Human studies of Listeria monocytogenes vectors

单核细胞增生李斯特氏菌载体的人体研究

• 批准号: 7659223
• 负责人: ELIZABETH L. HOHMANN
• 金额: $ 2.64万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-15 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659223
• 关键词: Animals; Antigens; Attenuated; Bacteria; Bacteriophages; CD8B1 gene; Cells; Chimeric Proteins; Clinical Research; Collaborations; Colony-forming units; Data; Development; Documentation; Dose; Elements; Engineering; Epitopes; Evaluation; Food; Freezing; Gagging; Growth; HIV; HIV-1; Haplotypes; Heterophile Antigens; Human; Human Volunteers; Hydrophobicity; Immune response; Immunization; In Vitro; Infection; Influenza; Inpatients; Intestines; Knowledge; Life; Listeria; Listeria monocytogenes; Listeria monocytogenes hlyA protein; Localized; Mus; Mutation; Neuraxis; Nucleoproteins; Oral; Organism; Pathogenesis; Placenta; Plasmids; Population; Principal Investigator; Process; Protocols documentation; Research Design; Research Ethics Committees; Safety; Salmonella Vaccines; Serious Adverse Event; Site; System; Technology; Testing; Therapeutic; Time; Tropism; Vaccines; Viral; Viral Antigens; Viral Tumor Antigens; Virulence; Virus; bacterial vector; base; design; enzyme linked immunospot assay; experience; gag Gene Products; genetic element; human study; immunogenicity; in vivo; mutant; programs; prophylactic; size; tissue culture; tool; vector; vector vaccine; volunteer

DESCRIPTION: (Provided by Applicant) Listeria monocytogenes are Gram-positive intracellular bacteria which stimulate cellular immune responses, those necessary for elimination of viruses. Engineered L. monocytogenes are effective vaccine vectors for delivery of both viral and tumor antigens in animals. Both therapeutic and prophylactic approaches are successful in animals. Listeria spp. Are present in foods, enter the body through the intestine and may disseminate to cause serious infection with a tropism for the central nervous system and placenta. Safety is therefore a major consideration in use of L. monocytogenes as a vector in humans. We have initiated (to our knowledge) the first safety study of a live attenuated L. monocytogenes vector organism in human volunteers. A highly attenuated derivative of L. monocytogenes 10403S deleted for the virulence elements actA and plcB is being studied. There have been no serious adverse events to date in 18 volunteers who received single oral escalating doses of this attenuated strain (10E5 to 10E9 colony forming units). This proposal sets forth a plan for ongoing evaluation of Listeria bacteria as vaccine vectors in humans. Attenuated L. monocytogenes will be engineered to express defined influenza A and HIV Gag epitopes as secreted fusion proteins of listeriolysin. Strains constructed will be evaluated bacteriologically, in mice and in tissue culture systems. Promising strains will be carried on for evaluation in small inpatient clinical studies designed to evaluate safety, shedding and human immunogenicity. Contemporary immunological studies using tetramer, FACS and ELISPOT technologies will be used to determine whether discrete human cellular immune responses to vectored viral antigens can be detected in humans after these investigational immunizations. These studies will provide important data on the feasibility and utility of using Listeria monocytogenes vectors in humans.

描述：（由申请人提供）单核细胞增生李斯特菌是革兰氏阳性菌 刺激细胞免疫反应的细胞内细菌 消除病毒所必需的。工程改造的单核细胞增生李斯特菌是有效的 用于在动物体内传递病毒和肿瘤抗原的疫苗载体。两个都 治疗和预防方法在动物身上取得了成功。李斯特菌 种。存在于食物中，通过肠道进入体内，可能 向中枢神经传播引起严重感染 系统和胎盘。因此，安全性是使用 L 的主要考虑因素。 单核细胞增多症作为人类的载体。据我们所知，我们已经发起了 首次对减毒活单核细胞增生李斯特氏菌载体生物体进行安全性研究 人类志愿者。单核细胞增生李斯特菌 10403S 的高度减毒衍生物 正在研究删除毒力元件 actA 和 plcB。有 迄今为止，接受单次治疗的 18 名志愿者没有出现严重不良事件 口服递增剂量的这种减毒菌株（10E5至10E9菌落形成 单位）。该提案提出了对李斯特菌进行持续评估的计划 细菌作为人类疫苗载体。减毒单核细胞增生李斯特氏菌将 设计用于表达确定的甲型流感和 HIV Gag 分泌表位 李斯特菌溶血素的融合蛋白。将评估构建的菌株 细菌学上，在小鼠和组织培养系统中。有前途的菌株 将在小型住院临床研究中进行评估 评估安全性、脱落和人体免疫原性。当代的 使用四聚体、FACS 和 ELISPOT 技术的免疫学研究将 用于确定离散的人类细胞免疫反应是否对载体 经过这些研究后，可以在人体中检测到病毒抗原 免疫接种。这些研究将为可行性和可行性提供重要数据。 在人类中使用单核细胞增生李斯特氏菌载体的效用。