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

第一阶段安全性研究

• 批准号: 7475286
• 负责人: ELLEN S VITETTA
• 金额: $ 32.17万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475286
• 关键词: PHASE; STUDY; SAFETY; IMMUNOGENICITY; ALUM

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.

描述（由申请人提供）： 蓖麻毒素是一种强效毒素，很容易从大量可用的蓖麻子中产生，目前没有疫苗可以预防中毒，也没有除了支持性护理之外的有效的暴露后治疗。 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，有证据表明恐怖组织曾试图将其开发为武器，并且已经发生过国内袭击事件。 研究人员通过引入两个位点特异性突变，从蓖麻毒素的 A 链亚基中开发出一种无毒的蓖麻毒素疫苗 RiVax，消除了其核糖毒性和血管渗漏综合征诱发活性。 一旦临床前测试证明这种疫苗（作为冷冻蔗糖/吐温制剂）对小鼠和兔子是安全的且具有免疫原性，研究人员就对 15 名人类志愿者进行了 1 期研究，结果表明它是安全的，并且能够引发蓖麻毒素中和免疫反应。 为了提高这种疫苗的功效，通过增加反应程度和持续时间，研究人员开发了氢氧化铝（AlHydrogel）制剂，并证明它可以大大提高小鼠的免疫原性。 研究人员现在提议进行剂量递增的一期试验，涉及 3 组，每组 10 名健康志愿者，以确定这种新制剂对人类是否安全，以及是否增强和延长反应。 将在第 0、6 和 26 周给予 1、10 和 100 微克的剂量，每种剂量含 0.5 毫克 AlHydrogel，并评估血清的抗疫苗和中和滴度。