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A Novel Approach for Mycobacterium Tuberculosis Vaccine Development

结核分枝杆菌疫苗开发的新方法

基本信息

批准号：
8660619
负责人：
Biao He
金额：
$ 22.28万
依托单位：
UNIVERSITY OF GEORGIA
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：
2013-05-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8660619
关键词：
Adolescence Aerosols Affect Animal Model Attenuated Attenuated Vaccines BCG Vaccine Bacteria Birth Canis familiaris Cavia Cells Cellular Immunity Characteristics Clinical Complementary DNA Coughing Country Gagging Generations Genes Genome HIV Health Human Human Cell Line Immune Immune response Immunity Individual Infection Intranasal Administration Lead Life Mediating Modeling Mucosal Immune Responses Mus Mycobacterium bovis Mycobacterium tuberculosis Mycobacterium tuberculosis antigen 85A Mycobacterium tuberculosis antigens Paramyxovirus Population Proteins RNA RNA Viruses Recombinants Research Risk Ruminants Safety Side System Testing Tuberculin Test Tuberculosis Tuberculosis Vaccines United States Public Health Service Vaccinated Vaccine Production Vaccines Vaccinia virus Variant Vero Cells Viral Vector Virus base gag Gene Products immunogenicity immunosuppressed in vivo influenza virus gene influenzavirus killings mouse model nonhuman primate novel novel strategies novel vaccines parainfluenza virus pathogen positional cloning prevent protective efficacy public health relevance recombinant virus respiratory respiratory virus vaccination against tuberculosis vaccine candidate vaccine development vector

项目摘要

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), is an intracellular bacterial pathogen that kills approximately 1.7 million people each year and infects one-third of the world's population. The most-widely used vaccine in use today is BCG, which is a live avirulent variant of M. bovis, a closely related species that causes tuberculosis in ruminants. BCG administration to an immunosuppressed individual can disseminate and lead to serious life-threatening infection. This inherent safety ris remains in second- generation BCG vaccines modified to express Mtb antigens and/or factors that imbue the bacteria with enhanced survival inside host cells. Thus, there is a need for a safe and more effective TB vaccine. In this proposal, we seek to develop a novel TB vaccine based on parainfluenza virus 5 (PIV5), a respiratory virus. Parainfluenza virus 5 (PIV5), a paramyxovirus, is thought to be a contributing factor for causing kennel cough and is not known to cause any illness in humans. Several characteristics of PIV5 make it an attractive vaccine candidate vector. First, kennel cough vaccines containing live PIV5 have been used in dogs over 30 years. Humans are likely exposed to this virus due to close contact to dogs. Yet, no recorded illness in humans has been associated with the virus. Second, it can be produced in high titers in many cells including Vero cells that have been approved for vaccine production. Third, PIV5 can infect human cell lines and primary human cells. Fourth, in our recent study, we have found that pre-existing immunity against PIV5 does not negatively affect immunity generated by a PIV5-based vaccine. Fifth, PIV5 expressing NP, an internal protein of influenza virus, protected against lethal influenza virus challenge in mice. Since NP-mediated protective immunity relies on cell-mediated immunity, the results suggest that PIV5-based vaccine is capable of inducing protective cellular immune responses. Sixth, in a side-by-side comparison of PIV5 expressing HIV Gag protein (PIV5-gag) and a vaccinia virus (MVA) expressing Gag (MVA-Gag), PIV5-Gag induced better cellular immune responses than MVA-Gag in mice in our preliminary studies. Finally, the intranasal administration of PIV5 is a very good feature for eliciting robust mucosal immune responses, and thus ideal for vaccinating against respiratory pathogens. This vector has not previously been evaluated as an Mtb vaccine vector. We hypothesize that PIV5 as a live vector will induce immunity to prevent Mtb infection. In this proposal, we plan to demonstrate the proof-of principal for using PIV5 as a vector for Mtb vaccine development. We will focus our efforts on the following specific aims: generate and analyze recombinant PIV5 expressing Mtb antigens 85A (PIV5-85A) and 85B (PIV5-85B) and evaluate immunogenicity and efficacy of recombinant viruses in vivo. At the end of this study, we expect to have determined whether PIV5 expressing Mtb antigens are good Mtb vaccine candidates. If we identify efficacious PIV5-based vaccine candidates in this study, we will further test the candidates in more relevant animal models such as guinea pig and non-human primate. We also will continue to modify the viral vector to make the vaccine candidate maximally effective.

描述（申请人提供）：结核分枝杆菌（Mtb）是结核病（TB）的病原体，是一种细胞内细菌病原体，每年导致约170万人死亡，感染世界三分之一的人口。目前使用最广泛的疫苗是BCG，它是M.牛，一种密切相关的物种，导致反刍动物结核病。对免疫抑制的个体施用BCG可以传播并导致严重的危及生命的感染。这种固有的安全性风险保留在第二代BCG疫苗中，所述第二代BCG疫苗经修饰以表达Mtb抗原和/或因子，所述Mtb抗原和/或因子使细菌在宿主细胞内的存活增强。因此，需要一种安全和更有效的结核病疫苗。在这项提案中，我们寻求开发一种基于副流感病毒5（PIV 5）的新型结核病疫苗，PIV 5是一种呼吸道病毒。副流感病毒5型（PIV 5）是一种副粘病毒，被认为是引起犬舍咳嗽的一个因素，目前还不知道它会引起人类任何疾病。PIV 5的几个特征使其成为有吸引力的疫苗候选载体。首先，含有活PIV 5的犬舍咳嗽疫苗已经在狗身上使用了30多年。人类可能会因与狗的密切接触而接触到这种病毒。然而，没有记录在案的人类疾病与该病毒有关。其次，它可以在许多细胞中以高滴度生产，包括已被批准用于疫苗生产的Vero细胞。第三，PIV 5可以感染人类细胞系和原代人类细胞。第四，在我们最近的研究中，我们发现预先存在的针对PIV 5的免疫力不会对基于PIV 5的疫苗产生的免疫力产生负面影响。第五，表达流感病毒内部蛋白NP的PIV 5在小鼠中保护免于致死性流感病毒攻击。由于NP介导的保护性免疫依赖于细胞介导的免疫，因此结果表明基于PIV 5的疫苗能够诱导保护性细胞免疫应答。第六，在我们的初步研究中，在表达HIV Gag蛋白的PIV 5（PIV 5-gag）和表达Gag的牛痘病毒（MVA）（MVA-Gag）的并行比较中，PIV 5-Gag在小鼠中诱导比MVA-Gag更好的细胞免疫应答。最后，PIV 5的鼻内给药是一个非常好的特征，可以引发强大的粘膜免疫应答，因此非常适合接种抗呼吸道病原体的疫苗。该载体之前未被评价为Mtb疫苗载体。我们假设PIV 5作为活载体将诱导免疫以预防Mtb感染。在本提案中，我们计划证明使用PIV 5作为Mtb疫苗开发载体的原理证明。我们将致力于以下具体目标：产生和分析表达Mtb抗原85 A（PIV 5 - 85 A）和85 B（PIV 5 - 85 B）的重组PIV 5，并评价重组病毒的体内免疫原性和有效性。在本研究结束时，我们期望确定表达Mtb抗原的PIV 5是否是良好的Mtb疫苗候选物。如果我们在本研究中鉴定出有效的基于PIV 5的候选疫苗，我们将进一步在更相关的动物模型如豚鼠和非人灵长类动物中测试候选物。我们还将继续修改病毒载体，使候选疫苗最大限度地有效。