Pre-Exposure Prophylaxis Against Francisella tularensis

针对土拉弗朗西斯菌的暴露前预防

基本信息

批准号：
8840491
负责人：
MARCUS AARON HORWITZ
金额：
$ 70.67万
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：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8840491
关键词：
Antibiotics Antigens Attenuated Attenuated Live Virus Vaccine Awareness BCG Vaccine Biological Bioterrorism Categories Cells Child Chimeric Proteins Collaborations Development Diagnosis Disease Disease Outbreaks Dose Francisella tularensis Future Generations Goals Grant Health Hospitalization Human Immune response Immunity Immunocompromised Host In Vitro Individual Intramuscular Laboratories Learning Licensing Life Mediating Medical Military Personnel Morbidity - disease rate Mus Oral Parents Patients Persons Population Prophylactic treatment Proteins Public Health Recombinant Proteins Recombinants Risk Route Safety Testing Time Toxic effect Tuberculosis Tuberculosis Vaccines Tularemia Vaccines Virulent aerosolized base emergency service responder immunogenic immunogenicity macrophage mortality mouse model mutant novel overexpression pathogen promoter protein expression prototype rBCG resistant strain success vaccine development vaccine efficacy vaccine evaluation vaccine safety vector weapons

项目摘要

DESCRIPTION (provided by applicant): Francisella tularensis (Ft) causes tularemia, a serious and potentially fatal disease. Because Ft has an extraordinarily high infectivity, causes high morbidity and mortality, is relatively easily cultured and dispersed, and has previously been weaponized, it is classified as a Category A potential agent of bioterrorism. As post- exposure prophylaxis is not a practical public health alternative for countering an outbreak of pneumonic tularemia, a safe and effective pre-exposure vaccine is needed. The goal of this application is a safer and more potent vaccine against aerosolized Ft than the current unlicensed, toxic, and insufficiently effective vaccine (LVS). Our strategy is to utilize a live attenuated recombinant homologous vector - an attenuated form of the LVS vaccine (this parent vaccine has already been tested in humans) - to overexpress highly immunoprotective Ft proteins such as IglC, previously demonstrated in this laboratory to enhance protective immunity against aerosolized Ft. The proposed 2nd generation recombinant LVS (rLVS¿capB) vaccine will be safer than LVS because the proposed vector already has been demonstrated to be >10,000 times more attenuated than LVS and yet induce strong cell-mediated and humoral immune responses. The proposed 2nd generation rLVS¿capB vaccine will be more potent than LVS because it will overexpress large amounts of highly immunoprotective Ft proteins via novel promoters. This strategy for a tularemia vaccine mimics that used successfully in this laboratory to develop the first vaccines against tuberculosis that are safer and more potent than the current BCG vaccine; one of these tuberculosis vaccines has already demonstrated safety and enhanced immunogenicity in human trials. In this application, to accomplish our goal of a vaccine against tularemia that is safer and more potent than LVS, we propose to build upon our preliminary success with 1st generation rLVS¿capB vaccines by constructing the aforementioned new 2nd generation rLVS¿capB vaccines and testing them systematically for stability; protein expression extracellularly and intracellularly; safety; immunogenicity; and near-term and long- term efficacy against lethal Ft challenge in a mouse model. At the same time we shall determine optimal mucosal and systemic routes for administration. By the completion of this project, we anticipate having a vaccine that is substantially safer and more potent than LVS and suitable for testing in humans. While the focus of our grant is on a tularemia vaccine, our approach is applicable to vaccines against intracellular pathogens in general. Thus, lessons learned and strategies developed during the development of a successful tularemia vaccine are likely to be broadly applicable.

描述（由适用提供）：弗朗西斯氏菌（Francisella tularensis）（FT）会引起tular症，这是一种严重且潜在的致命疾病。由于FT感染异常高，引起高发病率和死亡率，相对容易培养和分散，并且以前已被武器化，因此它被归类为生物恐怖主义的潜在药物的类别。由于预防后暴露是反对肺炎爆发的实际公共卫生替代方法，因此需要一种安全有效的暴露前疫苗。该应用的目的是，与当前无牌，有毒和不足有效疫苗（LVS）相比，针对雾化FT的安全性和潜在疫苗更大。我们的策略是利用活死的重组同源载体 - 一种LVS疫苗的衰减形式（该母疫苗已经在人类中进行了测试） - 过表达高度免疫保护的FT蛋白，例如IGLC，以前在该实验室中证明，在该实验室中证明了这项实验室以增强保护免疫免受抗空精FT的保护。拟议的第二代重组LVS（RLVS¿CAPB）疫苗将比LVS更安全，因为所提出的载体已被证明比LVS的衰减比LVS高出10,000倍，但虽然具有强烈的细胞介导的强烈细胞介导的体液介导的体液免疫反应。拟议的第二代RLVS¿CAPB疫苗将比LVS更具潜力，因为它将通过新型启动子过度表达大量高度免疫保护的FT蛋白。这种策略用于在该实验室成功使用的tularemia疫苗模仿，以开发针对结核病的第一批疫苗，比目前的BCG疫苗更安全，更有潜力。在人类试验中，这些结核病疫苗之一已经证明了安全性和免疫原性。在此应用中，为了实现与LVS相比更安全，更有潜力的疫苗的目标，我们提议通过第一代RLVS€CAPB疫苗以我们的初步成功来建立capb疫苗，通过构建大约新的第二代RLVS�CAPB疫苗并系统地测试它们以系统地测试稳定性；细胞外蛋白质表达；安全;免疫原性；以及在小鼠模型中针对致命FT挑战的近期和长期效率。同时，我们将确定最佳的粘膜和全身性途径。通过完成该项目的完成，我们预计疫苗比LVS更安全，更有潜力，并且适合于人类进行测试。虽然我们赠款的重点是to疫苗疫苗，但我们的方法通常适用于针对细胞内病原体的疫苗。这是在成功开发成功的Tularemia疫苗期间得知的经验教训和策略，这可能是广泛适用的。