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.

IgG Fc效应子功能对于HIV疫苗功效的重要性日益被认识到。虽然不同类型的疫苗显示诱导具有不同Fc活性的抗体，但没有明确的策略如何提高具有所需Fc效应子功能模式的HIV-Env抗体应答。先前我们证明了对Env的抗体反应似乎是有偏差的，在人类和小鼠中都是如此。而具有Th 2移位表型的Env特异性CD 4 + T细胞负责小鼠中的IgG 1偏倚。基于我们以前的研究结果，我们建议探索两种新的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（NP）。我们的目标是绕过Env诱导的T辅助细胞反应的偏差，并保持天然的Env免疫原的三聚体结构，需要提高抗体的构象表位。该工作计划包括一种新的双组分疫苗策略，其中第一组分被优化用于诱导T辅助细胞应答，而第二组分将Env免疫原以正确的构象呈递给B细胞。为了引发HIV-Env特异性T辅助细胞应答，我们提出将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Th 1 T细胞极化。用CD 11 c靶向抗体的表面功能化应该引导这些NP到树突细胞。为了靶向B细胞，我们的目标是开发和表征CaP NP，其定向涂覆有构象稳定的可溶性HIV-1 Env-刺突，并在内部用TLR-配体官能化。第二种疫苗接种策略包括募集由共同许可的诱导的异源Th细胞，以为Env官能化的CaP包裹的病毒颗粒提供有效的结构内帮助。许可疫苗中使用的包裹颗粒将被保护免受抗体应答，但由于抗原呈递细胞摄取后内溶酶体中的酸性pH，包裹颗粒会迅速解开。将在小鼠模型中测定两种不同疫苗接种策略的免疫原性。