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，证明我们通过在内部包裹NP来生物工程这些VLP的能力，以及这些材料在感染高达100倍LD50流感的小鼠中诱导CD8 T细胞依赖的强劲恢复的能力。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 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.