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收购的受保护效率的唯一疫苗试验（RV144）是基于 在痘病毒原始蛋白质上增强免疫抑制策略。虽然有效谦虚（〜31％），但 这些发现提供了一个有力的理由，以寻求改进的促进免疫方法和 为了更好地了解获得的保护免疫的性质。在此应用程序中，我们试图改进 通过三种独立方法的组合对Prime增强免疫的反应：（i）呈现 稳定在病毒样颗粒（VLP）上的三聚合物ENV峰值作为离甲酸病毒Prime和VLP的免疫原 促进; （ii）将来自多个分离株的稳定的三聚合物包膜（ENV）纳入多价VLP免疫原 增加响应的广度； （iii）探索可能增加SOSIP数量的方法 Trimer尖峰在VLP上。我们的整体工作假设是Prime-Boost的受保护效率 可以通过优化免疫原和免疫方案来改善免疫接种以提高宽度 与已与之中和的抗体反应的效力 人类和/或非人类私人模型的保护。具体来说，我们通过呈现来假设 在Poxvirus-Prime Boost方案中，在VLP上稳定的三聚合物ENV，我们将能够增强 中和抗体响应，并使用多价env并增加env尖峰的密度 在VLP免疫原中，我们将进一步扩大响应的宽度和效力。这 中和和非中和抗体反应的宽度和效力， 包括V1/V2定向抗体以及媒体抗病毒效应功能（例如ADCC）的抗体 将有助于痘病毒 - 蛋白质素促进剂免疫平台的受保护效率。 该提案的具体目的是：（1）确定结构和抗原和免疫原性 稳定的ENV三聚体的轮廓掺入VLP中； （2）确定是否稳定多个 可以将分离株纳入VLP，如果在素数/增压方案中使用时多价疫苗将 增加NAB和非NAB响应的广度； （3）确定细胞质尾部的修饰是否会 增加VLP上稳定的ENV峰值的密度，如果ENV密度增加将增强广度和 特定回应的效力； （4）检查是否是从下降的免疫抑制方案 兔子的先前研究可以翻译成猕猴。如果成功，则从这些研究中获得的见解 将告知疫苗和疫苗策略的临床开发，这些疫苗和疫苗策略可能比那些更有效 在RV144中用于防止人类中的HIV-1获取。