A Novel Recombinant Protein Vaccine Against Ricin Toxin

描述（由申请方提供）：蓖麻毒素是一种由蓖麻子产生的高致死性毒素。它是现成的，容易制造，和库存。蓖麻毒素在间谍活动和战争中的使用历史悠久，记录了750起中毒案件。蓖麻毒素被CDC列为B类生物威胁。在20世纪90年代，美国军方在获得恐怖组织储存这种毒素的信息后，对开发针对蓖麻毒素的疫苗产生了兴趣。蓖麻毒素类毒素对灵长类动物有保护作用，但毒性很大，没有得到FDA的批准。 我们已经产生了三个蓖麻毒素A链的重组突变体，它们在小鼠中缺乏血管渗漏活性和酶活性。当肌肉注射时，这些突变体保护小鼠免受非常大剂量的注射蓖麻毒素。我们的目标是将这些突变体之一开发成一种廉价，安全，有效，稳定和“用户友好”的疫苗，可以用于大规模人群。本提案的具体目的是：1）优化疫苗的生产、纯化、配方和稳定性。2)为了确定疫苗是否将保护小鼠免受雾化以及腹膜内（i.p.）蓖麻毒素攻击，如果是的话，最好的免疫方法（i.m.，口服或鼻内），以最长时间保护动物，和3）生产最佳候选疫苗的小型良好实验室规范（GLP）批次，并使用最佳给药途径免疫6只成年狒狒（3只雄性和3只雌性）。 当这三个目标完成后，疫苗应该准备好在两个物种中进行急性毒理学研究，并在人类中进行1期临床试验。

DESCRIPTION (provided by applicant): Ricin is a highly lethal toxin produced by castor beans. It is readily available, easy to make, and stockpile. Ricin has a long history of use in espionage and warfare with a documented 750 cases of intoxication. Ricin is classified by the CDC as a Class B biothreat. In the 1990s, the U.S. Military became interested in developing a vaccine against ricin after obtaining information that this toxin was being stockpiled by terrorist organizations. A ricin toxoid is protective in primates, but it is quite toxic and did not receive FDA approval. We have generated three recombinant mutants of ricin's A chain which are devoid of both vascular leak activity and enzymatic activity in mice. When injected i.m., these mutants protect mice against very large doses of injected ricin. Our goal is to develop one of these mutants into an inexpensive, safe, effective, stable, and "user-friendly" vaccine which can be administered to large groups of people. The specific Aims of this proposal are: 1) to optimize production, purification, formulation and stability of the vaccine. 2) to determine whether the vaccine will protect mice against aerosolized as well as intraperitoneal (i.p.) ricin challenge and if so, the best method of immunization (i.m., oral, or intranasal) to protect animals for the longest period of time and 3) to produce a small good laboratory practice (GLP) batch of the best candidate vaccine and use the best route of administration to immunize six adult baboons (three males and three females). When these three aims are completed, the vaccine should be ready for acute toxicology studies in two species and scale-up for Phase 1 clinical trials in humans.