Assessment of mFLSC(239)complex in cynomologus macaques

描述(申请人提供)：全长单链(FLSC)免疫原是一种遗传连接的HIV包膜-CD4复合体，它复制了所有HIV分离株在感染期间必须通过的过渡状态。这种疫苗概念的持续发展要求免疫原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病毒或病毒进入过程中形成的过渡态结构。第三，外周血源干细胞免疫必须证明有效。虽然抗体的特异性和安全性可以在动物模型中进行研究，但基于HIV的FLSC免疫原临床前有效性的演示受到当前基于SHIV的动物模型的限制。幸运的是，猪尾猕猴的SIVmac病毒挑战被普遍认为是一种严格的灵长类慢病毒模型，模拟了人类艾滋病毒感染的临床和病原学特征。为此，该模型已被广泛用于评估潜在的艾滋病毒疫苗概念。我们已经开发了一种基于SIVmac239的FLSC，mFLSC(239)，目的是在这个挑战模型中评估FLSC疫苗的概念。不幸的是，猪尾猕猴和恒河猴的可获得性有限，阻碍了我们在这些动物身上进行任何有统计学意义的初步研究。因此，我们建议研究mFLSC(239)在相关猕猴物种(猕猴或食蟹猴)中的安全性和免疫原性，作为实现我们目标的下一步。我们的假设是，mFLSC(239)可以诱导SFV特异性的广谱中和抗体反应，并且对CD4+细胞无害。我们将在三个目标上检验这一假设。首先，确定mFLSC(239)是否能诱导出针对多种SIV分离株的广谱中和抗体。第二，确定诱导的中和抗体反应是否是SIV包膜或猕猴CD4(MCD4)的特异性。第三，确定mFLSC(239)是否诱导潜在有害的自身抗CD4抗体。在这种探索性环境中成功证明这一假设将为进一步的、更详细的安全性研究以及对SIVmac239和异源SIV分离株的挑战性实验奠定基础。

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.