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: 8699135
• 负责人: Adam Driks
• 金额: $ 66.39万
• 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/8699135
• 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. Public Health Relevance: Bacillus anthracis spores, the cause of anthrax, are a highly effective biological weapon. We propose to generate a vaccine to protect against anthrax that will be suitable for mass immunization and will be effective against spores engineered to lack the usual surface proteins. This vaccine could not only greatly reduce loss of life in the event of an attack, but could reduce the appeal of the use of the biological weapon.

描述(申请人提供)：国家迫切需要一种针对炭疽芽孢杆菌的改进疫苗，该疫苗是炭疽病的病原体，可用于预防性大规模接种，以及在生物武器释放后立即使用。理想的疫苗将以高稠度和高纯度轻松配制，不需要冷链储存和运输，并且可以通过无针方法提供。它将具有强大的佐剂特性，并以容纳多个亚单位的平台为基础。最后，这种疫苗将预防疾病的早期阶段(例如，通过在吞噬细胞摄取之前识别肺粘膜中的孢子)。要做到这一点，疫苗必须针对孢子表面的表位。如果同样的疫苗还针对现有疫苗的主要成分保护性抗原(PA)，那么炭疽病的开始及其后期阶段可能会得到预防。已经有证据表明，这一策略很可能导致更好的系统反应，因为孢子成分已被证明可以增强以PA为基础的疫苗。在这项计划中，我们将利用纳米脂蛋白颗粒(NLP)技术，生产一种针对多种孢子表面抗原和保护性抗原(PA)的新型炭疽杆菌疫苗。NLP是由纯化的载脂蛋白和脂类试剂制成的自组装的纳米大小的盘状颗粒。因为它们可以很容易地被设计成结合和展示几乎任何蛋白质，NLP是作为疫苗向免疫系统递送抗原的理想平台。我们将利用我们实验室之前的研究，识别孢子表面蛋白并创造镍螯合纳米脂蛋白颗粒，以产生携带PA和至少三种孢子蛋白的纳米颗粒，并测试它们作为鼻用疫苗的能力，以保护小鼠免受有毒孢子的挑战。1)构建并分析了含PA和3种已知孢子表面蛋白BclA、BclB、ExsK的镍螯合纳米脂蛋白(NiNLP)疫苗。我们将研制这种疫苗，分析它刺激的粘膜和系统免疫反应，并测量它抵御Ames菌株炭疽芽胞的攻击的能力。2)生产和测试一种针对孢子的NiNLP疫苗，该疫苗被操纵以击败抗孢子疫苗。最外层的孢子结构，称为外孢子菌，可以很容易地被敌人移除，从而击败抗孢子疫苗。因此，我们将生产一种疫苗，该疫苗在缺乏外孢子菌的孢子表面(外壳)包含蛋白质。我们将加入一种已知的衣壳表面蛋白，并确定其他衣壳表面蛋白以纳入疫苗。我们将对它们进行免疫学分析，并测量它们的保护效果，如目标1所示。 公共卫生相关性：炭疽芽胞是炭疽病的起因，是一种高效的生物武器。我们建议生产一种疫苗来预防炭疽病，这种疫苗将适用于大规模免疫，并将有效地对抗缺乏常见表面蛋白的孢子。这种疫苗不仅可以大大减少发生袭击时的生命损失，而且可以减少使用生物武器的吸引力。