Development of a Virus-Like Particle Vaccine for Powassan Virus

波瓦桑病毒类病毒颗粒疫苗的研制

基本信息

批准号：
10407602
负责人：
ALEC J HIRSCH
金额：
$ 52.3万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10407602
关键词：
Adjuvant Alpha Particles Antibodies Antigens Attenuated Live Virus Vaccine B-Lymphocytes Black-legged Tick Brain C Type Lectin Receptors Canada Cell Communication Cell Culture Techniques Code Cultured Cells Development Disease Disease Outbreaks Dose Encephalitis Epitopes Evaluation Event Flavivirus Flavivirus Infections Formulation Generations Health Sciences Human Human Bites Immune Immune response Immunity Immunomodulators Individual Infection Ixodes Ixodidae Laboratory mice Lead Mammals Membrane Meningitis Modeling Montana Mus Neurologic Symptoms North America Oregon Pattern recognition receptor Phenotype Positioning Attribute Powassan virus Prevention Production Proteins Public Health Reporting Risk Russia Sampling Serum Structure Survival Analysis System T cell response T-Lymphocyte Testing Tick-Borne Diseases Ticks Time Tissues Toll-like receptors United States Universities Vaccinated Vaccination Vaccine Adjuvant Vaccine Antigen Vaccine Production Vaccines Viral Viral Load result Virion Virus Virus Diseases Virus-like particle Vulnerable Populations White-Footed Mouse Zika Virus base cohort cytokine design emerging pathogen env Gene Products experience immunogenicity member mouse model neurotropic virus neutralizing antibody novel novel vaccines pathogenic virus protective efficacy research clinical testing response scale up tick-borne tick-borne flavivirus vaccine delivery vaccine development vaccine efficacy vaccine evaluation vaccine safety vector vector tick viral transmission

项目摘要

PROJECT SUMMARY This proposal is focused on developing a vaccine for prevention of Powassan virus (POWV)- associated disease. POWV is a tick-borne flavivirus currently endemic to North America, primarily in the northeastern and north- central regions of the United States and extending north into Canada. Due to the expanding range of Ixodid tick vectors, POWV has the potential to become an emerging pathogen and public health threat. In humans, POWV is a neurotropic virus that can lead to severe, sometimes fatal encephalitis and meningitis. We propose to develop a vaccine based on non-replicating virus-like particle (VLP) antigens produced by expression of the viral pre-membrane (prM) and envelope (E) proteins in cultured cells followed by purification of VLP from the culture supernatant. VLPs will be paired with one of several novel vaccine adjuvants that stimulate specific pattern recognition receptors (PRRs). Each antigen/ adjuvant pairing will be tested in mice to quantify elicitation of neutralizing antibodies and POWV-specific T cells. We will also characterize B- and T-cell phenotypes in detail to determine how the vaccine-driven response compares to infection with intact POWV. Similarly to humans, POWV infection of wild-type laboratory mice results in lethal infection of the brain and CNS. Therefore, we will also evaluate vaccine efficacy in a challenge model of POWV infection in mice. Cohorts of mice vaccinated with individual antigen/ adjuvant pairings will be challenged with a lethal dose of POWV. These cohorts will be evaluated for increased survival, as well as, for reduction of viral load in tissues at multiple times post infection. Upon completion of this project, we expect to have developed an optimally formulated POWV vaccine which could move forward to clinical testing and be rapidly mobilized in the event of POWV emergence.

项目概要该提案的重点是开发一种用于预防波瓦桑病毒（POWV）相关疾病的疫苗。 POWV 是一种蜱传黄病毒，目前在北美流行，主要分布在东北部和北部地区。美国中部地区并向北延伸至加拿大。由于硬蜱的范围不断扩大媒介，POWV 有可能成为一种新兴病原体和公共卫生威胁。在人类中，POWV 是一种嗜神经病毒，可导致严重、有时致命的脑炎和脑膜炎。我们建议开发基于病毒表达产生的非复制病毒样颗粒（VLP）抗原的疫苗培养细胞中的前膜 (prM) 和包膜 (E) 蛋白，然后从培养物中纯化 VLP 上清液。 VLP 将与刺激特定模式的几种新型疫苗佐剂之一配对识别受体（PRR）。每个抗原/佐剂配对将在小鼠中进行测试，以量化诱导中和抗体和 POWV 特异性 T 细胞。我们还将详细描述 B 细胞和 T 细胞表型的特征以确定疫苗驱动的反应与完整 POWV 感染的比较。与人类类似，野生型实验小鼠的 POWV 感染会导致大脑和中枢神经系统的致命感染。因此，我们将还评估了小鼠 POWV 感染攻击模型中的疫苗功效。接种疫苗的小鼠群体个体抗原/佐剂配对将受到致死剂量的 POWV 的挑战。这些群体将是评估感染后多次存活率的提高以及组织中病毒载量的减少。该项目完成后，我们预计将开发出一种最佳配方的 POWV 疫苗，可以进入临床测试，并在出现 POWV 时迅速动员起来。