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.

项目概要 随着非常成功的抗逆转录病毒疗法的出现，与人类相关的死亡率和发病率 免疫缺陷病毒（HIV）感染已显着减少。尽管如此，仍有数十万 每年都会出现新的艾滋病毒感染，这表明需要安全有效的疫苗。艾滋病毒疫苗 基于广泛中和抗体（bNAb）的引发处于艾滋病毒研究的前沿。稳定化 HIV 免疫原现已显示出能够在恒河猴中引发 2 级中和抗体，并且 已从人类受试者中分离出大量 bNAb。此外，种系靶向免疫原 在人类体内诱导 bNAb 种系前体方面取得了初步成功。有效性的一个关键方面 HIV免疫原的传递方法是。体细胞超突变是优化和高效的关键事件 bNAb 诱导。重组 HIV Env 蛋白的免疫原性很差，无法跟随典型的淋巴结 (LN) 运输途径由于高糖基化和天然 IgM 的识别能力较差。相反，重组 HIV Env 蛋白被滤泡间巨噬细胞而不是被膜下巨噬细胞捕获 窦，导致抗原可用性差和有限的重复体细胞超突变。科学前提 该提案的理由是，由于重组 HIV Env 蛋白改变了 LN 运输，因此可生物降解的 LN 靶向纳米颗粒可促进可溶性 HIV 包膜三聚体直接转移至 LN，是一种很有前途的工具 规避当前的障碍。我们的目标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) 包膜产生的免疫反应 (Env) 蛋白质免疫原。该提议具有高风险，因为会引发广泛中和抗体 (bNAb) 的高滴度和长持续时间具有挑战性；尽管如此，如果成功的话，它会提供高额奖励 显着改善 HIV Env 疫苗反应。在具体目标 1 中，我们将确定 PLGA-b-PEG NP 是否 更有效地将种系靶向免疫原递送至淋巴结滤泡并增加体细胞超突变 与未封装的免疫原相比。将用种系靶向免疫原三聚体对小鼠进行免疫 封装在NP平台内，将完成血清学和细胞分析，包括监测 使用单细胞测序方法进行体细胞超突变。液氮在卵泡中的运输和积累 也将受到评估。在具体目标 2 中，我们将确定是否将不同的 HIV 包膜共同封装在 NP 中 增强 2 级中和广度的激发。来自两个病毒进化枝的 HIV Env SOSIP 三聚体将被组合 在单个 NP 中，将评估血清学反应。该提案是高度协作的，结合了 Dr. Jarrod Mousa，结构免疫学家和艾滋病疫苗学者计划获得者，和海泉博士 毛先生，生物材料和纳米医学专家。我们的研究结果具有显着改善 HIV 环境的巨大潜力 反应，我们的研究结果将适用于整个艾滋病毒疫苗领域。