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: 8892970
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8892970
• 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; 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）：国家迫切需要一种改进的抗炭疽芽孢杆菌疫苗，这种疫苗是炭疽的病原体，可以用于预防性大规模接种，也可以在生物武器释放后立即接种。理想的疫苗将很容易以高一致性和纯度配制，不需要冷链进行储存和运输，并且将通过无针方法交付。它将有很强的辅助性能，并基于一个平台容纳多个亚基的包含。最后，这种疫苗将预防疾病的早期阶段（例如，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，疫苗必须针对孢子表面的抗原表位。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，那么炭疽的开始及其后期阶段可能会被阻止。已经有证据表明，这种策略很可能导致更好的全身反应，因为孢子成分已被证明可以增强基于pa的疫苗。本研究将利用纳米脂蛋白颗粒（NLP）技术制备一种针对多种孢子表面抗原和保护性抗原（PA）的新型炭疽芽胞杆菌疫苗。nlp是自组装的纳米大小的圆盘状颗粒，由纯化的载脂蛋白和脂质试剂制成。因为它们可以很容易地结合和显示几乎任何蛋白质，nlp是将抗原作为疫苗呈递到免疫系统的理想平台。我们将利用我们实验室之前的研究，鉴定孢子表面蛋白并创造镍螯合纳米脂蛋白颗粒，以产生含有PA的纳米颗粒以及至少三种孢子蛋白，并测试它们作为鼻腔疫苗保护小鼠免受毒性孢子攻击的能力。我们有以下具体目标：1)生成并分析含有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。我们将研制这种疫苗，分析其刺激的粘膜和全身免疫反应，并测量其抵御毒性艾姆斯菌株b型炭疽芽孢挑战的能力。2)生成并测试一种NiNLP疫苗，以对抗被操纵以击败抗孢子疫苗的孢子。最外层的孢子结构，称为外孢子，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，该疫苗包括缺乏外孢子的孢子表面（外壳）上的蛋白质。我们将纳入已知的衣面蛋白，并确定其他的衣面蛋白以纳入疫苗。我们将对它们进行免疫学分析，并测量它们的保护功效。

项目成果

Role of novel polysaccharide layers in assembly of the exosporium, the outermost protein layer of the Bacillus anthracis spore.

• DOI: 10.1111/mmi.14966
• 发表时间: 2022-09
• 期刊: MOLECULAR MICROBIOLOGY
• 影响因子: 3.6
• 作者: Lehmann, Dorte;Sladek, Margaret;Khemmani, Mark;Boone, Tyler J.;Rees, Eric;Driks, Adam
• 通讯作者: Driks, Adam

Characterization of Bacillus anthracis Spore Proteins Using a Nanoscaffold Vaccine Platform.

使用纳米支架疫苗平台表征炭疽芽孢杆菌孢子蛋白。

• DOI: 10.3389/fimmu.2020.01264
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Weilhammer,DinaR;Dunkle,AlexisD;Boone,Tyler;Gilmore,SeanF;Khemmani,Mark;Peters,SandraKG;Hoeprich,PaulD;Fischer,NicholasO;Blanchette,CraigD;Driks,Adam;Rasley,Amy
• 通讯作者: Rasley,Amy

Coordinated Assembly of the Bacillus anthracis Coat and Exosporium during Bacterial Spore Outer Layer Formation.

细菌孢子外层形成期间，炭疽芽孢杆菌涂层和外孢子的配位组件。

• DOI: 10.1128/mbio.01166-18
• 发表时间: 2018-11-06
• 期刊: mBio
• 影响因子: 6.4
• 作者: Boone TJ;Mallozzi M;Nelson A;Thompson B;Khemmani M;Lehmann D;Dunkle A;Hoeprich P;Rasley A;Stewart G;Driks A
• 通讯作者: Driks A