A novel anti-spore nasal vaccine for protection from anthrax

一种新型抗孢子鼻疫苗，可预防炭疽病

• 批准号: 8502611
• 负责人: Adam Driks
• 金额: $ 62.41万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-19 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502611
• 关键词: Adjuvant; Anthrax disease; Antibodies; Antigens; Apolipoproteins; Bacillus anthracis; Bacillus anthracis spore; Binding; Biological; Capsid Proteins; Cold Chains; Data; Disease; Dose; Drug Formulations; Engineering; Epitopes; Escherichia coli; Event; Homologous Gene; Immune response; Immune system; Immunofluorescence Microscopy; Inbred BALB C Mice; Laboratories; Life; Lipids; Lung; Mass Immunization; Mass Spectrum Analysis; Measures; Membrane Proteins; Methods; Morbidity - disease rate; Mucosal Immune Responses; Mucous Membrane; Mus; Needles; Nickel; Nose; Phagocytes; Property; Protein Binding; Proteins; Reaction; Reagent; Reproduction spores; Research; Shapes; Staging; Structure; Surface; Surface Antigens; Technology; Testing; Vaccinated; Vaccination; Vaccines; Virulent; base; improved; in vivo; mortality; nanoparticle; nanoscale; novel; particle; prevent; prophylactic; protective efficacy; public health relevance; response; surface coating; uptake; weapons

DESCRIPTION (provided by applicant): There is a pressing national need for an improved vaccine against Bacillus anthracis, the causative agent of anthrax, that can be used for prophylactic mass inoculation as well as immediately after release of a biological weapon. An ideal vaccine will be easily formulated at high consistency and purity, will not require a cold chain for storage and transport, and will be deliverable by a needle-free method. It will have strong adjuvant properties and be based on a platform accommodating the inclusion of multiple subunits. Finally, this vaccine will protect against the earliest stages of the disease (e.g., by recognizing the spore in the lung mucosa, prior to uptake by phagocytic cells). To do this, the vaccine must target epitopes on the spore surface. If the same vaccine also targeted protective antigen (PA), the major component of the existing vaccine, then initiation of anthrax, as well as its later stages, might be prevented. There is already evidence that this strategy is very likely to result in a superior systemic response, since spore components have been shown to enhance a PA-based vaccine. In this proposal, we will generate a novel B. anthracis vaccine, directed against multiple spore-surface antigens and protective antigen (PA), using nanolipoprotein particle (NLP) technology. NLPs are self-assembled, nanometer-sized disk-shaped particles made from purified apolipoprotein and lipid reagents. Because they can be readily engineered to incorporate and display almost any protein, NLPs are an ideal platform for presenting antigens to the immune system as a vaccine. We will leverage prior research in our laboratories, identifying spore-surface proteins and creating nickel-chelated nanolipoprotein particles, to generate nanoparticles bearing PA as well as at least three spore proteins and test their ability to function as a nasal vaccine protecting mice from a challenge with virulent spores. We have the following specific aims: 1) Generate and analyze a nickel-chelated nanolipoprotein particle (NiNLP) vaccine bearing PA and the three known spore-surface proteins, BclA, BclB, ExsK. We will formulate this vaccine, analyze the mucosal and systemic immune responses that it stimulates, and measure its ability to protect against a challenge with virulent Ames strain B. anthracis spores. 2) Generate and test an NiNLP vaccine against spores manipulated to defeat anti-spore vaccines. The outermost spore structure, called the exosporium, could be easily removed by an enemy, thereby defeating an anti-spore vaccine. Therefore, we will generate a vaccine that includes proteins on the surface (the coat) of spores lacking the exosporium. We will incorporate a known coat-surface protein and identify additional coat-surface proteins for inclusion into the vaccine. We will analyze them immunologically and measure their protective efficacy as in Aim 1.

描述（由申请人提供）：国家迫切需要一种针对炭疽杆菌（炭疽的病原体）的改进疫苗，该疫苗可用于预防性大规模接种以及在生物武器释放后立即接种。理想的疫苗将容易配制成高浓度和高纯度的疫苗，不需要冷链储存和运输，并且可以通过无针方法输送。它将具有强佐剂性质，并且基于容纳多个亚基的包含的平台。最后，这种疫苗将保护免受疾病的最早阶段（例如，通过在被吞噬细胞摄取之前识别肺粘膜中的孢子）。要做到这一点，疫苗必须靶向孢子表面的表位。如果同样的疫苗也针对保护性抗原（PA），即现有疫苗的主要成分，那么炭疽病的发病以及后期阶段就可能被预防。已经有证据表明，这种策略很可能导致上级全身反应，因为孢子组分已显示出增强PA基疫苗。在这个提议中，我们将生成一个新的B。利用纳米脂蛋白颗粒（NLP）技术，针对多种孢子表面抗原和保护性抗原（PA）的炭疽疫苗。NLP是由纯化的载脂蛋白和脂质试剂制成的自组装的纳米尺寸的盘状颗粒。因为它们可以很容易地被改造成包含和展示几乎任何蛋白质，NLP是将抗原作为疫苗呈递给免疫系统的理想平台。我们将利用我们实验室先前的研究，鉴定孢子表面蛋白并产生镍螯合纳米脂蛋白颗粒，以产生含有PA以及至少三种孢子蛋白的纳米颗粒，并测试它们作为鼻疫苗保护小鼠免受有毒孢子挑战的能力。我们的具体目标如下：1）制备并分析含有PA和三种已知孢子表面蛋白BclA、BclB、ExsK的镍螯合纳米脂蛋白颗粒（NiNLP）疫苗。我们将配制这种疫苗，分析它刺激的粘膜和全身免疫应答，并测量它抵抗强艾姆斯毒株B攻击的能力。炭疽孢子2)生成并测试针对孢子的NiNLP疫苗，以击败抗孢子疫苗。最外面的孢子结构，称为外孢壁，可以很容易地被敌人移除，从而击败抗孢子疫苗。因此，我们将产生一种疫苗，其中包括蛋白质的表面（外套）的孢子缺乏外孢。我们将结合一个已知的外壳表面蛋白，并确定额外的外壳表面蛋白纳入疫苗。我们将对它们进行免疫学分析，并测量它们的保护效力，如目标1所述。