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: 8694579
• 负责人: Balaji Narasimhan
• 金额: $ 35万
• 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/8694579
• 关键词: Address; Adjuvant; Advanced Development; Animal Model; Anthrax disease; Antigens; Bacillus anthracis; Back; Bacteria; Binding; Biological Assay; CD8B1 gene; Categories; Cells; Cellular Immunity; Cold Chains; Communicable Diseases; Data; Development; Dinucleoside Phosphates; Dose; Drug Formulations; Evaluation; Event; Exposure to; 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 Pathway Gene; T-Lymphocyte; Technology; Temperature; Testing; Time; Universities; Vaccine Adjuvant; Vaccine Design; Vaccines; Work; Yersinia pestis; base; biodefense; chemokine; compliance behavior; cost effective; cytokine; design; falls; immunogenic; innovation; nanoparticle; nonhuman primate; novel; pathogen; pre-clinical; preclinical study; programs; protective efficacy; research study; respiratory; response; vaccine delivery

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）：我们已经开发出基于可生物降解聚酐的纳米疫苗平台并获得了专利保护。使用 F1-V 作为免疫原，我们证明了其能够在单次给药中诱导小鼠产生长达 40 周的长期保护性免疫力，以抵抗鼠疫耶尔森氏菌（肺鼠疫的病原体）的致命感染。我们建议将该纳米疫苗平台与基于环二核苷酸（CDN）的先天免疫诱导剂相结合，设计针对多种生物防御病原体（即鼠疫耶尔森氏菌和炭疽杆菌）的疫苗，从而打破“一种错误，一种药物”的范式。目前可用的疫苗制剂和佐剂缺乏长期稳定性，不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，并且也可用于对抗非防御性呼吸道病原体。此外，纳米疫苗具有热稳定性，从而避免了冷链。我们的中心假设是基于有关我们佐剂平台的可调性和功效的重要同行评审初步数据，聚酐纳米疫苗与 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，通过实现以下具体目标，推进针对 NIAID A 类优先药物的疫苗技术的开发，每个目标都受到里程碑、继续/不继续决策和后备位置的限制： 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致命攻击的保护。目标 2. 评估目标 1 中的先导组合纳米疫苗制剂对抗兔子炭疽杆菌和非人灵长类动物鼠疫杆菌致死攻击的保护能力。目标 3. 展示目标 1 和 2 中确定的优化先导组合纳米疫苗制剂的储存保质期性能增强。 合作伙伴包括：爱荷华州立大学，该大学将改进免疫原性剂量和组合纳米疫苗配方，展示疫苗在小鼠中的功效和保护能力，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体细胞的相互作用；洛夫莱斯生物医学和环境研究所将确定先导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未免疫人群进行快速免疫。