Assessment of mFLSC(239)complex in cynomologus macaques

描述（由申请人提供）：全长单链（FLSC）免疫原是一种基因连接的HIV包膜- cd4复合物，它复制所有HIV分离株在感染期间必须经过的过渡状态。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，中和性免疫反应必须针对HIV病毒或病毒进入过程中形成的过渡状态结构。第三，FLSC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免疫原的临床前疗效证明受到当前基于shiv的动物模型的限制。幸运的是，猪尾猴或恒河猴的SIVmac病毒攻击通常被认为是一种严格的灵长类慢病毒模型，它模仿了人类HIV感染的临床和致病特征。因此，该模型已被广泛用于评估潜在的艾滋病毒疫苗概念。我们开发了一种基于sivmac239的FLSC， mFLSC(239)，目的是在这种挑战模型中评估FLSC疫苗概念。不幸的是，猪尾猴和恒河猴的有限可用性使我们无法对这些动物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Macaco fascicularis或cynomologus猕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）可以诱导一种广泛中和的抗体反应，这种抗体反应是SFV特异性的，并且对CD4+细胞无害。我们将用三个目标来检验这一假设。首先，确定mFLSC（239）是否能引发针对多种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SIV包膜特异性的还是猕猴CD4 （mCD4）特异性的。第三，确定mFLSC（239）是否诱导潜在有害的自身抗cd4抗体。在这种探索性环境下成功证明这一假设将为进一步更详细的安全性研究奠定基础，并为SIVmac239和异种SIV分离株的挑战实验奠定基础。

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.