Novel Adjuvant Formulations for Genetic Vaccines

描述（由申请人提供）：非常需要开发用于疫苗应用的安全而有效的佐剂。随着对产生针对广泛范围的已建立和新出现的传染性病原体（A类、B类和C类）的保护性和治疗性疫苗的需求的增加，开发可能广泛适用于各种疾病靶标的平台技术和有效佐剂至关重要。目前，铝盐（明矾）是美国FDA批准的唯一疫苗佐剂。然而，其安全性，有效性和适用性，在刺激平衡的体液和细胞免疫的疫苗，特别是基因疫苗，是值得怀疑的。尽管几种新的佐剂处于临床前和临床试验中，并且一些已经在欧洲市场获得批准，但主要缺点是与药物相关的毒性。成功的疫苗开发仍然需要新的和改进的佐剂。已经观察到聚合物微粒在与蛋白质/肽抗原一起递送时可以充当有效的佐剂，尽管精确的机制大多是推测性的。这种排斥性可能是由于（a）被动靶向树突细胞（DC）（B）导致延长抗原暴露的持续释放（储库）效应和（c）最近观察到DC通过尚未鉴定的机制显著改善抗原呈递。我们已经开发了一种新的，表面功能化，微粒设计的基因疫苗和相关的免疫刺激分子的组合交付。基本假设是（i）生物可降解聚合物与转染增强多胺的合理组合将增加pDNA对抗原呈递细胞的转染，和（ii）来自所施用制剂的DC化学引诱剂的持续梯度将显著增强递送功效，导致针对遗传抗原的免疫应答增加。在这里，我们提出了一种在单一注射制剂中组合递送趋化因子和表面吸附的pDNA抗原/佐剂的策略。这些概念，协同作用，应显着提高合成聚合物颗粒在提供广泛的已建立和新兴的传染病的pDNA疫苗的亲和力。

DESCRIPTION (provided by applicant): There is a great need for developing safe, yet effective adjuvants for vaccine applications. With the increasing need in generating protective and therapeutic vaccines against a wide range of established and emerging infectious pathogens (Class A, B and C), it is critical that platform technologies and effective adjuvants are developed that might be widely applicable to a variety of disease targets. Currently, aluminum salts (Alum) are the only FDA approved vaccine adjuvants in the US. However, its safety, efficacy and applicability in stimulating a balanced humoral and cellular immunity in a wide range of vaccines, especially genetic vaccines, is questionable. Although, several new adjuvants are in pre-clinical and clinical trials and some have been approved in European markets, the primary drawback has been adjuvant-associated toxicity. Successful vaccine development still requires new and improved adjuvants. It has been observed that polymer microparticles could act as effective adjuvants when delivered with protein/peptide antigens, although the precise mechanisms are mostly speculative. The adjuvancy is likely due to (a) passive targeting to dendritic cells (DCs) (b) a sustained release (depot) effect leading to prolonged antigen exposure and (c) recent observations of significantly improved antigen presentation by DCs by as yet unidentified mechanism. We have developed a novel, surface-functionalized, microparticle design for the combinatorial delivery of genetic vaccines and associated immuno-stimulatory molecules. The fundamental hypotheses are (i) rational combination of biodegradable polymers with transfection-enhancing polyamines would increase pDNA transfection to antigen presenting cells and (ii) a sustained gradient of DC chemo-attractants from the administered formulation would significantly enhance delivery efficacy leading to increased immune response against genetic antigens. We propose here, a strategy for combinatorial delivery of chemokines and surface-adsorbed pDNA antigens/adjuvants within a single injectable formulation. These concepts, in synergy, should significantly enhance the adjuvancy of synthetic polymer particles in delivering pDNA vaccines for a wide range of established and emerging infectious diseases.