Engineering of a Novel CDN Nanoparticle Platform

描述（由申请人提供）：多年来，使用蛋白质和肽抗原诱导特异性免疫反应一直是一个努力开发改进疫苗的领域。原则上，这种方法是有吸引力的，因为它有可能提供免疫特异性，对制造过程进行更严格的控制，并消除与免疫原生产相关的大多数物质或污染物的次要来源。然而，当蛋白质和多肽被用作可溶性抗原时，通常在刺激宿主免疫反应方面是无效的。与免疫刺激佐剂分子（IAMs）共给药可以显著提高对蛋白质和肽抗原的免疫反应，但它们的物理化学性质的差异往往使它们一起递送到免疫系统细胞效率低下。由于蛋白质和肽抗原通常需要使用强佐剂来诱导有效的免疫反应，特别是细胞毒性T细胞反应，如果目标抗原可以与IAM一起包装在颗粒递送载体中，则可以创建更有效的免疫原。为了克服将蛋白质和肽抗原与强效佐剂分子结合在一起的问题，我们一直在开发一种基于纳米颗粒脂质体的技术，称为VesiVax (r)系统，以促进疫苗的开发过程。在这些研究中，我们建议证明VesiVax(r)配方的环二核苷酸（cdn）可以刺激有效的免疫反应。通过该提案创建的VesiVax(r) CDN配方将被设计为可扩展到商业数量，并具有成本效益。在SBIR一期研究中，我们将首先在VesiVax(r)系统中配制不同浓度的CDN模拟物。为了评估VesiVax(r) CDN制剂的免疫应答和疗效，脂质体将采用我们的特征抗原配制，该抗原基于单纯疱疹病毒2型（HSV2）的gD外结构域糖蛋白（gD1-306-HD）。将制备含有gD1-306-HD的VesiVax(r) CDN制剂，并在雌性小鼠和豚鼠HSV2感染模型中进行评估。

DESCRIPTION (provided by applicant): For many years, the use of protein and peptide antigens to induce specific immune responses has been an area of intense effort with the goal of developing improved vaccines. In principle, this approach is attractive because it has the potential to provide immunological specificity, tighter control of manufacturing processes, and elimination of most of the secondary sources of materials or contaminants associated with the production of the immunogen. However, proteins and peptides are typically ineffective at stimulating host immune responses when used as soluble antigens. Co-administration with immunostimulatory adjuvant molecules (IAMs) can significantly improve the immune response against protein and peptide antigens, but differences in their physicochemical properties often makes their delivery together to the cells of the immune system inefficient. Since protein and peptide antigens generally require administration with a strong adjuvant to induce potent immune responses, in particular, cytotoxic T cell responses, if the target antigen can be packaged together with an IAM in a particulate delivery vehicle, a much more effective immunogen could be created. To overcome the problem of combining protein and peptide antigens together with a potent adjuvant molecule, we have been developing a nanoparticulate liposome-based technology, called the VesiVax (r) system, to facilitate the vaccine development process. In these studies, we propose to demonstrate that VesiVax(r) formulations of cyclic dinucleotides (CDNs) can stimulate potent immune responses. The VesiVax(r) CDN formulation to be created through this proposal will be designed to be scalable to commercial quantities and cost effective to manufacture. In the SBIR Phase I studies, we will first formulate different concentration of a CDN analog in the VesiVax(r) system. To evaluate the immune response and efficacy of the VesiVax(r) CDN formulations, the liposomes will be formulated with our well-characterized antigen that is based on the gD ectodomain glycoprotein (gD1-306-HD) of the herpes simplex virus type 2 (HSV2). VesiVax(r) CDN formulations containing gD1-306-HD will be prepared and evaluated in female mouse and guinea pig models of HSV2 infection.