MICROSPHERE VACCINE AGAINST AEROSOLIZED RICIN TOXIN

描述(申请人提供)：拟议研究的主要目标是开发一种可在人体临床测试中快速评估并储存用于战场或保护平民人口的微囊化蓖麻毒素候选疫苗。该疫苗将基于微胶囊技术，可以用目前的工艺轻松制造，并可以开发为口服或鼻腔注射疫苗，具有更大的预防雾化蓖麻毒素的潜力。这种技术将适用于其他可雾化毒素和微生物制剂。针对蓖麻毒素的疫苗将是防止在战场上或在潜在的恐怖袭击中使用蓖麻毒素的可能性的唯一实用方法。蓖麻毒素是一种在中东地区被用作生物战剂的制剂。蓖麻毒素是一种有效的上皮活性毒素，可以通过雾化作用作为武器部署，目前还没有已知的有效解毒剂或疫苗。吸入蓖麻毒素造成的肺损伤迅速且不可逆转。推进临床研究的理想配方是口服疫苗，它能激发分泌型抗体，中和肺部表面的毒素。拟议的研究将集中于开发一种基因灭活的蓖麻毒素A链的配方，该链没有残留毒性，但仍具有完全的免疫原性，因此被认为是迄今为止最有希望和最可行的蓖麻毒素候选疫苗之一。我们建议开发基于微囊化控释聚合物载体的蓖麻毒素疫苗配方。这些制剂将通过口服、鼻腔和非肠道免疫在动物身上进行评估。根据这些研究的结果，将出现临床开发的候选者。这项研究将集中在将重组蓖麻毒素A链突变体包裹在控释聚合物载体中，并通过口服、鼻腔和肠外免疫来评估其在啮齿动物模型中的佐剂效果。对于初步研究，选择控制释放系统进行评估的依据是：过去在动物研究中使用有毒蓖麻毒素(甲醛灭活的全毒素)或与其他抗原的有效性证据，是否存在可扩大到商业生产水平的制造技术和工艺，成分的配伍和稳定性证据，以及人类疫苗或其他控制释放药物产品的安全性历史。

DESCRIPTION (provided by applicant): The major goal of the proposed studies is to develop a microencapsulated ricin toxin vaccine candidate that could be evaluated quickly in human clinical testing and stockpiled for use on the battlefield or to protect civilian populations. The vaccine will be based on microencapsulation technology that can be easily manufactured with current processes and can be developed as an orally or nasally administered vaccine with greater potential to protect against aerosolized ricin. Such technologies will be applicable to other aerosolizable toxins and microbial agents. A vaccine against ricin would be the only practical way to protect against the possibility use of ricin either on the battlefield or in a potential terrorist attack. Ricin is an agent that has been used as a biological warfare agent in the Mideast. Ricin is a potent, epithelially active toxin that could be deployed as a weapon by aerosolization, and for which there is no known effective antidote or vaccine. Lung damage caused by inhalation of ricin toxin is quick and irreversible. The ideal formulation for advancing to clinical studies would be an orally administered vaccine, eliciting secretory antibodies that neutralize toxin at the surface of the lung. The proposed research will focus on the development of formulations of a genetically inactivated ricin A chain that lacks residual toxicity but retains full immunogenicity and thus is considered to be one of the most promising and viable ricin vaccine candidates to date. We are proposing to develop ricin vaccine formulations based on microencapsulated controlled-release polymeric vehicles. The formulations will be evaluated in animals via oral, intranasal and parenteral immunization. Based on the outcomes of these studies, a candidate for clinical development will emerge. The research will center around encapsulating recombinant ricin toxin A chain mutant in controlled release polymer vehicles and evaluating the adjuvant effect in rodent models by oral, intranasal and parenteral immunization. For initial studies, the controlled release systems will be selected for evaluation based on past evidence of efficacy in animal studies with toxoided ricin (formaldehyde-inactivated holotoxin) or with other antigens, the existence of manufacturing techniques and processes that can be scaled up to commercial production levels, evidence of compatibility and stability of ingredients, and a history of safety in human vaccines or other controlled release drug products.