Development of a Safe and Potent Vaccine Against Melioidosis using the LVS dcapB Vector Platform

使用 LVS dcapB 载体平台开发安全有效的类鼻疽疫苗

基本信息

批准号：
10642711
负责人：
MARCUS AARON HORWITZ
金额：
$ 62.07万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10642711
关键词：
Accidents Aerosols Animals Antibiotic Resistance Antibiotics Antigens Area Attenuated Attenuated Vaccines Bacillus anthracis Bacteria Bioterrorism Burkholderia pseudomallei CD8B1 gene Categories Cells Cellular Immunity Centers for Disease Control and Prevention (U.S.)Cessation of life Chimeric Proteins Chromosomes Chronic Disease Classification Clinical Combined Vaccines Cytosol DNA cassette Development Diagnosis Disease Disease Outbreaks Dose Endemic Diseases Environment Formulation Francisella tularensis Fresh Water Future Goals Gram-Negative Bacteria Growth Health Policy Human Immune Immune response Immunity Immunocompetent Immunologics In Vitro Inbred BALB C Mice Individual Infection Ingestion Inhalation Invaded Kinetics Laboratories Licensing Life Style Listeria monocytogenes Marker Vaccines Mediating Melioidosis Military Personnel Mucous Membrane Mus Persons Phagocytes Plasmids Pneumonia Property Prophylactic treatment Protein Secretion Proteins Public Health Recombinant Vaccines Recombinants Regimen Resistance Risk Reduction Route Safety Skin Soil Symptoms T-Lymphocyte Testing Vaccines Vacuole Virulence Virulent Water aerosolized biodefense bioweapon booster vaccine cell mediated immune response cost efficacy evaluation improved manufacturing cost novel overexpression pathogen protective efficacy protein expression respiratory respiratory challenge safety assessment subcutaneous vaccine efficacy vaccine evaluation vaccine platform vaccine safety vector vector vaccine

项目摘要

PROJECT SUMMARY/ABSTRACT Burkholderia pseudomallei (Bp), an environmental bacterium capable of infecting humans and animal hosts, is the causative agent of melioidosis, a highly fatal disease endemic in many tropical areas. In addition to its significant public health burden in endemic regions, causing ~89,000 deaths annually, Bp is categorized as a Tier 1 Select Agent of bioterrorism, in large part because inhalation of low doses of Bp can cause rapidly fatal pneumonia. As naturally acquired melioidosis is often difficult to diagnose and requires very lengthy treatment, and as post-exposure prophylaxis is not a practical public health policy for countering an outbreak of pneumonic melioidosis from a bioterrorist attack, a safe and effective pre-exposure vaccine would be highly beneficial in both circumstances. Currently, there are no licensed vaccines against Bp. Hence, a vaccine against Bp would be of great benefit to people living in endemic regions, travelers, and military personnel stationed in these areas, and it would also reduce the risk from an intentional release in a bioterrorist attack. The goal of this application is to develop a safe and highly potent vaccine against Bp, suitable for both biodefense and public health purposes, based on a readily expandable single vector platform vaccine. Specifically, we shall use a novel, safe, yet potent live attenuated vector, LVS ΔcapB. The LVS ΔcapB vector, developed in this laboratory, is a further attenuated version (>10,000 fold less virulent in mice) of a multi- deletional Francisella tularensis vaccine (F. tularensis subsp. holarctica Live Vaccine Strain; LVS) already extensively tested in humans; hence, LVS ΔcapB is anticipated to be exceedingly safe. Moreover, recombinant vaccines comprising this vector have been shown to induce potent humoral and cell-mediated (including both CD4+ and CD8+) immune responses, all likely important to long-lasting potent immunoprotection against Bp. In preliminary studies, homologous boosting with rLVS ΔcapB vaccines expressing immunoprotective Bp antigens has already demonstrated impressive protective efficacy against respiratory challenge with virulent Bp in sensitive BALB/c mice; protection was superior to the unlicensed attenuated Bp82 vaccine, which is unlikely to be approved because of concerns about reversion to virulence and the possibility of causing chronic disease. To accomplish our goal of developing a safe and highly potent vaccine against Bp, we shall a) construct optimized rLVS ΔcapB vaccines expressing multiple immunoprotective Bp antigens as fusion proteins; b) evaluate the vaccines systematically in vitro for protein expression, growth kinetics, and stability; c) evaluate the vaccines administered by different routes for safety, dissemination, clearance, and stability in both immune competent and immune deficient mice; d) evaluate protective efficacy against challenge with highly virulent Bp by the respiratory (IN) route, the route of greatest concern in a bioterrorist attack, and by the subcutaneous route, the route principally responsible for natural infection; and e) explore correlates of protective immunity using vaccines of escalating efficacy.

项目摘要/摘要 Burkholderia pseudomallei（BP），一种能够感染人类和动物的环境细菌宿主是Melioidosis的病因，这是许多热带地区致命性疾病的高度致命性疾病。此外 BP对其内在地区的重要公共卫生伯恩伯恩（Burnen）造成约89,000人的死亡，BP被分类作为生物恐怖主义的1层选择药物，在很大程度上是因为吸入低剂量的BP会迅速引起致命的肺炎。由于自然获得的梅洛尼病通常很难诊断，并且需要很长时间治疗，并且作为暴露后预防是对抗爆发的实际公共卫生政策生物恐怖攻击发作的肺炎黑胶质病，安全有效的暴露前疫苗将是高度的在这两种情况下有益。目前，没有针对BP的许可疫苗。因此，一种疫苗反对BP将对居住在地方性地区，旅行者和军事人员中的人们带来巨大好处驻扎在这些地区，这也将降低在生物恐怖袭击中有意释放的风险。该应用的目的是开发针对BP的安全且高潜在的疫苗，适合两者 Biodefense和公共卫生目的是基于易于扩展的单个矢量平台疫苗。具体而言，我们将使用一种新型，安全但潜在的活衰减载体，LVSΔCAPB。 LVSΔCAPB载体，在该实验室中开发的是一个进一步的减弱版本（在小鼠中少10,000倍）已缺失的francisella tularensis疫苗（F. tularensissubsp。HolarcticaLive疫苗菌株； LVS）在人类中进行了广泛的测试；因此，LVSΔCAPB预计将非常安全。而且，重组完成该载体的疫苗已显示可诱导有效的体液和细胞介导的疫苗（包括 CD4+和CD8+）免疫复杂，所有这些对BP的持久有效免疫保护都可能很重要。在初步研究中，用RLVSΔCAPB疫苗表达免疫保护BP的同源增强抗原已经表现出具有强大的BP呼吸挑战的令人印象深刻的保护有效性敏感的BALB/C小鼠；保护优于无载的减毒BP82疫苗，这不太可能由于担心反向病毒和引起慢性疾病的可能性而被批准。为了实现我们开发针对BP的安全且高潜在疫苗的目标，我们将a）建造优化的RLVSΔCAPB疫苗表达多种免疫保护BP抗原作为融合蛋白； b）系统地在体外评估疫苗的蛋白质表达，生长动力学和稳定性； c）评估两种免疫的安全，传播，清除和稳定性的不同路线施用的疫苗有能力和免疫缺陷的小鼠； d）评估具有高毒BP挑战的保护有效性通过呼吸道路线，生物恐怖袭击中最大的关注路线，以及皮下路线，主要负责自然感染的路线； e）探索保护性免疫的相关性使用升级效率的疫苗。