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.

人们越来越认识到 IgG Fc 效应子功能对于 HIV 疫苗功效的重要性。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如何提高具有所需 Fc 效应器功能模式的 HIV-Env 抗体反应。之前我们证明，无论是在人类还是在小鼠中，对 Env 的抗体反应似乎都是有偏差的。具有 Th2 转变表型的 Env 特异性 CD4+ T 细胞是小鼠中 IgG1 偏倚的原因。根据我们之前的结果，我们建议探索两种新型 HIV-1 疫苗接种策略，两者均基于多功能磷酸钙 (CaP) 纳米颗粒 (NP)。我们的目标是绕过 T 辅助细胞反应中 Env 诱导的偏差，并维持产生针对构象表位的抗体所需的 Env 免疫原的天然三聚体结构。该工作计划包括一种新型双组分疫苗策略，其中第一个组分针对诱导 T 辅助细胞反应进行了优化，而第二个组分则将 Env 免疫原以正确的构象呈现给 B 细胞。为了引发 HIV-Env 特异性 T 辅助细胞反应，我们建议将 HIV-Env 的线性合成肽与用于 Th1 T 细胞极化的 TLR 配体一起封装在 CaP 纳米颗粒中。 CD11c 靶向抗体的表面功能化应引导这些 NP 到达树突状细胞。为了靶向 B 细胞，我们的目标是开发和表征 CaP NP，定向包被有构象稳定的可溶性 HIV-1 Env-spike，并在内部用 TLR 配体进行功能化。第二种疫苗接种策略包括招募由通用许可诱导的异源 Th 细胞，为 Env 功能化的 CaP 包裹的病毒颗粒提供有效的内部结构帮助。许可疫苗中使用的包裹颗粒将受到保护，免受抗体反应，但由于抗原呈递细胞摄取后内溶酶体的酸性 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。