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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 蓖麻毒素是已知的最有效的生物毒素之一，被CDC列为B类生物威胁。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管理，疫苗接种可能是唯一的方式来防止蓖麻毒素。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。 我们已经完成了候选Rivax疫苗在非人灵长类动物中的I期有效性试验。 动物（n=6）用吸附于铝胶的100微克疫苗进行三次（初免，两次加强）或四次疫苗接种（初免，三次加强）免疫，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试验。 然后用致死剂量（1 LD^50）的蓖麻毒素气雾剂对所有动物进行攻击。 结果表明，两个免疫组的存活率均较差（1/3，33%; 3-接种组; 0/3，0%，4接种组），假免疫对照组的致死率为100%（0/3）。 本研究的结果与本研究I期的结果（16;免疫动物的存活率为16%）配对表明，尽管所有免疫动物的α蓖麻毒素IgG终点滴度相对较高（2.0E+04），但如结合抗体ELISA进行的体外中和测定所示，对蓖麻毒素全毒素的中和能力相对较低。 此外，抗体产生和动力学在初免后+14天显示出峰值，在任一免疫加强时均没有可定义的记忆应答。 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。 本研究的第二阶段正在进行中，并将纳入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，并增加候选疫苗的总体保护能力。