Enhanced Shelf-life Nanovaccine Formulation for Immunity to Biodefense Pathogens

延长保质期的纳米疫苗配方，可增强对生物防御病原体的免疫力

• 批准号: 9120299
• 负责人: Balaji Narasimhan
• 金额: $ 34.68万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9120299
• 关键词: Address; Adjuvant; Advanced Development; Animal Model; Anthrax disease; Antigens; Bacillus anthracis; Back; Bacteria; Binding; Biological Assay; Biotechnology; CD8B1 gene; Categories; Cells; Cellular Immunity; Cold Chains; Communicable Diseases; Data; Development; Dinucleoside Phosphates; Dose; Evaluation; Event; Exposure to; Formulation; Genes; Goals; Health; Heating; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunization; Infection; Infectious Agent; Inflammatory; Interferons; Iowa; Lead; Legal patent; Life; Listeria monocytogenes; Military Personnel; Modeling; Mus; National Institute of Allergy and Infectious Disease; Natural Immunity; Oryctolagus cuniculus; Pathogenesis; Peer Review; Performance; Pharmaceutical Preparations; Plague; Pneumonic Plague; Polyanhydrides; Population; Positioning Attribute; Principal Investigator; Public Health; Recombinants; Regimen; Research Institute; Role; Signaling Protein; T-Lymphocyte; Technology; Temperature; Testing; Time; Universities; Vaccine Adjuvant; Vaccine Design; Vaccines; Work; Yersinia pestis; adaptive immunity; base; biodefense; chemokine; compliance behavior; cost effective; cytokine; design; falls; immunogenic; innovation; nanoparticle; nanovaccine; nonhuman primate; novel; pathogen; pre-clinical; preclinical study; programs; protective efficacy; research study; respiratory; response; vaccine delivery; vaccine development

DESCRIPTION (provided by applicant): We have developed and received patent protection for a biodegradable polyanhydride-based nanovaccine platform. Using F1-V as the immunogen, we have demonstrated its ability to induce, in a single administration, long-lived protective immunity in mice for up to 40 weeks against a lethal infection with Yersinia pestis, the causative agent of pneumonic plague. We propose to combine this nanovaccine platform with cyclic dinucleotide (CDN)-based innate immune inducers to design vaccines against multiple biodefense pathogens (i.e., Y. pestis and Bacillus anthracis), thereby breaking the "one-bug, one-drug" paradigm. Currently available vaccine formulations and adjuvants lack long-term stability, do not promote induction of antigen-specific cellular and humoral immunity, and/or are reactogenic. Our combination nanovaccine platform will overcome all these shortcomings, will be broadly applicable to infectious diseases, and will have application against non- defense respiratory pathogens as well. Furthermore, the nanovaccine is heat stable, thereby obviating the cold chain. Our central hypothesis, based on significant peer-reviewed preliminary data on the tunability and efficacy of our adjuvant platforms, is that polyanhydride nanovaccines together with CDNs can be used to formulate efficacious, single-dose vaccines against multiple biodefense pathogens. We will position this platform for preclinical studies that will advance the development of vaccine technologies specific for NIAID Category A priority agents by accomplishing the following Specific Aims, each of which is bounded by milestones, go/no-go decisions and fall-back positions: Aim 1. Optimize the immunization regimen of combination nanovaccine formulations to provide protection against lethal challenge with two biodefense agents. Aim 2. Evaluate the protective capabilities of the lead combination nanovaccine formulation from Aim 1 against lethal challenge with B. anthracis in rabbits and Y. pestis in non-human primates. Aim 3. Demonstrate enhanced storage shelf life performance of optimized lead combination nanovaccine formulation identified in Aims 1 and 2. Partners include: Iowa State University, who will refine the immunogenic dose and combination nanovaccine formulations, demonstrate the efficacy and protective capabilities of the vaccines in mice, and perform the storage shelf life studies; Aduro BioTech, who will prepare innate immune stimulators and evaluate interactions of combination nanovaccine formulations with human cells; and Lovelace Biomedical and Environmental Research Institute, who will determine the efficacy of the lead combination nanovaccine in rabbits and NHPs. At the end of the project period, we will deliver a single-dose combination nanovaccine formulation capable of safely inducing protective immunity against two biodefense pathogens that is ready for preclinical studies. The long-term impact of this work is protection of our militry troops prior to deployment as well as rapid immunization of an immunologically naive population following an exposure event.

描述（由申请人提供）：我们已经开发并获得了基于生物可降解聚苯胺的纳米疫苗平台的专利保护。使用F1-V作为免疫原，我们已经证明了它的能力，诱导，在一个单一的管理，长寿的保护性免疫小鼠长达40周的致命感染鼠疫耶尔森氏菌，肺鼠疫的病原体。我们建议将这种纳米疫苗平台与基于环二核苷酸（CDN）的先天免疫诱导剂结合联合收割机，以设计针对多种生物防御病原体的疫苗（即，Y.鼠疫和炭疽杆菌），从而打破了“一种病菌，一种药物”的模式。目前可用的疫苗制剂和佐剂缺乏长期稳定性，不能促进抗原特异性细胞和体液免疫的诱导，和/或具有反应原性。我们的组合纳米疫苗平台将克服所有这些缺点，将广泛适用于传染病，并将对非防御性呼吸道病原体以及应用。此外，纳米疫苗是热稳定的，从而避免了冷链。我们的中心假设，基于我们佐剂平台的可调性和有效性的重要同行评审的初步数据，是聚酸酐纳米疫苗与CDN一起可用于配制针对多种生物防御病原体的有效的单剂量疫苗。我们将把这个平台定位于临床前研究，通过实现以下特定目标，推进NIAID A类优先药物特定疫苗技术的开发，每个目标都由里程碑、进行/不进行决策和后退位置限定：目标1。优化组合纳米疫苗制剂的免疫方案，以提供针对两种生物防御剂的致命攻击的保护。目标2.评价来自目标1的先导组合纳米疫苗制剂针对B致死性攻毒的保护能力。兔炭疽菌和Y.非人类灵长类动物身上的鼠疫目标3。证明目标1和2中确定的优化的先导化合物纳米疫苗制剂的储存有效期性能增强。 合作伙伴包括：爱荷华州州立大学，将改进免疫原性剂量和组合纳米疫苗制剂，证明疫苗在小鼠中的有效性和保护能力，并进行储存保质期研究; Aduro BioTech，将制备先天免疫刺激剂，并评估组合纳米疫苗制剂与人类细胞的相互作用;和Lovelace生物医学和环境研究所，他们将确定领先的组合纳米疫苗在兔子和NHP中的功效。 在项目期结束时，我们将提供一种单剂量组合纳米疫苗制剂，能够安全地诱导针对两种生物防御病原体的保护性免疫力，为临床前研究做好准备。这项工作的长期影响是在部署前保护我们的军队，以及在暴露事件后对免疫学幼稚人群进行快速免疫。