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）：我们已经开发了并获得了可生物降解的基于多丙二醇的纳米酮平台的专利保护。使用F1-V作为免疫原，我们证明了它在小鼠中诱导长期延长的保护性免疫的能力长达40周，以抗致命感染Pestis，pestis是肺炎鼠疫的病因。我们建议将这个纳米霉素平台与循环二核苷酸（CDN）的先天免疫诱导剂相结合，以设计针对多种生物化病原体（即Y. Pestis和anthracis）的疫苗，从而破坏了“一只猪，一次性drug”范式。当前可用的疫苗配方和佐剂缺乏长期稳定性，不会促进抗原特异性细胞和体液免疫的诱导，并且/或反应源性。我们的组合纳米霉素平台将克服所有这些缺点，将广泛适用于传染病，并将针对非国防呼吸道病原体应用。此外，纳米酮是热稳定的，从而避免了冷链。我们的中心假设基于有关辅助平台可调节性和功效的大量同行评审的初步数据，是多醇hydride Nanovaccines与CDN一起可用于制定有效的，单剂量的疫苗针对多种生物粘剂病原体。我们将通过实现以下特定目标来推进针对NIAID类别A的疫苗技术的开发，以推动该疫苗技术的开发，每种疫苗技术都受到以下特定目的的影响，每个目标都受到里程碑，进行/不进行的决策和倒塌的立场：AIM 1。优化组合Nanovaccine nanovaccine nanovaccine nanovaccine nanovaccine nanovaccine nanovaccine fiver twibi Bibientabie twip twibiagient afie twibi bigients two lietal攻击。 AIM 2。评估铅组合纳米甲苯甲虫制剂的保护能力，反对非人类灵长类动物的兔子和鼠b.炭疽病的致命挑战。 AIM 3。证明在AIM 1和2中确定的优化铅组合纳米酮配方的储存货架寿命性能增强。 合作伙伴包括：爱荷华州立大学，他将完善纳米酮配方的免疫原性剂量和组合，证明了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将准备先天免疫刺激剂并评估组合纳米酮配方与人类细胞的相互作用；以及Lovelace生物医学和环境研究所，他们将确定铅组合纳米酮在兔和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酮配方，能够安全地诱导针对两种准备用于临床前研究的生物化病原体的保护性免疫。这项工作的长期影响是在部署之前保护我们的武装部队，以及在暴露事件发生后对免疫学幼虫的快速免疫接种。