A Novel Approach for Mycobacterium Tuberculosis Vaccine Development

结核分枝杆菌疫苗开发的新方法

• 批准号: 8583108
• 负责人: Biao He
• 金额: $ 17.45万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 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/8583108
• 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

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（由申请人提供）：结核分枝杆菌（MTB），结核病的病因（TB）是一种细胞内细菌病原体，每年杀死约170万人，感染了世界人群的三分之一。当今使用的最具使用的疫苗是BCG，BCG是Bovis M. Bovis的活节菌变体，这是一种密切相关的物种，会导致反刍动物的结核病。 BCG给予免疫抑制的个体可以传播并导致严重威胁生命的感染。这种固有的安全性RI仍在修改的第二代BCG疫苗中，以表达MTB抗原和/或因素，这些疫苗将细菌与宿主细胞内部生存增强相同。因此，需要使用安全，更有效的结核病疫苗。在此提案中，我们试图基于呼吸道病毒的Parainfluenza病毒5（PIV5）开发一种新型的TB疫苗。帕丙素氟扎病毒5（PIV5）是一种帕托马病毒，被认为是引起狗窝咳嗽的因素，尚不知道会在人类中引起任何疾病。 PIV5的几种特征使其成为有吸引力的疫苗候选载体。首先，含有活PIV5的狗窝咳嗽疫苗已在30年以上用于狗。由于与狗的密切接触，人类可能会暴露于该病毒。然而，人类没有记录的疾病与该病毒有关。其次，它可以在许多细胞中的高滴度中产生，包括已批准用于疫苗生产的Vero细胞。第三，PIV5可以感染人类细胞系和原代人细胞。第四，在我们最近的研究中，我们发现对PIV5的免疫力不会对基于PIV5的疫苗产生的免疫力产生负面影响。第五，PIV5表达NP是一种流感病毒的内部蛋白质，可防止小鼠致命的流感病毒挑战。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PIV5的疫苗能够诱导保护性细胞免疫反应。第六，在表达HIV GAG蛋白（PIV5-GAG）和表达GAG（MVA-GAG）的PIV5比较中，PIV5-GAG在我们的初步研究中诱导了比MVA-GAG更好的细胞免疫反应。最后，PIV5的鼻内给药是引起健壮粘膜免疫反应的一个非常好的特征，因此是针对呼吸道病原体进行疫苗接种的理想特征。该载体先前尚未被评估为MTB疫苗载体。我们假设PIV5作为活载体将诱导免疫以防止MTB感染。在此提案中，我们计划证明将PIV5用作MTB疫苗开发向量的本金证明。我们将重点放在以下特定目标上：生成和分析表达MTB抗原85A（PIV5-85A）和85B（PIV5-85B）的重组PIV5，并评估重组病毒在体内的免疫原性和功效。在这项研究结束时，我们希望已经确定表达MTB抗原的PIV5是否是良好的MTB疫苗候选物。如果我们在这项研究中确定有效的基于PIV5的疫苗候选物，我们将进一步 在更相关的动物模型（例如豚鼠和非人类灵长类动物）中测试候选者。我们还将继续修改病毒载体，以使疫苗候选者最大程度地有效。