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.

越来越多的人认识到IgG fc效应功能对HIV疫苗效力的重要性。尽管不同类型的疫苗被证明可以诱导具有不同fc活性的抗体，但目前还没有明确的策略来提高HIV-Env抗体反应，使其具有所需的fc效应功能模式。先前我们证明了对Env的抗体反应似乎是有偏见的，无论是在人类还是在小鼠中。具有th2移位表型的env特异性CD4+ t细胞是小鼠IgG1偏向的原因。基于我们之前的研究结果，我们提出探索两种新的HIV-1疫苗接种策略，这两种策略都基于多功能磷酸钙（CaP）纳米颗粒（NPs）。我们的目标是在t辅助细胞反应中绕过Env诱导的偏倚，并维持Env免疫原的天然三聚体结构，以提高对构象表位的抗体。工作计划包括一种新的双组分疫苗策略，其中第一个组分为诱导t辅助细胞反应而优化，而第二个组分则以正确的构象向b细胞提供Env免疫原。为了启动HIV-Env特异性t辅助细胞反应，我们建议将HIV-Env的线性合成肽与tlr配体一起封装在CaP纳米颗粒中，用于Th1 t细胞极化。cd11c靶向抗体的表面功能化可以引导这些NPs进入树突状细胞。为了靶向b细胞，我们的目标是开发和表征CaP NPs，这些NPs被构象稳定的可溶性HIV-1 env -spike定向包裹，并被tlr配体功能化。第二种疫苗接种策略包括募集异源Th细胞，这些细胞由一种常见的许可诱导，为env功能化的cap包裹病毒颗粒提供有效的基础结构帮助。许可疫苗中使用的包裹颗粒将免受抗体反应的影响，但在被抗原呈递细胞摄取后，由于内切溶酶体的酸性pH值，包裹颗粒会迅速解开。两种不同疫苗接种策略的免疫原性将在小鼠模型中确定。