Continued Development of a Recombinant Vaccine (RivaxTM) against Ricin Toxin

描述（由申请人提供）：蓖麻毒素是已知最有效的生物毒素之一，被CDC归类为B类生物威胁。最近，许多注意力集中在实际使用蓖麻毒素的潜在威胁上。由于暴露后的治疗是无效的，除非在一个狭窄的时间窗口内，接种疫苗可能是唯一的方法，以防止致命性和组织损伤所造成的蓖麻毒素。我们已经开发了一种安全有效的疫苗（RiVax（tm）），该疫苗基于消除A链毒性的重组突变体。已经实现了用于制造疫苗的稳健、高产率和可扩展的工艺。基于临床前安全性和有效性数据，启动了一项小型I期试验，以测试疫苗在人类志愿者中的耐受性和免疫原性。我们已经确定了疫苗的佐剂配方，接下来将在志愿者中进行测试。该疫苗已经通过了最初的开发障碍。这个项目的目的是继续发展这个既定的候选人。具体而言，我们将对溶液中的蛋白质和吸附至铝盐佐剂的蛋白质进行长期稳定性研究。我们将评估蛋白质的构象方面，并将其与效价相关。其次，我们的目标是证明疫苗将在兔和人体内产生抗体，这些抗体可以在气雾剂或口服蓖麻毒素暴露后被动地为兔提供保护。使用小鼠以外的其他动物物种将为关键动物疗效试验奠定基础，这些试验必须代替人体试验进行（根据FDA动物规则）。第三，我们将在小鼠和家兔中进行GLP临床前毒理学和有效性试验，以支持佐剂疫苗的临床评价。我们的目标是获得数千剂已发布的疫苗，并对其进行稳定性评估。最后，我们打算执行IND提交所需的监管工作。该提案代表了Rivax进一步发展的关键一步，以进行更多的临床试验并最终注册和上市。在生物恐怖主义中使用蓖麻毒素是一个非常真实的世界性的威胁。一种安全有效的FDA批准的疫苗是迫切需要的军事人员，并在发生国内攻击，为第一反应，也许为广大公众。

DESCRIPTION (provided by applicant): Ricin is one of the most potent biological toxins known, and is classified by the CDC as a category B biothreat. Much attention has been recently focused on the potential threat of actual ricin use. Since post exposure treatment is ineffective unless administered within a narrow window of time, vaccination may be the only ways to prevent lethality and damage to tissue caused by ricin. We have developed a safe and effective vaccine (RiVax(tm)) based on a recombinant mutant that eliminates the toxicities of the A chain. A robust, high yield and scalable process for manufacturing the vaccine has been achieved. Based on preclinical safety and efficacy data, a small Phase I trial was initiated to test the tolerability and immunogenicity of the vaccine in human volunteers. We have characterized adjuvant formulations of the vaccine which will be tested next in volunteers. The vaccine has passed the initial development hurdles. The purpose of this project is to continue development of this established candidate. Specifically, we will conduct long term stability studies of the protein in solution and adsorbed to aluminum salts adjuvant. We will assess the conformational aspects of the protein and relate them to potency. Secondly, we aim to demonstrate that the vaccine will generate antibodies in rabbits and humans that can passively confer protection to rabbits after aerosol or oral ricin exposure. The use of an additional animal species other than mice will lay the groundwork for pivotal animal efficacy trials which must be conducted in place of human trials (under the FDA animal rule). Thirdly, we will conduct GLP preclinical toxicology and efficacy trials in mice and rabbits to support the clinical evaluation an adjuvanted vaccine. Our goal is to obtain several thousand doses of released vaccine that has been evaluated for stability. And finally, we intend to perform the regulatory work necessary for IND submission. This proposal represents a critical step in the further development of Rivax towards additional clinical trials and ultimately registration and marketing. There is a very real worldwide threat for the use of ricin in bioterrorism. A safe and effective FDA-approved vaccine is urgently needed for military personnel and, in the event of a domestic attack, for first responders and perhaps for the general public.