VIRUS-LIKE PARTICLES WITH STABILIZED TRIMERIC ENVELOPE FOR PRIME BOOST IMMUNIZATION

具有稳定三聚体包膜的病毒样颗粒，用于初免加强免疫

• 批准号: 9530535
• 负责人: Shiu-Lok Hu
• 金额: $ 61.53万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-18 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9530535
• 关键词: AIDS/HIV problem; Animal Model; Antibodies; Antibody Response; Antigens; Antiviral Agents; Canarypox virus; Clinic; Complementarity Determining Regions; Cytoplasmic Tail; HIV; HIV Antigens; HIV Envelope Protein gp120; HIV envelope protein; HIV-1; Human; Immunity; Immunization; Macaca; Mediating; Membrane Proteins; Modeling; Modification; Nature; Oryctolagus cuniculus; Polyvalent Vaccine; Poxviridae; Proteins; Recombinants; Regimen; Resistance; Risk; Structure; Testing; Translating; Vaccines; Vaccinia virus; Viral; Virus; Virus-like particle; antibody-dependent cell cytotoxicity; base; clinical development; cross reactivity; density; design; immunogenic; improved; insight; neutralizing antibody; nonhuman primate; novel; prevent; protective efficacy; response; vaccine development; vaccine trial

To date, the only vaccine trial (RV144) that has shown any protective efficacy against HIV acquisition is based on a poxvirus prime–protein boost immunization strategy. Although the efficacy achieved was modest (~31%), these findings provide a strong rationale to seek improvements for the prime-boost immunization approach and to gain better insight on the nature of the protective immunity achieved. In this application, we seek to improve responses to prime boost immunization by a combination of three independent approaches: (i) to present stabilized trimeric Env spikes on virus-like particles (VLP) as immunogens for vaccinia virus prime and VLP boost; (ii) to incorporate stabilized trimeric envelope (Env) from multiple isolates as polyvalent VLP immunogen to increase the breadth of response; and (iii) to explore approaches that may increase the number of SOSIP trimer spikes on VLP. Our overall working hypothesis is that the protective efficacy of prime-boost immunization can be improved by optimizing immunogen and immunization regimen to enhance the breadth and potency of both neutralizing and non-neutralizing antibody responses that have been associated with protection in human and/or non-human primate models. Specifically, we hypothesize that by presenting stabilized trimeric Env on VLP in the poxvirus-protein prime boost regimen, we will be able to enhance neutralizing antibody responses, and by using polyvalent Env and increasing the density of Env spikes on the VLP immunogens, we will further amplify the breadth and the potency of response. The enhanced breadth and potency of both neutralizing and non-neutralizing antibody responses, including V1/V2-directed antibodies and those that mediate antiviral effector functions, such as ADCC, will contribute to the protective efficacy of the poxvirus-protein prime boost immunization platform. The Specific Aims of this proposal are: (1) To determine the structure and the antigenic and immunogenic profiles of stabilized Env trimers incorporated into VLP; (2) To determine if stabilized Env trimers from multiple isolates can be incorporated on VLP and if such polyvalent vaccines when used in a prime/boost regimen will increase the breadth of Nab and non-Nab responses; (3) To determine if cytoplasmic tail modifications will increase the density of stabilized Env spikes on VLP and if increased Env density will enhance the breadth and potency of Env specific responses; and (4) To examine if immunization regimens down-selected from the preceding studies in rabbits can be translated to macaques. If successful, insights obtained from these studies will inform the clinical development of vaccines and vaccine strategies that may be more effective than those used in RV144 to prevent HIV-1 acquisition in humans.

迄今为止，唯一显示出对 HIV 感染具有保护作用的疫苗试验 (RV144) 是基于 痘病毒初免蛋白加强免疫策略虽然取得了一定的效果（~31%）， 这些发现为寻求改进初免-加强免疫方法和 为了更好地了解所实现的保护性免疫的本质，我们寻求改进。 通过结合三种独立方法来应对初免加强免疫： (i) 提出 病毒样颗粒 (VLP) 上稳定的三聚体 Env 尖峰作为痘苗病毒初免和 VLP 的免疫原 加强；(ii)掺入来自多个分离株的稳定三聚体包膜(Env)作为多价VLP免疫原 扩大应对范围；(iii) 探索可能增加 SOSIP 数量的方法； 我们的总体工作假设是，prime-boost 的保护功效。 通过优化免疫原和免疫方案，提高免疫广度 以及与相关的中和和非中和抗体反应的效力 具体来说，我们通过介绍这一点来实现对人类和/或非人类灵长类动物模型的保护。 在痘病毒蛋白初免加强方案中，VLP 上稳定的三聚体 Env，我们将能够增强 中和抗体反应，并使用多价 Env 并增加 Env 尖峰的密度 关于VLP免疫原，我们将进一步扩大反应的广度和效力。 增强中和和非中和抗体反应的广度和效力， 包括 V1/V2 定向抗体和介导抗病毒效应功能的抗体，例如 ADCC， 将有助于痘病毒-蛋白初免加强免疫平台的保护功效。 该提案的具体目标是：（1）确定结构以及抗原性和免疫原性 (2) 从多个中确定稳定的Env三聚体 分离株可以合并到 VLP 上，并且如果这种多价疫苗在初免/加强方案中使用时将 增加 Nab 和非 Nab 反应的广度；(3) 确定细胞质尾部修饰是否会影响 增加 VLP 上稳定的 Env 尖峰的密度，如果增加的 Env 密度将增强宽度和 Env 特异性反应的效力；以及 (4) 检查是否从免疫方案中向下选择 如果成功的话，之前对兔子的研究可以转化为猕猴。 将为疫苗的临床开发和可能比这些更有效的疫苗策略提供信息 用于RV144以防止人类感染HIV-1。