CONTINUED DEVELOPMENT OF RIVAX VACCINE FOR RICIN

RIVAX 蓖麻毒素疫苗的持续开发

• 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
• 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; 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

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 Ricin是已知的最有效的生物毒素之一，由CDC分类为B类Biothreat。最近，人们关注了实际使用Ricin的潜在威胁。由于暴露后治疗是无效的，除非在狭窄的时间窗口内给药，否则疫苗接种可能是防止ricin引起的组织致死性和损害的唯一方法。我们基于消除A链的毒性的重组突变体开发了一种安全有效的疫苗（Rivax（TM））。已经实现了制造疫苗的强大，高收益和可扩展的过程。根据临床前的安全性和疗效数据，开始了一项小型I期试验，以测试人类志愿者中疫苗的耐受性和免疫原性。我们已经表征了疫苗的辅助配方，该疫苗将在志愿者中进行接下来测试。疫苗已经通过了最初的发展障碍。该项目的目的是继续发展这位既定候选人。具体而言，我们将对溶液中的蛋白质进行长期稳定研究，并吸附到铝盐佐剂上。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，我们的目的是证明该疫苗将产生兔子和人类中的抗体，这些抗体可以在气溶胶或口服ricin暴露后被动地赋予兔子保护。除小鼠以外的其他动物物种的使用将为关键动物效能试验奠定基础，必须代替人类试验（根据FDA动物规则）进行。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，以支持辅助疫苗的临床评估。我们的目标是获得数千剂释放的疫苗，这些疫苗已被评估以达到稳定性。最后，我们打算执行提交所需的监管工作。该提案代表了Rivax朝着其他临床试验以及最终注册和营销的进一步发展的关键步骤。在生物恐怖主义中使用赖以生物素有一个非常现实的威胁。军事人员迫切需要一种安全有效的FDA批准的疫苗，如果发生国内袭击，则需要对急救人员甚至公众。 我们已经完成了非人类灵长类动物中候选Rivax疫苗的疗效试验的I期。 动物（n = 6）被免疫（Prime，两个增强），并用100 ug的疫苗吸附到阿物凝胶或仅用辅助剂（n = 3）进行了假疫苗。 ELISA和Ricin细胞毒性测定法分别进行了血清抗体（αricin IgG）和抗体中和能力。 然后，气溶胶向所有动物挑战ricin毒素的致命剂量（1 LD/50）。 结果表明，免疫组的生存率较差（1/6，16％）和假免疫对照中的杀伤力100％（0/3）。 这项研究的结果表明，尽管在免疫动物中αricin IgG终点滴度相对较高（2.0e+04），但在与抗体ELISAS结合进行的体外中和测定中所示，对Ricin Holotoxin的中和能力相对较低。 此外，抗体的产生和动力学在原始免疫后显示出峰值+14天，在任何一个免疫增强剂中均无可确定的记忆反应。 该结果表明，只有当抗体的质量与体内产生的数量相匹配时，才可以赋予保护。 这项研究的第二阶段正在进行中，并将结合Rivax免疫剂量和时间表的变化，这可能会刺激免疫动物中的记忆反应，并增加候选疫苗的总体保护能力。