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

描述（由申请人提供）： 蓖麻毒素是一种非常有效的毒素，很容易从丰富的蓖麻子中产生，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列为B级生物威胁。 事实上，已经发现的证据表明，恐怖主义团体曾试图将其发展为一种武器，并发生了国内袭击事件。 研究人员从蓖麻毒素的A链亚基中开发了一种无毒的蓖麻毒素疫苗RiVax，通过引入两个位点特异性突变来消除其核糖毒性和血管渗漏综合征诱导活性。 一旦临床前试验证明这种疫苗作为冷冻蔗糖/吐温制剂在小鼠和兔子中是安全和免疫原性的，研究人员在15名人类志愿者中进行了1期研究，并表明它是安全的，能够引起蓖麻毒素中和免疫应答。 为了通过增加应答的程度和持续时间来提高该疫苗的效力，研究人员开发了一种氢氧化铝（Alhydrogel）制剂，并已证明其大大提高了小鼠的免疫原性。 研究人员现在建议进行一项剂量递增的1期试验，涉及3组10名健康志愿者，以确定这种新制剂是否对人类安全，并增加和抑制反应。 将在第0、6和26周给予1、10和100 μ g剂量-各含0.5 mg Alhydrogel，并评估血清的抗疫苗和中和滴度。

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.