Lymph node-targeted delivery of HIV vaccine candidates

HIV 候选疫苗的淋巴结靶向递送

• 批准号: 10011559
• 负责人: Geraldine Goebrecht
• 金额: $ 2.89万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-07-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011559
• 关键词: Affinity; Antibodies; Antibody Formation; Antibody Repertoire; Antibody Response; Antigen Presentation; Antigen Targeting; Antigens; Area; B-Cell Activation; B-Cell Development; B-Lymphocytes; Binding; Bolus Infusion; CD4 Positive T Lymphocytes; Cell Compartmentation; Cells; Characteristics; Clinical; Coculture Techniques; Complement; Complement 3d Receptors; Complex; Confocal Microscopy; Dendritic Cells; Development; Encapsulated; Endocytosis; Epitopes; Flow Cytometry; Follicular Dendritic Cells; Formulation; Generations; Glycoproteins; Goals; HIV; HIV Antigens; HIV vaccine; Helper-Inducer T-Lymphocyte; Immune response; Immunization; Immunization Schedule; Immunoglobulin Somatic Hypermutation; Immunoliposome; Infection; Link; Liposomes; Membrane; Membrane Glycoproteins; Memory; Oryctolagus cuniculus; Particulate; Phenotype; Population; Preventive vaccine; Production; Proteins; Role; Sampling; Serum; Structure; Structure of germinal center of lymph node; Surface; Techniques; Vaccine Design; Vaccines; Virus; Work; XCR1 gene; design; flexibility; global health; glycosylation; humanized mouse; improved; in vivo; in vivo imaging; lymph nodes; lymphoid organ; neutralizing antibody; nonhuman primate; receptor; release of sequestered calcium ion into cytoplasm; response; sample fixation; secondary infection; secondary lymphoid organ; targeted delivery; trafficking; uptake; vaccine candidate; vaccine development

PROJECT SUMMARY/ABSTRACT There is a critical need for a preventative vaccine against human immunodeficiency virus (HIV). Despite continued structural refinement, immunization with soluble HIV envelope glycoprotein (Env) trimer has yet to elicit the desired broadly neutralizing antibodies (bNabs). This delay may in part be due to the inefficient delivery of Env trimer to the follicles of secondary lymphoid organs. The heavy glycosylation of Env, poor complement fixation, and instability in sera all contribute to inefficient trafficking. Previous work to array Env trimer on the surface of liposomes has revealed improved antibody responses following immunization. Here we seek to target Env-displaying liposomes to relevant cell populations native to the lymph node follicle with the goal of increased neutralizing antibody production. We hypothesize that improved targeting of Env trimer to the lymph node will bias the antibody repertoire towards neutralizing phenotypes. This will be accomplished by targeting liposome-bound Env trimer to the two cell populations directing germinal center (GC) B cell affinity maturation. First, the antigen reservoir of follicular dendritic cells will be targeted, allowing for continual exposure of GC B cells to neutralizing epitopes. During natural infection, sustained antigen presentation to GC B cells has been shown to stimulate somatic hypermutation, affinity maturation, and the development of unusually long heavy chain complementary determining region 3 (HCDR3), characteristic of bNabs. Second, antigen-specific cognate T follicular helper (Tfh) cell populations will be increased by targeting immunogen to CLEC9A+XCR1+ dendritic cells, responsible for activating Tfh cells. Previous work has shown that a large Tfh cell population may reduce competition between neutralizing and non-neutralizing epitope-specific B cells, favoring the development of neutralizing antibodies. Aim 1 focuses on the delivery of intact Env trimer to the follicular dendritic cell antigen reservoir, while Aim 2 looks to target delivery to CLEC9A+XCR1+ dendritic cells with the goal of expanding the antigen specific Tfh cell population. The final Aim looks to characterize the Tfh and B cell response to immunization with each targeting approach alone and in combination. If successful, this work will provide a flexible platform for targeted antigen delivery capable of boosting neutralizing antibody production against HIV. !

项目摘要/摘要 迫切需要一种针对人类免疫缺陷病毒(HIV)的预防性疫苗。尽管 继续进行结构优化，用可溶性HIV包膜糖蛋白(Env)三聚体免疫尚未 诱导所需的广谱中和抗体(BNAb)。这种延迟可能在一定程度上是由于交付效率低下 Env三聚体对次级淋巴器官滤泡的影响。包膜蛋白糖基化严重，补体贫乏 凝固性和血清中的不稳定性都导致了低效的贩运。之前对阵列环境三聚体所做的工作 脂质体表面的抗体反应在免疫后有所改善。在这里，我们试图将目标 向淋巴滤泡固有的相关细胞群展示包膜脂质体，目的是增加 中和抗体的产生。我们假设，改进的Env三聚体对淋巴的靶向将 使抗体谱系偏向于中和表型。 这将通过将脂质体结合的Env三聚体靶向引导生发的两个细胞群来实现 中心(GC)B细胞亲和力成熟。首先，毛囊树突状细胞的抗原库将成为目标， 允许GC B细胞持续暴露于中和表位。在自然感染期间，持续抗原 呈递给GC B细胞已被证明可以刺激体细胞的超突变、亲和力成熟和 超长重链互补决定区3(HCDR3)的开发 BNAbs。其次，抗原特异性同源T滤泡辅助细胞(TFH)细胞群将通过靶向增加 免疫基因为CLEC9A+XCR1+树突状细胞，负责激活TFH细胞。先前的研究表明， 大量的TFH细胞群可能会减少中和和非中和表位特异性B之间的竞争 细胞，有利于中和抗体的产生。目标1重点是将完整的环境三聚体交付到 滤泡树突状细胞抗原库，而AIM 2着眼于靶向CLEC9A+XCR1+树突状细胞 目的是扩大抗原特异的TFH细胞群。最终的目标是描述TFH的特征 和B细胞对免疫的反应，每种靶向方法单独和联合使用。如果成功，这将是 这项工作将为靶向抗原传递提供一个灵活的平台，能够增强中和抗体 针对艾滋病毒的生产。 好了！