Multifunctional calcium phosphate nanoparticles as novel HIV-1 vaccine platform

多功能磷酸钙纳米颗粒作为新型 HIV-1 疫苗平台

• 批准号: 432828510
• 负责人: Professor Dr. Matthias Epple
• 金额: --
• 依托单位: Virologisches Institut - Klinische und Molekulare Virologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/432828510?language=en
• 关键词: Multifunctional; calcium; phosphate; nanoparticles; novel

The importance of IgG Fc-effector functions for the efficacy of HIV vaccines is increasingly recognized. Although different types of vaccines were shown to induce antibodies with different Fc-activities, there is no clear strategy how to raise HIV-Env antibody responses with a desired pattern of Fc-effector functions. Previously we demonstrated that the antibody responses to Env appear to be biased, both in humans and in mice. And Env-specific CD4+ T-cells with a Th2-shifted phenotype are responsible for the IgG1 bias in mice. Based on our previous results, we propose to explore two novel HIV-1 vaccination strategies, both based on multifunctional calcium-phosphate (CaP) nanoparticles (NPs). We aim to bypass the Env-induced bias in T-helper cell responses, and maintain the native trimeric structure of the Env immunogen required to raise antibodies to conformational epitopes. The work programme includes a novel two component vaccine strategy, in which first component is optimized for induction of T-helper cell responses, while the second component presents the Env immunogen in the correct conformation to the B-cells. For priming of HIV-Env specific T-helper cell responses, we propose to encapsulate linear synthetic peptides of HIV-Env together with TLR-ligands for Th1 T-cell polarization in CaP nanoparticles. Surface functionalization with CD11c-targeting antibodies should guide these NPs to dendritic cells. To target B-cells we aim to develop and characterize CaP NPs directionally coated with conformationally stabilized, soluble HIV-1 Env-spikes and functionalized with TLR-ligands inside. A second vaccination strategy includes the recruitment of heterologous Th cells induced by a common licensed to provide efficient intrastructural help for Env-functionalized CaP-wrapped virus particles. Wrapped particles used in licensed vaccines will be protected from the antibody responses, but be rapidly unwrapped due to the acidic pH in the endo-lysosome after uptake by antigen-presenting cells. The immunogenicity of the two different vaccination strategies will be determined in mouse models.

越来越多地认识到IgG FC效应对HIV疫苗功效的重要性。尽管显示出不同类型的疫苗可诱导具有不同FC活性的抗体，但没有明确的策略如何提高使用FC效应功能模式的HIV-ENV抗体反应。以前，我们证明了对ENV的抗体反应在人类和小鼠中似乎都是有偏见的。带有Th2移位表型的ENV特异性CD4+ T细胞负责小鼠的IgG1偏差。根据我们以前的结果，我们建议探索两种基于多功能磷酸钙（CAP）纳米颗粒（NPS）的两种新型HIV-1疫苗接种策略。我们的目标是绕过ENV诱导的T螺旋细胞反应中的偏置，并维持构造构象表位抗体所需的ENV免疫原的天然三聚体结构。该工作计划包括一种新型的两种组成疫苗策略，其中优化了第一个成分以诱导T-助细胞反应，而第二个成分则以对B细胞的正确构型呈现ENV免疫原。为了启动HIV-ENV特异性T-助细胞反应，我们建议将HIV-ENV的线性合成肽与TLR - 配体以及CAP纳米颗粒中的Th1 T细胞极化一起封装。用CD11C靶向抗体的表面功能应引导这些NPS到树突状细胞。为了靶向B细胞，我们旨在开发和表征用构型稳定，可溶性HIV-1 env-spikes的CAP NP，并用内部的TLR配体功能化。第二种疫苗接种策略包括由常见许可诱导的异源TH细胞募集，以提供有效的内部结构帮助为环境功能化的帽包裹的病毒颗粒。在许可疫苗中使用的包裹颗粒将受到抗体反应的保护，但由于抗原呈递细胞的摄取后内糖体的酸性pH值而迅速解开。在小鼠模型中将确定两种不同的疫苗接种策略的免疫原性。