Multi-gene plague vaccine with expanded protection

具有扩大保护作用的多基因鼠疫疫苗

• 批准号: 6689736
• 负责人: Shan Lu
• 金额: $ 55.02万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6689736
• 关键词: CHO cells; DNA; Yersinia pestis; bacterial antigens; bacterial proteins; biotechnology; cell line; cooperative study; enzyme linked immunosorbent assay; flow cytometry; genes; immunization; laboratory mouse; laboratory rabbit; mucosal immunity; proteins; vaccine development; vector vaccine; western blottings

DESCRIPTION (provided by applicant): The overall objective of this application is to rapidly develop much needed alternative plague vaccine candidate formulations based on our recent discovery that a modified Y. pestis V antigen (LcrV) based DNA vaccine was highly effective in protecting experimental mice against lethal intranasal challenge with Y. pestis. Our preliminary data suggested that good protection resulted from improved antigen presentation and possibly through improved Th1 type immune responses. This is the first time a DNA-based plague vaccine induced complete protection against lethal mucosal challenge in any animal model. We now propose to conduct vigorous validation and testing in the first 18-24 months to develop a subunit plague vaccine formulation using this novel modified V antigen as the core protective component. The protection efficacy of this subunit vaccine, delivered in the forms of DNA, protein, or a combination of both, will be evaluated against lethal Y. pestis challenge via the airway mucosa. Additional immunological studies will be conducted to confirm the improved efficacy of this modified V antigen. We also propose to continue our search for additional protective Y. pestis antigens to be incorporated into the above primary formulation so that a true multi-gene plague vaccine can be developed to achieve broader protection to discourage attempts to engineer vaccine resistant Y. pestis strains. This search will focus primarily on antigens involved in the function of the Y. pestis Type III secretion apparatus including YopB, YopD and YscF. A variety of combination formulations will be tested among these candidates and the modified V antigen to identify the formulation that can provide the most effective protection. This project will employ the most advanced DNA immunization technology in combination with small-scale protein production to quickly develop potential subunit-based plague vaccine products.

描述（由申请人提供）：基于我们最近发现，基于我们最近发现的Y. Pestis V抗原（LCRV）DNA疫苗的替代瘟疫疫苗候选候选候选候选疫苗候选候选疫苗的总体目标是非常有效的，可在保护实验性小鼠免受对Y. PESTIS的杀伤力挑战方面非常有效。我们的初步数据表明，良好的保护是由于改善的抗原表现，可能是通过改善TH1型免疫反应而产生的。这是第一次基于DNA的鼠疫疫苗在任何动物模型中都诱发了针对致命粘膜挑战的完全保护。 现在，我们建议在最初的18-24个月内进行剧烈的验证和测试，以使用这种新颖的修饰V抗原作为核心保护成分来开发亚基瘟疫疫苗的制剂。该亚基疫苗以DNA，蛋白质或两者组合的形式传递的保护疗效将通过气道粘膜来评估致命的鼠疫杆菌挑战。将进行其他免疫学研究，以确认改进的V抗原的疗效。 我们还建议继续寻找将其他保护性pestis抗原纳入上述初级配方中，以便可以开发出真正的多基因瘟疫疫苗，以实现更广泛的保护，以阻止试图设计耐药性pestis菌株。该搜索将主要集中在涉及Y. Pestis型III型分泌功能的抗原上，包括YOPB，YOPD和YSCF。这些候选者和修改的V抗原将测试各种组合制剂，以识别可以提供最有效保护的配方。该项目将采用最先进的DNA免疫技术与小规模蛋白质生产结合使用，以快速开发潜在的基于亚基的瘟疫疫苗产品。