Assessment of mFLSC(239)complex in cynomologus macaques

食蟹猴 mFLSC(239) 复合物的评估

• 批准号: 7028889
• 负责人: Timothy R Fouts
• 金额: $ 26.8万
• 依托单位: PROFECTUS BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7028889
• 关键词: AIDS vaccines; HIV envelope protein; Macaca fascicularis; antibody formation; antibody neutralization test; antigen antibody reaction; autoantibody; disease /disorder model; drug adverse effect; drug quality /standard; flow cytometry; helper T lymphocyte; immunoaffinity chromatography; neutralizing antibody; nonhuman therapy evaluation; simian immunodeficiency virus; vaccine evaluation; virus antigen

DESCRIPTION (provided by applicant): The full-length single chain (FLSC) immunogen is a genetically linked HIV envelope-CD4 complex which replicates a transition state that all HIV isolates must pass through during infection. Continued development of this vaccine concept requires that the immunogen demonstrate three key features. First, the immunogen must be safe. Second, the neutralizing immune response must be directed against HIV virus or a transition state structure that forms during viral entry. Third, immunization with FLSC must demonstrate efficacy. While the antibody specificity and safety can be investigated in animal models, preclinical demonstration of efficacy with HIV based FLSC immunogens is limited by the current SHIV-based animal models. Fortunately, the SIVmac virus challenge of Pigtail or Rhesus macaques is generally recognized as a rigorous primate lentiviral model that mimics the clinical and pathogenic features of human HIV infection. For this reason, this model has been utilized extensively to evaluate potential HIV vaccine concepts. We have developed a SIVmac239-based FLSC, mFLSC(239), with the goal to evaluate the FLSC vaccine concept in this challenge model. Unfortunately, the limited availability of Pigtail and Rhesus macaques prevents us from performing any statistically meaningful preliminary studies in these animals. Therefore, we propose to investigate the safety and immunogenicity of the mFLSC(239) in a related macaque species, Macaco fascicularis or cynomologus macaque, as the next step to reaching our goal. Our hypothesis is that mFLSC(239) can induce a broadly neutralizing antibody response that is SFV specific, and is not deleterious to CD4+ cells. We will test this hypothesis in three aims. First, to determine whether the mFLSC(239) can elicit broadly neutralizing antibodies against a wide range of SIV isolates. Second, to determine whether the induced neutralizing antibody response is specific for the SIV envelope, or macaque CD4 (mCD4). Third, to determine whether the mFLSC(239) induces potentially deleterious auto-anti-CD4 antibodies. Successful demonstration of the hypothesis in this exploratory setting would lay the foundation for further, more detailed, safety studies, as well as challenge experiments with SIVmac239 and heterologous SIV isolates.

描述（由申请人提供）：全长单链（FLSC）免疫原是一种遗传连接的HIV Invelope-CD4复合物，它复制了过渡状态，所有HIV分离株在感染过程中必须通过。这种疫苗概念的持续开发要求免疫学表现出三个关键特征。首先，免疫原必须是安全的。其次，中和免疫反应必须针对HIV病毒或在病毒进入过程中形成的过渡状态结构。第三，使用FLSC的免疫必须表现出功效。虽然可以在动物模型中研究抗体的特异性和安全性，但基于HIV的FLSC免疫原子的临床前证明了功效的临床前证明受到当前基于SHIV的动物模型的限制。幸运的是，辫子或恒河猕猴的SIVMAC病毒挑战通常被认为是一种模仿人类HIV感染的临床和致病特征的严格灵长类动物慢病毒模型。因此，该模型已广泛用于评估潜在的HIV疫苗概念。我们已经开发了基于SIVMAC239的FLSC MFLSC（239），其目标是在此挑战模型中评估FLSC疫苗概念。不幸的是，辫子和恒河猕猴的可用性有限使我们无法在这些动物中进行任何统计学上有意义的初步研究。因此，我们建议研究Macaque物种，Macaco fascicularis或Cynomologus Macaque的MFLSC（239）的安全性和免疫原性，这是实现我们目标的下一步。我们的假设是MFLSC（239）可以诱导特定于SFV的广泛中和抗体反应，并且对CD4+细胞没有有害。我们将以三个目标检验这一假设。首先，确定MFLSC（239）是否可以引起针对广泛的SIV分离株的广泛中和抗体。其次，确定诱导的中和抗体反应是对SIV包膜的特异性或猕猴CD4（MCD4）。第三，确定MFLSC（239）是否诱导了潜在的有害自动-ANTI-CD4抗体。在这种探索性环境中的假设的成功证明将为进一步，更详细的安全研究以及SIVMAC239和异源SIV分离株的挑战实验奠定基础。