PHASE 1 STUDY OF SAFETY & IMMUNOGENICITY OF AN ALUM-FORMULATED RECOMBINANT RICIN

描述(由申请人提供)： 蓖麻毒素是一种高度有效的毒素，很容易从大量可获得的蓖麻豆中产生，对于这种毒素，除了支持性护理外，没有疫苗可以防止中毒或有效的接触后治疗。这导致疾病控制和预防中心将蓖麻毒素归类为B级生物制剂。事实上，已发现证据表明，恐怖组织曾试图将其发展为武器，并发生了国内袭击事件。 研究人员已经从蓖麻毒素的A链亚单位中开发出一种无毒的蓖麻毒素疫苗RiVax，方法是引入两个位点特异性突变，消除其核毒性和血管泄漏综合征诱导活性。一旦临床前测试证明这种冷冻蔗糖/吐温配方的疫苗对小鼠和兔子是安全和免疫原性的，研究人员在15名人类志愿者身上进行了一项第一阶段研究，表明它是安全的，能够激发蓖麻毒素中和免疫反应。为了提高这种疫苗的效力，通过增加应答的程度和持续时间，研究人员开发了一种氢氧化铝(Alwater Gel)配方，并证明它极大地提高了小鼠的免疫原性。研究人员现在提议进行一项剂量递增的第一阶段试验，涉及3组10名健康志愿者，以确定这种新配方是否对人类安全，并增加和延长反应。在0、6和26周将分别给予1、10和100微克的剂量-每个剂量含有0.5毫克的铝水凝胶，并将评估血清的抗疫苗和中和效价。

DESCRIPTION (provided by applicant): Ricin is a highly potent toxin, easily produced from abundantly available castor beans, for which there is no vaccine to protect against intoxication or effective post-exposure treatment beyond supportive care. This has led the Centers for Disease Control and Prevention to classify ricin as a level B biothreat. Indeed, evidence has been found suggesting that terrorist groups have attempted to develop it as a weapon, and there have been instances of domestic attacks. The investigators have developed a non-toxic ricin vaccine, RiVax, from the A-chain subunit of ricin, by introducing two site-specific mutations that eliminate both its ribotoxic and vascular leak syndrome-inducing activities. Once preclinical testing demonstrated that this vaccine, as a frozen sucrose/Tween formulation, was safe and immunogenic in mice and rabbits, the investigators conducted a Phase 1 study in 15 human volunteers and showed that it was safe and able to elicit ricin neutralizing immune responses. In order to improve the efficacy of this vaccine, by increasing the degree and duration of the response, the investigators have developed an aluminum hydroxide (Alhydrogel) formulation and have shown that it greatly improves immunogenicity in mice. The investigators now propose to conduct a dose-escalating Phase 1 trial, involving 3 groups of 10 healthy volunteers to determine if this new formulation is safe in humans and increases and prolongs the response. Doses of 1, 10 and 100 micrograms - each with 0.5 mg Alhydrogel, will be given at weeks 0, 6, and 26 and serum will be assessed for anti-vaccine and neutralizing titers.