Enhanced Shelf-life Nanovaccine Formulation for Immunity to Biodefense Pathogens

描述(申请人提供)：我们已经开发并获得了一种可生物降解的聚酸酐纳米疫苗平台的专利保护。使用F1-V作为免疫原，我们已经证明了它能够在一次给药中诱导小鼠长达40周的长期保护性免疫，以抵御致命的鼠疫耶尔森氏菌感染，鼠疫是肺鼠疫的病原体。我们建议将这一纳米疫苗平台与基于环二核苷酸(CDN)的天然免疫诱导剂相结合，设计针对多种生物防御病原体(即鼠疫杆菌和炭疽杆菌)的疫苗，从而打破“一虫一药”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，并将应用于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，基于对我们佐剂平台的可调性和有效性的重要同行评议初步数据，聚酸酐纳米疫苗与CDN一起可用于研制针对多种生物防御病原体的有效、单剂疫苗。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来推动针对NIAID A类优先代理的疫苗技术的开发，每个目标都有里程碑、通过/不通过决定和后备位置：目标1.优化组合纳米疫苗配方的免疫方案，以提供对两种生物防御剂的致命挑战的保护。目的2.评价来自目标1的先导组合纳米疫苗制剂对炭疽杆菌对兔致死攻击和对非人类灵长类动物对鼠疫菌致死攻击的保护能力。目的3.展示AIMS 1和2中确定的优化的铅组合纳米疫苗配方的储存期性能增强。 合作伙伴包括：爱荷华州立大学，他们将完善免疫原性剂量和复合纳米疫苗配方，展示疫苗在小鼠身上的效力和保护能力，并进行保质期研究；Aduro生物技术公司，他们将准备天然免疫刺激剂，并评估复合纳米疫苗制剂与人类细胞的相互作用；Lovelace生物医学和环境研究所，他们将确定联合纳米疫苗在兔和NHP中的疗效。 在项目期结束时，我们将提供一种单剂组合纳米疫苗配方，能够安全地诱导对两种生物防御病原体的保护性免疫，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事部队，以及在暴露事件之后对免疫能力不强的人群进行快速免疫接种。

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.