Lipid/DNA/Antigen Complexes for Pseudomonas vaccines

描述(申请人提供)：华雷斯生物治疗公司正在开发和鉴定一种独特的天然免疫佐剂和刺激剂，其基础是阳离子脂质载体和非编码DNA(CLDC)的络合。该产品通过包括非肠道、呼吸和口服在内的多种途径有效。脂基复合体与抗原(LADC)的结合产生了强大的佐剂效应以及对靶抗原的强大的CTL反应。这项建议的总体目的是通过研制一种针对革兰氏阴性细菌铜绿假单胞菌III型毒素递送系统的疫苗来测试CLDC的佐剂作用。铜绿假单胞菌是呼吸机相关性肺炎(VAP)、严重烧伤、化疗引起的免疫抑制、囊性纤维化或留置导尿管患者的重要机会性病原体。在这些患者中，铜绿假单胞菌通过释放外毒素来致病，外毒素会损害或摧毁周围的宿主组织，促进有机体的传播，并使巨噬细胞的吞噬机制瘫痪。由于危险患者的类型不同，假单胞菌感染通常发生在医院环境中。脓毒症的死亡率为20%-50%，肺炎假单胞菌的死亡率为30%-40%。这项建议的具体目标是优化CLDC的体外天然免疫和体内特异性免疫，并使用此优化配方来评估铜绿假单胞菌与气管内给药的保护能力。如果成功，第二阶段将比较CLDC介导的针对PcrV的疫苗接种与其他假单胞菌抗原在已确定的假单胞菌感染的不同阶段预防性和治疗性疫苗接种。

DESCRIPTION (provided by applicant): Juarez BioTherapeutics is developing and characterizing a unique adjuvant and stimulant of innate immunity based on the complexation of a cationic lipid carrier and non-coding DNA (CLDC). The product is effective via multiple routes including parenteral, respiratory and oral. The combination of the lipid-based complex with antigen (LADC) results in a potent adjuvant effect as well as a robust CTL response to the target antigen. The overall purpose of this proposal is to test the adjuvant effect of CLDC by formulating a vaccine against the type III toxin delivery system of the gram negative bacteria Pseudomonas aeruginosa. P. aeruginosa is a significant opportunistic pathogen in patients with ventilator associated pneumonia (VAP), severe bums, immunosuppression due to chemotherapy, cystic fibrosis, or patients with indwelling catheters. In these patients, P. aeruginosa causes disease by the release of exotoxins, which damage or destroy the surrounding host tissue, promote dissemination of the organism and paralyze the phagocytic mechanism of macrophages. Because of the types of patients at risk, Pseudomonas infections usually occur in a hospital setting. Pseudomonas sepsis has a mortality rate of 20-50% and Pseudomonas pneumonia has a 30-40% mortality rate. The specific goals of this proposal are to optimize the CLDC for innate immunity in vitro, specific immunity in vivo, and use this optimal formulation to evaluate the ability to confer protection versus intratracheal administration of P. aeruginosa. If successful, Phase II will compare CLDC-mediated vaccination against PcrV with other Pseudomonas antigens for both prophylactic and therapeutic vaccine administration in various stages of established Pseudomonas infection.