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Human Studies of Attenuated Salmonella Vectors

减毒沙门氏菌载体的人体研究

基本信息

批准号：
7275912
负责人：
ELIZABETH L. HOHMANN
金额：
$ 49.11万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7275912
关键词：
Acute Adenovirus Vector Adjuvant Adult Animal Model Antigens Attenuated Automobile Driving Clinical Clinical Research Cutaneous Administration Data Development Disease Dose Enzyme-Linked Immunosorbent Assay Equilibrium Follow-Up Studies Foundations Gagging Gene Deletion Genes Goals HIV HIV-1 Heating Human Human Volunteers Immune response Immunity Immunization Immunoglobulin A Investigation Laboratories Laboratory Animals Life Mammals Maximum Tolerated Dose Measures Membrane Membrane Fusion Methods Mus Oral Organism Peptides Pharmacologic Substance Phase Plasmids Proteins Purpose Range Recombinants Research Design Safety Salmonella Salmonella typhi Salmonella typhimurium Schedule Surface System Testing Toxin Treatment Protocols Type III Secretion System Pathway Vaccination Vaccines Vaccinia Vibrio cholerae Virulence Work attenuation bacterial vector base clinically relevant day design experience gag Gene Products human study immunogenicity pre-clinical prevent promoter prototype research study response vaccine efficacy vaccine safety vector vector vaccine volunteer

项目摘要

DESCRIPTION (provided by applicant): Vaccination is an effective and economical method of preventing disease. It is hoped that orally administered vaccines will have the widest application and induce immunity at mucosal surfaces. Live, orally administered attenuated bacterial vectors have been very effective in animal models. The purpose of this project is to gain important safety and immunogenicity data on Salmonella typhimurium vectors expressing a clinically relevant HIV-1 antigen by studying this prototype vaccine organism in human volunteers. The proposal describes an integrated laboratory and clinical project. The application proposes completion of an ongoing Phase I dose escalation study of a Salmonella typhimurium vector expressing HIV-1 Gag (CKS257), and describes follow-up studies designed to enhance immune responses to HIV-1 Gag in humans. These experiments include multi-dosing, transcutaneous boosting, and study of a "mucosal prime/systemic boost" strategy, if possible. The phoP/phoQ/aroA-deleted bacterial vector and expression system were chosen based upon pre-clinical laboratory and animal studies which suggest that this strain will be safe and engender cellular immune responses to the vectored antigen. The phoP/phoQ and aroA genes are important for Salmonella persistence/virulence within mammals; deletion of these genes results in major attenuation. A rationally-engineeered HIV-1 Gag antigen is expressed from a balanced-lethal plasmid and secreted from the Salmonella vector via the Type III Secretion System(TTSS). In mice, antigens secreted via the TTSS results in superior immune responses and greater vaccine efficacy than vector associated antigens. Clinical safety and vaccine shedding is carefully evaluated and humoral, mucosal and cellular immune responses to the vector and HIV-Gag are measured. In addition, new constructs will be generated in the laboratory to clinically test a promising approach which enhances the immunogenicity of Salmonella-vectored antigens in animal models, but has never been tested in humans: driving antigens from PhoP-activated promoters. This will necessitate using a vector attenuation strategy different from the well-characterized PhoP/PhoQ null strains, and therefore require significant preclinical work. The laboratory has significant experience in translational investigation of live bacterial vectors. The major goal of the project is to provide practical safety and immunogenicity data in humans which will help efficiently direct development of live bacterial vectors.

描述（由申请人提供）：疫苗接种是预防疾病的有效和经济的方法。人们希望口服疫苗将有最广泛的应用，并在粘膜表面诱导免疫。活的、口服给药的减毒细菌载体在动物模型中非常有效。本项目的目的是通过在人类志愿者中研究这种原型疫苗生物体，获得表达临床相关HIV-1抗原的鼠伤寒沙门氏菌载体的重要安全性和免疫原性数据。该提案描述了一个综合的实验室和临床项目。该申请建议完成正在进行的表达HIV-1 Gag（CKS 257）的鼠伤寒沙门氏菌载体的I期剂量递增研究，并描述了旨在增强人类对HIV-1 Gag的免疫应答的后续研究。这些实验包括多次给药、经皮加强和“粘膜初免/全身加强”策略的研究（如果可能）。 phoP/phoQ/aroA缺失的细菌载体和表达系统是基于临床前实验室和动物研究选择的，这些研究表明该菌株将是安全的，并产生对载体抗原的细胞免疫应答。phoP/phoQ和aroA基因对于沙门氏菌在哺乳动物中的持久性/毒力是重要的;这些基因的缺失导致主要减毒。合理工程化的HIV-1 Gag抗原从平衡致死质粒表达，并通过III型分泌系统（TTSS）从沙门氏菌载体分泌。在小鼠中，通过TTSS分泌的抗原导致比载体相关抗原更上级的免疫应答和更大的疫苗功效。仔细评估临床安全性和疫苗脱落，并测量对载体和HIV-Gag的体液、粘膜和细胞免疫应答。此外，新的构建体将在实验室中产生，以临床测试一种有前途的方法，该方法在动物模型中增强沙门氏菌载体抗原的免疫原性，但从未在人类中进行过测试：从PhoP激活的启动子驱动抗原。这将需要使用不同于充分表征的PhoP/PhoQ无效菌株的载体减毒策略，因此需要大量的临床前工作。该实验室在活细菌载体的转化研究方面具有丰富的经验。该项目的主要目标是提供人类的实际安全性和免疫原性数据，这将有助于有效地指导活细菌载体的开发。