VACCINE TO INDUCE NEUTRALIZATION OF PRIMARY HIV STRAINS

诱导 HIV 原发株中和的疫苗

• 批准号: 2751238
• 负责人: DAVID DAVIS
• 金额: $ 15万
• 依托单位: INSTITUTE OF TROPICAL MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2751238
• 关键词: AIDS vaccines; HIV envelope protein gp120; Macaca mulatta; antibody formation; genetic strain; human immunodeficiency virus 1; laboratory rabbit; laboratory rat; monoclonal antibody; neutralizing antibody; neutrophil; phytohemagglutinins; protein engineering; protein structure; recombinant proteins; simian immunodeficiency virus; synthetic vaccines; vaccine development; virus antigen

DESCRIPTION (adapted from the applicant's abstract): The broad long-term objective is to develop a human immunodeficiency virus type 1 (HIV-1) recombinant gpl20 prime, peptide boost vaccination strategy using an immunogen, adjuvant and injection schedule, which would be acceptable for human use. The specific aim of the present project is to study the neutralizing and enhancing responses, assayed with laboratory and primary isolates of homologous and heterologous HIV-1 clade B isolates, in rhesus monkeys, rabbits and rats primed with recombinant HIV-1 SF2gpl20 immune stimulating complexes (ISCOM) formulations and boosted with synthetic peptides. The research design and methods will be as follows: A sensitive assay will be developed for monitoring neutralizing and enhancing antibody against the homologous HIV-1 SF2 and heterologous primary clade B viruses (HIV-1 DH12, HIV-1 HAN2, for which stocks titrated in chimps exist) in already existing sera of successfully prime-boost vaccinated rhesus-monkeys. Non-phytohemagglutinin (PHA) stimulated peripheral blood mononuclear cells (PBMC), as well as enriched purified T4, CD3+, CD4+, HLA-DR+ non-PHA stimulated cells, will be evaluated as host cells in the neutralization assay. Enhancement of the monkey sera against primary clade B viruses (see above) will be monitored in enriched human macrophage cultures. In primed and boosted rabbits and rats, the effect of the following parameters on the production of neutralizing and/or enhancing antibodies against laboratory and primary HIV-1 clade B viruses will be studied: priming with HIV-2 SF2 gpl20 coupled to ISCOM either via their protein backbone or their carbohydrates; the effect of two prime boost regimens, prime with recombinant immunogen and boost with peptides versus prime with peptides and boost with recombinant immunogen; boosting with mimotopes which have shown high affinity to the human monoclonal antibody (mAb) immunoglogulin G (IgG) 1 bl2, which is known to neutralize primary HIV-1 isolates; the use of single copy 15 mer V2, V3 and CD4 peptide to boost versus shorter, overlapping peptides, presented as a multiple antigenic peptide. The prime-boost regimen, which induces in rabbits and rats the broadest cross-neutralization response and the lowest enhancement against the various primary HIV-1 clade B viruses, will be selected to go forward to challenge studies in rhesus monkeys with chimeric simian/human immunodeficiency virus (SHIV)-DH12 or SHIV HAN2. Ultimately, the most successful approach will be tested later on in chimpanzees.

描述(改编自申请人的摘要)：广泛的长期 目的是开发一种人类免疫缺陷病毒1型(HIV-1) 重组gpl20Prime、多肽Boost疫苗接种策略 免疫原、佐剂和注射时间表，适用于 为人类所用。本项目的具体目的是研究 中和和增强反应，实验室和初级检测 恒河猴HIV-1 B分支同源和异源分离株的分离 重组HIV-1 SF2gp20免疫猴、兔和大鼠 刺激性复合体(ISCOM)配方和合成助剂 多肽。研究的设计和方法如下：敏感的 将开发用于监测中和和增强抗体的检测方法 抗同源HIV-1SF2和异种原发B分支病毒 (HIV-1 DH12，HIV-1 HAN2，存在在黑猩猩中滴定的股票) 已有的已成功加强免疫的恒河猴血清。 非植物血凝素(PHA)刺激外周血单核细胞 (PBMC)，以及纯化的T4、CD3+、CD4+、HLA-DR+非PHA 被刺激的细胞，将被评估为中和宿主细胞 化验。猴血清对初级B分支病毒的增强作用(见 将在浓缩的人类巨噬细胞培养中进行监测。在Primed中 并对大白兔和大鼠进行免疫增强，观察以下参数对小鼠运动功能的影响。 实验室中和和/或增强抗体的产生 将研究主要的HIV-1 B分支病毒：用HIV-2 SF2进行引爆 GPL20通过它们的蛋白质骨架或它们的 碳水化合物；两种主要增强方案的效果，主要与 重组免疫原和增强多肽与基本肽和 用重组免疫原增强；用模拟表位增强 与人单抗免疫球蛋白G的高亲和力 1 BL2，已知可中和HIV-1初级分离株；使用 单拷贝15聚体V2、V3和CD4多肽增强与更短， 重叠多肽，呈现为多个抗原肽。 最好的强化疗法，在兔和大鼠体内诱导最广泛的 交叉中和反应和对不同种类的 主要HIV-1 B分支病毒，将被选为前进的挑战 猕猴携带猴/人免疫缺陷嵌合病毒的研究 (Shiv)-DH12或Shiv HAN2。归根结底，最成功的方法是 后来在黑猩猩身上进行了测试。