EVALUATION OF A PRIME-BOOST VACCINE FOR AEROSOL RICIN EXPOSURE IN NHPS

评估 NHPS 中气溶胶蓖麻毒素暴露的初免加强疫苗

• 批准号: 8358152
• 负责人: Herman F Staats
• 金额: $ 2.9万
• 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/8358152
• 关键词: Adjuvant; Aerosols; Aluminum Hydroxide; Animals; Antibodies; Antigens; Biological; Biological Assay; Biological Warfare; Blood Vessels; Dose; Evaluation; Funding; Generations; Grant; Hour; Immune response; Immunization; Immunoglobulin A; Immunoglobulin G; In Vitro; Injection of therapeutic agent; Intoxication; Irrigation; Lead; Macaca mulatta; Methods; Modeling; National Center for Research Resources; Needles; Nose; Population; Primates; Principal Investigator; Process; Proteins; Regimen; Research; Research Infrastructure; Resources; Ricin; Ricin Vaccine; Route; Saline; Schedule; Secretory Immunoglobulin A; Serum; Site; Source; Swab; Syndrome; Toxic effect; Toxin; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; abstracting; cost; cytotoxicity; immunogenicity; improved; mastoparan; neutralizing antibody; nonhuman primate; novel; 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. Abstract: Ricin is a highly potent and rapidly acting biological toxin which has been employed for biologic warfare. An effective strategy to protect threatened populations against biological attack by ricin is to generate vaccines comprising a modified ricin. RiVax is a novel genetically modified ricin vaccine candidate that has shown promising but not optimal results in nonhuman primate models when parenterally administered. The efficacy of RiVax may be significantly improved by altering the site and manner of its delivery. First, nasal vaccination provides a needle-free method of immunization that has the potential to induce antigen-specific systemic IgG as well as mucosal IgA. Second, heterologous prime/boost immunization regimens often induce immune responses that are superior to those induced by homologous prime/boost immunization. We hypothesized that the use of a novel adjuvant (Mastoparan-7; MP-7) and a novel nasal delivery method will enhance the immunogenicity of the nasally delivered RiVax vaccine and provide a needle-free method of immunization that when combined with a parenteral RiVax priming immunization, will induce antibodies in vaccinated animals. Our specific aim is to determine if a heterologous prime/boost immunization strategy utilizing a parenteral prime and a nasal boost with RiVax is superior to parenteral immunization for its ability to induce serum ricin-neutralizing antibodies. A group of rhesus macaques (M. mulatta) (n=6) were heterologously vaccinated by prime immunizing intramuscularly (IM) with RiVax and then boosted twice with ricin vaccine (protein only) admixed with Mastoparan-7 and administered intranasally (IN) 30 days apart. Other groups were primed and boosted with RiVax admixed with aluminum hydroxide by the same schedule using only IM injection as the vaccination route or sham vaccinated with saline. Serum immune response among the groups receiving vaccine were comparable regardless of route, with endpoint IgG titer ranging from 1:4,500 to 1:10,500 in the animals receiving vaccine heterologously or solely by IM injection, respectively. Neutralizing capability of serum antibodies, as determined by an in vitro cytotoxicity assay, showed little to no activity in the animals receiving the vaccine heterologously, whereas the group receiving the vaccine IM resulted in neutralizing titers up to 1:400. Secretory IgA analysis of bronchoalevolar lavage and buccal swabs is in process. Approximately 45 days after the 2nd boost, all animals were challenged with ricin toxin by aerosol at a dose equivalent to multiple (2-5) LD^50s. All animals in the sham-vaccinated group succumbed to intoxication approximately +45-50 hours postexposure. One of the six animals (1/6; 16%) in the IM-vaccinated group survived challenge. Four of the six animals in the heterologous vaccinated group survived challenge (4/6; 66%). Results indicate that the heterologous route of vaccine administration paired with the use of MP-7 as a mucosal adjuvant proved more efficacious than traditional vaccine administration, although serum IgG levels of a-ricin neutralizing antibodies was not predictive of this response. Increased survival in the IN vaccinated group may be due to generation of secretory IgA that neutralized toxin at the site of entry rather than in the periphery of the animal, thereby reducing the toxic effects that lead to vascular leak syndrome.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 【摘要】：蓖麻毒素是一种高效、快速作用的生物毒素,已被用于生物战。 保护受威胁人群免受蓖麻毒素生物攻击的有效策略是生产包含改良蓖麻毒素的疫苗。 RiVax 是一种新型转基因蓖麻毒素候选疫苗，在非人灵长类动物模型中肠胃外给药时显示出有希望但不是最佳的结果。 通过改变其递送部位和方式，RiVax 的疗效可能会得到显着提高。首先，鼻腔疫苗接种提供了一种无针免疫方法，有可能诱导抗原特异性全身 IgG 以及粘膜 IgA。 其次，异源初免/加强免疫方案通常诱导的免疫反应优于同源初免/加强免疫所诱导的免疫反应。 我们假设使用新型佐剂（Mastoparan-7；MP-7）和新型鼻腔给药方法将增强鼻腔给药 RiVax 疫苗的免疫原性，并提供一种无针免疫方法，当与肠胃外 RiVax 初免免疫相结合时，将在接种动物中诱导抗体。 我们的具体目的是确定利用 RiVax 肠外初免和鼻加强的异源初免/加强免疫策略是否优于肠外免疫，因为它能够诱导血清蓖麻毒素中和抗体。 一组恒河猴 (M. mulatta) (n=6) 通过 RiVax 肌内初免 (IM) 进行异源疫苗接种，然后使用与 Mastoparan-7 混合的蓖麻毒素疫苗（仅蛋白质）加强两次，并间隔 30 天进行鼻内 (IN) 给药。 其他组按照相同的时间表使用与氢氧化铝混合的 RiVax 进行初免和加强，仅使用肌内注射作为疫苗接种途径或用盐水进行假疫苗接种。 无论何种途径，接受疫苗的各组之间的血清免疫反应均具有可比性，接受异源疫苗或仅通过肌注注射疫苗的动物的终点 IgG 效价范围分别为 1:4,500 至 1:10,500。 通过体外细胞毒性测定测定，血清抗体的中和能力在接受异源疫苗的动物中几乎没有表现出活性，而接受疫苗 IM 的组的中和滴度高达 1:400。 支气管肺灌洗液和口腔拭子的分泌型 IgA 分析正在进行中。 第二次加强后约 45 天，所有动物均通过气雾剂以相当于多倍 (2-5) LD^50 的剂量接受蓖麻毒素攻击。 假疫苗接种组中的所有动物在暴露后大约+45-50小时死于中毒。 IM 疫苗接种组中的六只动物中的一只（1/6；16%）在挑战中幸存下来。 异源疫苗接种组中的六只动物中有四只在挑战中幸存下来（4/6；66%）。 结果表明，异源疫苗给药途径与使用 MP-7 作为粘膜佐剂相比，被证明比传统疫苗给药更有效，尽管α-蓖麻毒素中和抗体的血清 IgG 水平并不能预测这种反应。 IN 疫苗接种组的存活率增加可能是由于分泌性 IgA 的产生，该 IgA 中和了进入部位而不是动物外周的毒素，从而减少了导致血管渗漏综合征的毒性作用。