CONTINUED DEVELOPMENT OF RIVAX VACCINE FOR RICIN

RIVAX 蓖麻毒素疫苗的持续开发

基本信息

批准号：
8173020
负责人：
CHAD J. ROY
金额：
$ 6.18万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8173020
关键词：
Adjuvant Aerosols Alhydrogel Aluminum Animals Antibodies Antibody Formation Attention Biological Biological Assay Bioterrorism Categories Centers for Disease Control and Prevention (U.S.)Clinical Trials Computer Retrieval of Information on Scientific Projects Database Data Development Dose Drug Formulations Enzyme-Linked Immunosorbent Assay Event FDA approved Funding General Population Goals Grant Human Human Volunteers Immunization Immunoglobulin G In Vitro Institution Kinetics Marketing Memory Military Personnel Mus Oral Oryctolagus cuniculus Phase Phase I Clinical Trials Proteins Recombinants Research Research Personnel Resources Ricin Ricin Vaccine Salts Schedule Serum Solutions Source Testing Time Tissues Toxic effect Toxicology Toxin United States National Institutes of Health Vaccinated Vaccination Vaccines Variant Work animal efficacy animal rule base biothreat cytotoxicity efficacy trial emergency service responder holotoxins immunogenicity in vivo manufacturing process mutant nonhuman primate pre-clinical preclinical safety prevent research clinical testing response vaccine candidate volunteer

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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. We have completed Phase I of an efficacy trial with the candidate Rivax vaccine in nonhuman primates. Animals (n=6) were immunized (prime, two boosts) with 100 ug of the vaccine adsorbed to alhydrogel or sham-vaccinated with adjuvant only (n=3). Serum antibodies (alpha ricin IgG) and neutralizing capacity of antibodies were performed by ELISA and ricin cytotoxicity assay, respectively. All animals were then challenged by aerosol to a lethal dose (1 LD/50) of ricin toxin. Results indicated poor survival in the immunized group (1/6, 16%) and 100% lethality in the sham-immunized controls (0/3). The results of this study suggest that, although alpha ricin IgG endpoint titers were relatively high in immunized animals (2.0E+04), the neutralizing capacity to ricin holotoxin was relatively low as shown in the in vitro neutralization assay performed in conjunction with the antibody ELISAs. In addition, antibody production and kinetics showed a peak +14 days post prime immunization, with no definable memory response at either of the immunizing boosts. This result suggests that protection may only be conferred when the quality of the antibodies match the quantity produced in vivo. The second phase of this study is ongoing and will incorporate a variation of RiVax immunizing doses and schedule which may stimulate a memory response in the immunized animals and increase the overall protective capacity of the candidate vaccine.

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目及研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是中心，不一定是研究者的机构。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，人们的注意力集中在实际使用蓖麻毒素的潜在威胁上。由于除非在很短的时间范围内进行，否则暴露后治疗是无效的，因此疫苗接种可能是防止蓖麻毒素引起的致死和组织损伤的唯一方法。我们开发了一种基于消除 A 链毒性的重组突变体的安全有效的疫苗 (RiVax(tm))。已经实现了稳健、高产量和可扩展的疫苗生产工艺。根据临床前安全性和有效性数据，启动了一项小型一期试验，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佐剂配方的特征，接下来将在志愿者中进行测试。该疫苗已经克服了最初的开发障碍。该项目的目的是继续开发这个已确定的候选者。具体来说，我们将对溶液中的蛋白质和吸附到铝盐佐剂上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力联系起来。其次，我们的目标是证明该疫苗将在兔子和人类体内产生抗体，这些抗体可以在暴露于气溶胶或口服蓖麻毒素后被动地为兔子提供保护。使用小鼠以外的其他动物物种将为关键的动物功效试验奠定基础，这些试验必须代替人体试验（根据 FDA 动物规则）。第三，我们将在小鼠和兔子中进行GLP临床前毒理学和功效试验，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，并对其稳定性进行了评估。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 进一步开发以进行更多临床试验以及最终注册和营销的关键一步。在生物恐怖主义中使用蓖麻毒素确实构成了全球威胁。军事人员迫切需要一种经 FDA 批准的安全有效的疫苗，在发生国内袭击时，急救人员甚至公众也迫切需要这种疫苗。我们已经完成了候选 Rivax 疫苗在非人类灵长类动物中的功效试验的第一阶段。用吸附至水凝胶的100ug疫苗对动物(n＝6)进行免疫(初免，两次加强)或仅用佐剂进行假疫苗接种(n＝3)。血清抗体（α蓖麻毒素IgG）和抗体的中和能力分别通过ELISA和蓖麻毒素细胞毒性测定进行。然后用气溶胶对所有动物进行致死剂量（1 LD/50）蓖麻毒素的攻击。结果表明，免疫组的存活率很差（1/6，16%），而假免疫对照组的致死率则为 100%（0/3）。本研究的结果表明，虽然免疫动物中α蓖麻毒素 IgG 终点滴度相对较高 (2.0E+04)，但与抗体联合进行的体外中和测定显示，对蓖麻毒素全毒素的中和能力相对较低ELISA。此外，抗体产生和动力学显示在初次免疫后+14天达到峰值，在任何一次免疫加强时都没有明显的记忆反应。这一结果表明，只有当抗体的质量与体内产生的数量相匹配时，才能提供保护。这项研究的第二阶段正在进行中，将纳入 RiVax 免疫剂量和时间表的变化，这可能会刺激免疫动物的记忆反应，并提高候选疫苗的整体保护能力。