Development of Vaccine Carriers

疫苗载体的开发

• 批准号: 6433808
• 负责人: LANCE L SIMPSON
• 金额: $ 29.25万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6433808
• 关键词: bacterial disease; bacterial toxins; biological models; botulinum toxins; chimeric proteins; communicable disease control; diphtheria toxin; gastrointestinal absorption /transport; gastrointestinal epithelium; guinea pigs; immunoconjugates; immunologic substance development /preparation; immunotherapy; immunotoxicity; inhalation drug administration; laboratory mouse; laboratory rat; nonhuman therapy evaluation; oral administration; pertussis toxin; protein structure function; respiratory epithelium; tetanus toxin; tissue /cell culture; transcytosis; vaccine development

DESCRIPTION (provided by applicant): The broad objective of the proposed research is to develop a novel methodology for creating oral and inhalation vaccines. This methodology will utilize the techniques of molecular biology to create fusion proteins that contain two partners: a carrier domain and a vaccine domain. The carrier domain will be a modified and non-toxic variant of botulinum toxin that possesses the ability to cross gut and airway epithelial cells to reach the general circulation. The vaccine domains will be non-toxic polypeptide fragments obtained from tetanus toxin, diphtheria toxin and pertussis toxin. Each of these fragments will have the ability to evoke neutralizing antibodies and therefore resistance against the parent toxins. Initially, the goal of the work will be to create monovalent vaccines (i.e., carrier plus a single immunogen). If this succeeds, a subsequent goal will be to create polyvalent vaccines (i.e., carrier plus a string of two or more immunogens). Generally speaking, experiments will be conducted in a logical progression of steps. The major steps will be: a.) construction of fusion genes that encode carrier and immunogenic components, b.) expression and isolation of the chimeric proteins, c.) evaluation of each putative vaccine to determine whether it crosses gut and/or airway epithelial cells of laboratory animal and human origin, d.) testing of each chimeric vaccine for toxicity when assayed in vitro or in vivo, and e.) testing of each chimeric vaccine to determine whether it will evoke systemic resistance when administered orally or by inhalation to laboratory animals. To be gauged successful, a monovalent or polyvalent vaccine must be able to evoke resistance to at least 1,000 lethal doses of each immunogen in the compound. In the aggregate, the data from this work should indicate whether any particular carrier-immunogen conjugate is worthy of further consideration as a potential human vaccine. If successful, the work should culminate in the generation of monovalent and polyvalent vaccines against tetanus, diphtheria and pertussis toxins. In addition, the work should establish a general approach that could be used to create oral and inhalation vaccines against a broad array of human diseases.

描述(由申请人提供)：建议的总体目标 研究旨在开发一种新的方法来创造口腔和吸入 疫苗。这一方法论将利用分子生物学技术 创建包含两个伙伴的融合蛋白：一个载体结构域和一个 疫苗领域。载体结构域将是一种经修饰的无毒变体 具有穿过肠道和呼吸道上皮的能力的肉毒杆菌毒素 细胞才能进入大循环。疫苗领域将是无毒的 从破伤风毒素、白喉毒素和 百日咳毒素。这些片段中的每一个都有能力唤起 中和抗体，因此对母体毒素具有抵抗力。 最初，这项工作的目标将是创造单价疫苗(即， 载体加单一免疫原)。如果这成功了，接下来的目标将是 以制造多价疫苗(即，载体加上两串或更多串 免疫原)。 一般说来，实验将按以下逻辑顺序进行 台阶。主要步骤将是：a.)编码重组蛋白融合基因的构建 载体和免疫原组分，b.)目的基因的表达和分离 嵌合蛋白，c.)对每种推定疫苗进行评估，以确定 它跨越实验动物和人的肠道和/或呼吸道上皮细胞。 来源：D.)体外检测每种嵌合疫苗的毒性 或在体内，以及e。)对每个嵌合疫苗进行测试，以确定它是否 口服或吸入会引起全身抵抗力 实验动物。要衡量成功，单价或多价疫苗 必须能够引起对每种至少1000致命剂量的抵抗力 免疫基因在化合物中。总的来说，这项工作的数据应该是 指出是否有任何特定的载体-免疫原结合物值得 进一步考虑作为一种潜在的人类疫苗。 如果成功，这项工作将最终产生单价和 破伤风、白喉和百日咳毒素的多价疫苗。在……里面 此外，这项工作应确立一种可用于 创造针对多种人类疾病的口服和吸入疫苗。