Lymph node targeting nanoparticles for HIV Env proteins

淋巴结靶向 HIV 包膜蛋白纳米颗粒

• 批准号: 10681430
• 负责人: Jarrod Mousa
• 金额: $ 0.52万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-10 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10681430
• 关键词: Adjuvant; Animals; Antibodies; Antigen Presentation; Antigen-Antibody Complex; Antigens; Autologous; B-Lymphocytes; Benchmarking; Binding; Biocompatible Materials; Cells; Clinical Trials; Data; Dose; Drug Delivery Systems; Effectiveness; Encapsulated; Ensure; Epidemic; Epitope Mapping; Epitopes; Event; Formulation; Future; Goals; HIV; HIV Infections; HIV envelope protein; HIV vaccine; Homologous Protein; Human; Immune; Immune response; Immunization; Immunize; Immunoglobulin M; Immunoglobulin Somatic Hypermutation; Immunologics; Immunologist; Immunology procedure; Infection; Lymph Node Subcapsular Sinus; Macaca mulatta; Macrophage; Methods; Modeling; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mus; Oryctolagus cuniculus; Pathway interactions; Phase; Protein Engineering; Proteins; Recombinant Proteins; Recombinants; Research; Research Proposals; Scholars Program; Serology; Specificity; Structure of germinal center of lymph node; Surface; Technology; Testing; Time; Vaccinated; Vaccination; Vaccines; Viral; Virus; Virus Diseases; antiretroviral therapy; base; booster vaccine; clinical translation; draining lymph node; env Gene Products; ethylene glycol; glycosylation; high reward; high risk; human subject; immune activation; immunogenic; immunogenicity; improved; innovation; lymph nodes; mortality; nanomedicine; nanoparticle; neutralizing antibody; particle; prevent; response; scaffold; single cell sequencing; success; tool; trafficking; vaccine response; vaccine-induced antibodies

PROJECT SUMMARY With the advent of highly successful antiretroviral therapy, mortality and morbidity associated with human immunodeficiency virus (HIV) infection has been significantly reduced. Despite this, hundreds of thousands of new HIV infections occur each year, demonstrating the need for a safe and effective vaccine. HIV vaccines based on the elicitation of broadly neutralizing antibodies (bNAbs) are at the forefront of HIV research. Stabilized HIV immunogens have now shown the ability to elicit tier 2 neutralizing antibodies in rhesus macaques, and numerous bNAbs have been isolated from human subjects. Furthermore, germline targeting immunogens have demonstrated initial success in humans in eliciting bNAb germline precursors. A key aspect in the effectiveness of HIV immunogens is the delivery method. Somatic hypermutation is a critical event for optimal and efficient bNAb elicitation. Recombinant HIV Env proteins are poorly immunogenic and fail to follow typical lymph node (LN) trafficking pathways due to high glycosylation and poor recognition by natural IgM. Instead, recombinant HIV Env proteins are captured by interfollicular macrophages rather than by macrophages in the subcapsular sinus, leading to poor antigen availability and limited repeated somatic hypermutation. The scientific premise for this proposal is that since recombinant HIV Env proteins have altered LN trafficking, biodegradable LN targeting nanoparticles that facilitate transfer of soluble HIV Env trimers directly to LNs are a promising tool to circumvent current barriers. Our objective is to test the hypothesis that a lymph node (LN) targeting nanoparticle (NP) technology will improve immune responses generated by human immunodeficiency virus (HIV) envelope (Env) protein immunogens. This proposal is high risk, as the elicitation of broadly neutralizing antibodies (bNAbs) at a high titer and long duration is challenging; nonetheless, if successful, it offers high reward by substantially improving HIV Env vaccine responses. In Specific Aim 1, we will determine if PLGA-b-PEG NPs more efficiently deliver germline targeting immunogens to LN follicles and increase somatic hypermutation compared to unencapsulated immunogens. Mice will be immunized with germline targeting immunogen trimers encapsulated within the NP platform, and serological and cellular analysis will be completed, including monitoring of somatic hypermutation using single cell sequencing approaches. LN trafficking and accumulation in follicles will also be assessed. In Specific Aim 2, we will determine if co-encapsulation of diverse HIV Envs in NPs enhances elicitation of tier 2 neutralization breadth. HIV Env SOSIP trimers from two viral clades will be combined in a single NP, and serological responses will be assessed. This proposal is highly collaborative, combining Dr. Jarrod Mousa, a structural immunologist and HIV/AIDS Vaccine Scholars Program recipient, and Dr. Hai-Quan Mao, a biomaterials and nanomedicine expert. Our findings have high potential to dramatically improve HIV Env responses, and our findings will be applicable to the entire HIV vaccine field.

项目摘要 随着非常成功的抗逆转录病毒疗法的出现，与人相关的死亡率和发病率 免疫缺陷病毒（HIV）感染已大大降低。尽管如此，成千上万 每年都会发生新的HIV感染，表明需要安全有效的疫苗。 HIV疫苗 基于对广泛中和抗体（BNAB）的启发，是HIV研究的最前沿。稳定 HIV免疫原子现已显示出在恒河猕猴中中和抗体中和抗体的能力，并且 已经从人类受试者中分离出许多BNAB。此外，种系靶向免疫原具有 在引发BNAB种系前体中，在人类中表现出了最初的成功。有效性的关键方面 艾滋病毒免疫原是输送方法。躯体超誉是最佳有效的关键事件 BNAB启发。重组HIV ENV蛋白的免疫原性较差，无法遵循典型的淋巴结 （LN）由于天然IgM高糖基化和不良识别而导致的运输途径。相反，重组 HIV Env蛋白是由际巨噬细胞捕获的 鼻窦，导致抗原的可用性差，并且反复的体细胞超含力有限。科学前提 因为该提议是，由于重组HIV ENV蛋白已改变LN运输，因此可生物降解LN 靶向促进可溶性HIV Env Trimers直接转移到LNS的纳米颗粒是一种有前途的工具 规避当前障碍。我们的目的是检验靶向纳米颗粒的淋巴结（LN）的假设 （NP）技术将改善人类免疫缺陷病毒（HIV）信封产生的免疫反应 （ENV）蛋白质免疫原。该提议是高风险，因为引起广泛中和抗体 （bnabs）在高滴度和长时间的持续时间都具有挑战性；尽管如此，如果成功的话，它会提供高度的奖励 大大改善了HIV Env疫苗反应。在特定目标1中，我们将确定PLGA-B-PEG NPS是否 更有效地将靶向免疫原靶向LN卵泡的生殖线并增加体细胞超成熟 与未包容的免疫原子相比。小鼠将用靶向免疫原子的种系免疫 封装在NP平台内，将完成血清学和细胞分析，包括监视 使用单细胞测序方法的体细胞超成名。 LN贩运和卵泡中的积累 也将评估。在特定的目标2中，我们将确定NPS中各种HIV ENV的共同服为 增强了2层中和宽度的启发。将组合来自两个病毒进化枝的HIV Env SOSIP三聚体 在单个NP中，将评估血清学反应。该建议是高度协作的，结合了博士。 贾罗德·穆萨（Jarrod Mousa），结构性免疫学家和艾滋病毒/艾滋病疫苗学者计划的收件人，以及海夸博士 毛，生物材料和纳米医学专家。我们的发现具有很大的潜力，可以显着改善HIV Env 反应，我们的发现将适用于整个HIV疫苗领域。