Epitope-targeted Vaccines for HIV-1 Prevention

描述(申请人提供)：最近的RV144临床疫苗试验在健康人中对HIV-1感染产生了适度和短暂的保护，并被认为是微乎其微的成功。为了提高抗体(Ab)反应的有效性和持续时间，需要更好的免疫原。我们推测，由新构建的疫苗诱导的抗体将具有更高的特异性活性，更强的抗体效价，在总抗体应答中， 保护所需的抗体比例。这些新的构建物可以在不同于整个包膜(Env)的情况下呈现病毒表位，也可以避免与整个Env相关的瞬时抗体反应的问题。我们和其他人已经证明，通过将抗体反应集中在V3上，可以诱导出交叉中和抗体，这些抗体在免疫后一年可检测到。因此，我们现在建议扩展我们以前开发的用于设计和开发V3支架免疫原的平台，以创建和测试新的表位支架蛋白免疫原，该抗原将集中抗体反应在环境中另外两个脆弱部位：V2环和由V2和V3部分组成的四元中和表位簇(QNE)。HIVRAD将包括：项目1：诱导针对V2环的功能性抗体的疫苗；项目2：针对HIV-1 V2/V3四元中和表位的免疫原的合理设计；核心A：行政核心；核心B：蛋白质生产核心；以及核心C：动物研究核心。将开发的表位支架免疫原可以单独使用，也可以联合使用，将成为诱导广泛而有效的保护性抗体的强有力的新工具。许多参与者一起工作了20年，以开发和鉴定抗艾滋病毒和其他病原体的100人单抗。最近，该团队通力合作，制备和分析了单抗和单抗/表位复合体的晶体，开发了DNA环境素和表位-支架免疫原，并进行了免疫实验。我们的经验使我们处于有利地位，可以将我们的研究扩展到最近才被认为对预防艾滋病毒感染具有重要意义的表位。到拟议的计划完成时，我们计划确定表位靶向免疫原和免疫方案，以产生具有保护性抗病毒功能的抗体，这些抗体专门针对HIV-1 gp120的V2环和V2/V3四元中和表位的保守区。

DESCRIPTION (provided by applicant): The recent RV144 clinical vaccine trial induced modest and transient protection in healthy individuals against HIV-1 infection, and is considered to be a marginal success. To improve the efficacy and duration of the antibody (Ab) response, better immunogens are required. We postulate that Abs induced by novel vaccine constructs will have higher specific activity, with stronger Ab titers and, within the total Ab response, a greater proportion of the Abs needed for protection. Such novel constructs, which could present viral epitopes in a context other than that of the whole envelope (Env), may also obviate the problems of the transient Ab response associated with whole Env. We and other have demonstrated that, by focusing the Ab response on V3, cross-clade neutralizing Abs are elicited which are detectable >1 year after immunization. Therefore, we now propose to extend the platform we previously developed for designing and developing V3-scaffold immunogens in order to create and test new epitope-scaffold protein immunogens that will focus the Ab response on two additional sites of vulnerability in Env: the V2 loop and the cluster of quaternary neutralizing epitopes (QNEs) composed of portions of V2 and V3. The HIVRAD will be composed of: Project 1: Vaccines to Induce Functional Abs Targeting the V2 Loop; Project 2: Rational Design of Immunogens Targeting the HIV-1 V2/V3 Quaternary Neutralizing Epitopes; Core A: Administrative Core; Core B: Protein Production Core; and, Core C: Animal Studies Core. The epitope-scaffold immunogens to be developed can be used individually or in combination, and will constitute powerful new tools for inducing broad and potent protective Abs. Many of the participants have worked together for >20 years to develop and characterize >100 human mAbs to HIV and other pathogens. Recently, the team has worked collaboratively and synergistically, preparing and analyzing >25 crystals of monoclonal Abs (mAbs) and mAb/epitope complexes, developing DNA Env primes and epitope-scaffold immunogens, and performing immunization experiments. Our experience places us in a strong position to extend our studies to epitopes that only recently have been recognized as important for protection from HIV infection. By the completion of the proposed Program, we plan to have identified epitope-targeting immunogens and immunization protocols that will generate Abs with protective anti-viral functions directed specifically toward the conserved regions of the V2 loop and the V2/V3 quaternary neutralizing epitopes of HIV-1 gp120.