High-density flagellin-displayed virus-like particle for universal influenza vaccine development'

项目摘要/摘要 目前的流感疫苗主要诱导毒株特异性保护。通用流感疫苗正在研发中 积极发展，形成广泛的交叉保护。基质蛋白2胞外结构域(M2e)和 细胞内核蛋白(NP)在病毒株间高度保守，是普遍存在的有吸引力的靶标 流感疫苗研发。各种临床前和临床研究支持抗M2E抗体的诱导 抗体和抗NP细胞毒性T淋巴细胞(CTL)诱导广泛的交叉保护性免疫。由于 M2E和NP的低免疫原性、高免疫原性的疫苗载体需要呈现这些 保守的疫苗抗原，以诱导强大的交叉反应免疫反应。这项建议探索了我们的 最近发展起来的高密度鞭毛蛋白显示的乙肝病毒样颗粒(VLP)(FH VLP) 与临床CpG佐剂(FHC VLP)相结合，用于开发通用流感疫苗。跳频VLP 在疫苗开发方面，表现出比FljB更好的免疫原性和安全性，以及比HBc VLP更多的通用性。 此外，临床CpG佐剂将被封装到FH VLP的核心中，以增强疫苗- 诱导体液免疫应答，同时诱导有效的CTL应答。这项建议 制备M2E和NP展示的基于FHC VLP的通用流感疫苗(特定目标1)并探索 它们在小鼠模型中的安全性、免疫原性和交叉保护效力(特定目标2)。这项建议是 应国家变态反应与传染病研究所S号召推进研究 需要开发一种通用流感疫苗(PA-18-858)。

Project Summary/Abstract Current influenza vaccines mainly induce strain-specific protection. Universal influenza vaccines are under active development to induce broad cross-protection. Extracellular ectodomain of matrix protein 2 (M2e) and intracellular nucleoprotein (NP) are highly conserved across viral strains and are attractive targets in universal influenza vaccine development. Various preclinical and clinical studies support the induction of anti-M2e antibodies and anti-NP cytotoxic T lymphocytes (CTLs) to induce broad cross-protective immunity. Due to the low immunogenicity of M2e and NP, highly immunogenic vaccine carriers are demanded to present these conserved vaccine antigens to induce potent cross-reactive immune responses. This proposal explores our recently developed high-density flagellin-displayed hepatitis b core (HBc) virus-like particles (VLPs) (FH VLPs) in combination with a clinical CpG adjuvant (FHc VLPs) for universal influenza vaccine development. FH VLPs show better immunogenicity and safety than FljB and more versatility than HBc VLPs for vaccine development. Furthermore, a clinical CpG adjuvant will be encapsulated into the core of FH VLPs to potentiate vaccine- induced humoral immune responses and at the same time to induce potent CTL responses. This proposal prepares M2e and NP-displayed FHc VLP-based universal influenza vaccines (Specific aim 1) and explore their safety, immunogenicity, and cross-protective efficacy in murine models (Specific aim 2). This proposal is in response to National Institute of Allergy and Infectious Diseases (NIAID)'s call for Advancing Research Needed to Develop a Universal Influenza Vaccine (PA-18-858).