Enhanced Shelf-life Nanovaccine Formulation for Immunity to Biodefense Pathogens

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酸酐的纳米疫苗平台的专利保护。使用F1-V作为免疫原，我们已经证明它能够在单次给药中诱导小鼠对鼠疫耶尔森菌（肺鼠疫的病原体）的致命感染产生长达40周的长期保护性免疫。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起来，设计针对多种生物防御病原体（即鼠疫杆菌和炭疽芽孢杆菌）的疫苗，从而打破“一虫一药”的范式。目前可用的疫苗配方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。我们的联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。基于我们的佐剂平台的可调性和有效性的重要同行评议的初步数据，我们的中心假设是，聚酸酐纳米疫苗与cdn一起可用于制备有效的、针对多种生物防御病原体的单剂量疫苗。我们将定位该平台用于临床前研究，通过实现以下具体目标，推进NIAID A类优先药物特异性疫苗技术的开发，每个目标都有里程碑、进行/不进行的决定和后退位置：优化联合纳米疫苗配方的免疫方案，以提供对两种生物防御剂致命挑战的保护。目标2。评估来自Aim 1的铅组合纳米疫苗制剂对家兔炭疽芽胞杆菌和非人灵长类动物鼠疫杆菌致死性攻击的保护能力。目标3。证明在目标1和目标2中确定的优化的铅组合纳米疫苗配方提高了储存保质期。

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.