Novel Adjuvant Formulations for Genetic Vaccines

描述(申请人提供)：非常需要为疫苗应用开发安全而有效的佐剂。随着针对各种既有和新出现的传染病病原体(A、B和C类)产生保护性和治疗性疫苗的需求日益增加，开发可广泛适用于各种疾病靶点的平台技术和有效佐剂至关重要。目前，铝盐(明胶)是美国FDA批准的唯一疫苗佐剂。然而，在广泛的疫苗，特别是基因疫苗中，它在刺激平衡的体液和细胞免疫方面的安全性、有效性和适用性值得怀疑。尽管有几种新的佐剂处于临床前和临床试验中，一些已经在欧洲市场获得批准，但主要的缺点是佐剂相关的毒性。成功的疫苗开发仍然需要新的和改进的佐剂。人们已经观察到，当聚合物微粒与蛋白质/多肽抗原一起传递时，可以作为有效的佐剂，尽管确切的机制大多是推测的。这种佐剂可能是由于(A)被动靶向树突状细胞(DC)，(B)持续释放(DPOT)效应导致抗原暴露时间延长，以及(C)最近观察到树突状细胞(DC)抗原提呈显著改善，其机制尚不清楚。我们开发了一种新颖的、表面功能化的微粒子设计，用于组合输送基因疫苗和相关的免疫刺激分子。基本假设是：(I)可生物降解的聚合物与转染性增强型多胺的合理结合将增加PDNA对抗原提呈细胞的转染率；(Ii)来自所给药的DC化学诱导剂的持续梯度将显著提高递送效率，从而增强对遗传抗原的免疫应答。我们在这里提出了一种在单一注射制剂中组合传递趋化因子和表面吸附的PDNA抗原/佐剂的策略。在协同作用下，这些概念将显著增强合成聚合物颗粒在为各种既有和新出现的传染病提供PDNA疫苗时的佐剂作用。

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.