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：
10176399
负责人：
ALEC J HIRSCH
金额：
$ 50.04万
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/10176399
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 Deer Tick 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 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.

项目摘要该提案的重点是开发预防Powassan病毒（POWV） - 相关疾病的疫苗。 POWV是目前北美特有的tick传播黄病毒，主要在东北和北部美国的中部地区，延伸到加拿大。由于ixodid tick的范围不断扩大向量，POWV有可能成为新兴的病原体和公共卫生威胁。在人类中，POWV 是一种神经性病毒，可能导致严重的，有时是致命的脑炎和脑膜炎。我们建议基于病毒表达产生的非复制病毒样颗粒（VLP）抗原开发疫苗培养细胞中的膜前（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/辅助配对将在小鼠中进行测试，以量化中和抗体和POWV特异性T细胞。我们还将详细描述B-和T细胞表型确定疫苗驱动的反应与完整POWV的感染相比。与人类类似野生型实验室小鼠的POWV感染会导致大脑和中枢神经系统的致命感染。因此，我们会的还评估小鼠POWV感染挑战模型中的疫苗功效。接种疫苗的小鼠队列单个抗原/辅助配对将通过致命的POWV挑战。这些队列将是评估感染后多次的生存率增加，以及减少组织中病毒载量的降低。该项目完成后，我们希望开发出一种最佳配制的POWV疫苗可能会前进进行临床测试，并在POWV出现时迅速动员。