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

用于通用流感疫苗开发的高密度鞭毛蛋白展示病毒样颗粒

基本信息

批准号：
10427432
负责人：
Xinyuan Chen
金额：
$ 23.63万
依托单位：
UNIVERSITY OF RHODE ISLAND
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-11 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10427432
关键词：
Adjuvant Adverse reactions Affect Agonist Animal Model Antibodies Antibody titer measurement Body Weight decreased Cell Maturation Clinical Clinical Research Clinical Trials Cytotoxic T-Lymphocytes Dendritic Cells Development Dose Encapsulated Epitopes Flagellin Head Hemagglutinin Hepatitis B Human Immune response Immunity Influenza A Virus, H1N1 Subtype Influenza A Virus, H3N2 Subtype Influenza A virus Length Lung Morphology Mus National Institute of Allergy and Infectious Disease Natural Immunity Nucleoproteins Production Proteins Recombinant Vaccines Recombinants Research Risk Role Safety Surface TLR5 gene Testing Time Vaccine Antigen Vaccines Viral Virus-like particle antiviral immunity base cross immunity cross reactivity density extracellular immunogenic immunogenicity improved influenza virus vaccine mouse model neutralizing antibody nicotine vaccine nonhuman primate novel virus pre-clinical preclinical evaluation preclinical study protective efficacy response self assembly universal influenza vaccine vaccine development vaccine immunogenicity vaccine safety virus core

项目摘要

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).

项目概要/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以诱导广泛的交叉保护。基质蛋白 2 (M2e) 的胞外域和细胞内核蛋白（NP）在病毒株中高度保守，是普遍的有吸引力的靶点流感疫苗的开发。各种临床前和临床研究支持抗 M2e 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的免疫原性低，需要高免疫原性的疫苗载体来呈现这些保守的疫苗抗原可诱导有效的交叉反应免疫反应。该提案探讨了我们的最近开发的高密度鞭毛蛋白展示乙型肝炎核心（HBc）病毒样颗粒（VLP）（FH VLP）与临床 CpG 佐剂 (FHc VLP) 组合用于通用流感疫苗的开发。跳频VLP 在疫苗开发方面，VLP 比 FljB 表现出更好的免疫原性和安全性，比 HBc VLP 更具多功能性。此外，临床 CpG 佐剂将被封装到 FH VLP 的核心中，以增强疫苗的效力。诱导体液免疫反应，同时诱导有效的 CTL 反应。这个提议制备基于M2e和NP展示的FHc VLP的通用流感疫苗（具体目标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功效（具体目标 2）。这个提议是响应国家过敏和传染病研究所 (NIAID) 推进研究的号召需要开发通用流感疫苗 (PA-18-858)。