Biomaterials and Nanovaccines

项目总结/摘要 开发一种能够引发保护性广泛中和抗体的疫苗将 需要开发改进的策略来控制包膜靶抗原的抗原性， 可以通过引发足够/适当的T细胞帮助来驱动高水平亲和力成熟的佐剂， 促进生发中心发育，并驱动长寿浆细胞和记忆B- 细胞获得持久的反应。该P01程序特别关注膜近端外部 gp 41的MPER区域（MPER）作为几种广泛中和抗体的验证靶标，包括最近的 发现了10 E8抗体，其表现出高效力而没有自身反应性的证据。协同 在Reinherz实验室（项目1），我们最近开发了一种脂质体疫苗平台， 疏水性的，膜相关的MPER片段，允许持久的，实质性的滴度针对这种差 免疫原性肽在正常小鼠中产生。基于这些有希望的初步数据和我们非常 最近发现脂质体表面抗原寡聚化状态在调节B细胞 触发，我们在这里提出了一套互补的策略，旨在控制抗原性， MPER序列免疫原性进一步增强了Tfh细胞发育和抗体亲和力成熟， 并促进体液反应的持久性。我们将与项目1密切合作， 脂质体疫苗和新型佐剂的需求，其结构为重点的研究，同时追求 深入了解抗原呈递、佐剂信号传导和T辅助细胞分化如何影响 诱导针对HIV的MPER序列的高亲和力抗体应答。我们的具体目标是：（1） 确定MPER寡聚化状态对MPER特异性B细胞和体液免疫识别的作用。 免疫，（2）测试控制抗体接近MPER序列角度的策略 （3）开发新的淋巴结靶向佐剂，触发STING 有效的干扰素驱动的体液应答的途径，和（4）测试直接调节的新佐剂 辅助性T细胞中的信号传导途径以促进Tfh分化和生发中心诱导。当 结合项目1中追求的结构进步，我们的目标是通过以下方式引发广泛中和抗体： 以正确的构型呈现MPER序列以及适当的辅助信号， 促进MPER特异性B细胞的引发和亲和力成熟。

Project Summary/Abstract The development of a vaccine capable of eliciting protective broadly neutralizing antibodies against HIV will require the development of improved strategies to control the antigenicity of envelope target antigens and adjuvants that can drive high levels of affinity maturation by eliciting sufficient/appropriate T-cell help, promoting germinal center development, and drive differentiation of long-lived plasma cells and memory B- cells to obtain a durable response. This P01 program focuses particularly on the membrane-proximal external region (MPER) of gp41 as a validated target for several broadly neutralizing antibodies, including the recently discovered 10E8 antibody that exhibits high potency without evidence of autoreactivity. In collaboration with the Reinherz lab (Project 1), we have recently developed a liposomal vaccine platform for delivery of hydrophobic, membrane-associated MPER fragments that allows durable, substantial titers against this poorly immunogenic peptide to be raised in normal mice. Building on this promising preliminary data and our very recent discoveries regarding the role of antigen oligomerization state on liposome surfaces in regulating B-cell triggering, we propose here a set of complementary strategies aiming to control the antigenicity and immunogenicity of MPER sequences, further enhance Tfh cell development and antibody affinity maturation, and promote humoral response durability. We will work in close collaboration with Project 1, providing liposomal vaccines and novel adjuvants on demand for their structure-focused studies, while pursuing a deeper understanding of how antigen presentation, adjuvant signaling, and T helper cell differentiation impact induction of high-affinity antibody responses against the MPER sequence of HIV. Our specific aims are (1) To determine the role of MPER oligomerization state on recognition by MPER-specific B-cells and humoral immunity, (2) To test strategies for controlling the angle of approach of antibodies to MPER sequences displayed on liposomal vectors, (3) To develop novel lymph node targeted adjuvants triggering the STING pathway for potent interferon-driven humoral responses, and (4) To test novel adjuvants directly modulating signaling pathways in helper T-cells to promote Tfh differentiation and germinal center induction. When combined with the structural advances pursued in Project 1, we aim to elicit broadly neutralizing antibodies by presenting MPER sequences in a correct configuration together with appropriate adjuvant signals that will promote the priming and affinity maturation of MPER-specific B-cells.