SALMONELLA-HIV CHIMERA AS VACCINE

沙门氏菌-HIV 嵌合体作为疫苗

• 批准号: 3141945
• 负责人: BRUCE A STOCKER
• 金额: $ 18.53万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-12-01 至 1990-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3141945
• 关键词: AIDS; Salmonella; Salmonella typhimurium; cellular immunity; gene deletion mutation; genetic manipulation; human immunodeficiency virus; humoral immunity; laboratory mouse; laboratory rabbit; live vaccine; oligonucleotides; passive immunization; plasmids; simian immunodeficiency virus; synthetic nucleotide; viral vaccines; virus antigen; virus protein

The long-term objective of the research is to construct strains of Salmonella which produce antigens of HIV for use as live vaccine, given by mouth, to humans, in the expectation that delivery of HIV antigens in this way will evoke strong immune responses, both humoral and cellular to the "passenger" HIV antigen(s) and with the hope that such responses will serve not only to prevent infection if administered to uninfected subjects but perhaps also to arrest progression from silent infection to AIDS if given to symptom-free antibody positive subjects. The bacterial carriers for immunization of laboratory animals are S. typhimurium and S. dublin strains with non-reverting mutations at aroA, blocking aromatic biosynthesis and causing requirement for p-aminobenzoic acid, not available in host tissues; these strains are safe and effective as live vaccines, parenteral or oral, for protection of animals against systemic salmonella infections and are effective presenters of cloned antigen genes from other organisms, e.g. the M protein of Streptococcus pyogenes. They will be given constructed plasmids which include HIV DNA sequences for production of HIV antigens, either as proteins or fusion proteins or as exposed amino acid sequences in the flagellin of host flagella. Plasmids from E. coli strains expressing HIV antigens will be transferred to S. typhimurium or S. dublin live-vaccine strains for test of expression and stability, in vitro and in vivo, and for ability to evoke HIV immune responses in laboratory animals. Plasmids evoking good responses will be transferred to available S. typhi candidate live-vaccine strains, such as 541Ty and 543Ty, made non-virulent by deletion mutation at aroA and at purA (causing adenine requirement) which caused no adverse effects when fed to volunteers and evoked cellular immune responses in all such volunteers. If the S. typhi live-vaccine strains given the constructed plasmids appear satisfactory in respect of expression of HIV epitopes and of stability they will be made available for testing elsewhere, in volunteers.

这项研究的长期目标是构建菌株 产生艾滋病毒抗原用作活疫苗的沙门氏菌， 通过口服给人类，期望艾滋病毒的传播 以这种方式产生的抗原会引起强烈的免疫反应， 体液和细胞对乘客艾滋病毒抗原(S)和与 希望这样的反应不仅有助于预防感染 如果注射给未感染的受试者，也可能是为了阻止 如果服用无症状药物，从无症状感染发展为艾滋病 抗体阳性受试者。 实验动物免疫的细菌携带者是 鼠伤寒沙门氏菌和都柏林沙门氏菌不可逆转突变株 在AROA，阻止芳香生物合成并导致对 对氨基苯甲酸，寄主组织中不存在；这些菌株 作为活疫苗，无论是非肠道疫苗还是口服疫苗，安全有效 保护动物免受系统性沙门氏菌感染和 是来自其他物种的克隆抗原基因的有效呈现者 生物体，例如化脓性链球菌的M蛋白。他们会 被给予包括HIV DNA序列的构建的质粒 以蛋白质或融合蛋白的形式生产艾滋病毒抗原 或作为寄主鞭毛蛋白中暴露的氨基酸序列 鞭毛。表达人类免疫缺陷病毒抗原的大肠杆菌表达载体 将被转移到鼠伤寒沙门氏菌或都柏林沙门氏菌活疫苗 用于体内外表达和稳定性测试的菌株， 以及在实验室中唤起艾滋病毒免疫反应的能力 动物。激发良好反应的质粒会被转移到 现有的伤寒沙门氏菌候选活疫苗株，如541Ty 和543Ty，通过Aroa和At的缺失突变而变得无毒 PURA(引起腺嘌呤需求)，未引起不良反应 当喂给志愿者并在所有人中激发细胞免疫反应时 这样的志愿者。如果给予伤寒沙门氏菌活疫苗株 构建的质粒在表达方面似乎令人满意 关于艾滋病毒表位和稳定性，它们将用于 在其他地方，在志愿者身上进行测试。