CONTINUED DEVELOPMENT OF RIVAX VACCINE FOR RICIN

RIVAX 蓖麻毒素疫苗的持续开发

• 批准号: 8358110
• 负责人: CHAD J. ROY
• 金额: $ 3.72万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358110
• 关键词: Adjuvant; Aerosols; Alhydrogel; Animals; Antibodies; Antibody Formation; Biological; Biological Assay; Categories; Centers for Disease Control and Prevention (U.S.); Development; Dose; Enzyme-Linked Immunosorbent Assay; Funding; Grant; Immunization; Immunoglobulin G; In Vitro; Kinetics; Memory; National Center for Research Resources; Phase; Primates; Principal Investigator; Recombinants; Research; Research Infrastructure; Resources; Ricin; Ricin Vaccine; Schedule; Serum; Source; Time; Toxic effect; Toxin; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; Variant; base; biothreat; cost; cytotoxicity; efficacy trial; holotoxins; in vivo; mutant; nonhuman primate; phase 1 study; response; vaccine candidate

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Ricin is one of the most potent biological toxins known, and is classified by the CDC as a category B biothreat. Since post exposure treatment is ineffective unless administered within a narrow window of time, vaccination may be the only way to protect against ricin. We have developed a safe and effective vaccine (RiVax(tm)) based on a recombinant mutant that eliminates the toxicities of the A chain. We have completed Phase I of an efficacy trial with the candidate Rivax vaccine in nonhuman primates. Animals (n=6) were immunized either with three (prime, two boosts) or four vaccinations (prime, three boosts) with 100 micrograms 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 both of the immunized groups (1/3, 33%; 3-vaccination group; 0/3, 0%, 4 vaccination group) and 100% lethality in the sham-immunized controls (0/3). The results of this study paired with the results from phase I of this study (1/6; 16% survival in immunized animals) suggest that, although alpha ricin IgG endpoint titers were relatively high in all 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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 Ricin是已知的最有效的生物毒素之一，由CDC分类为B类Biothreat。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预防Ricin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））。 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）用三个（素数，两次提升）或四种疫苗接种（素数，三个提升）进行免疫，并用100微克吸附的疫苗吸附到alhyhydrogel或仅用佐剂进行了sham-vacccccccacccaccccaccccacccaccccccccccccccing（n = 3）。 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，所有动物都被气溶胶挑战了ricin毒素的致命剂量（1 ld^50）。 结果表明，两个免疫组的存活率较差（1/3，33％； 3-疫苗接种组； 0/3，0％，4个疫苗接种组）和假免疫的对照组（0/3）中的100％致死性（0/3）。 这项研究的结果与本研究的I期的结果配对（1/6;在免疫动物中生存16％）表明，尽管在所有免疫动物中αricin IgG终点滴度相对较高（2.0e+04），但在中性化的中性化表现中，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。