Modulating durability of HIV-1 env specific humoral immunity with a novel TLR7/8 targeted formulation

用新型 TLR7/8 靶向制剂调节 HIV-1 包膜特异性体液免疫的持久性

• 批准号: 9205089
• 负责人: Sudhir Pai Kasturi
• 金额: $ 35万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-08 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9205089
• 关键词: AIDS Vaccines; ALVAC; Acquired Immunodeficiency Syndrome; Adjuvant; Agonist; Antibody Response; Antigens; B cell differentiation; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Blood; Bone Marrow; Cells; Clinic; Clinical; Communicable Diseases; Cyclic GMP; Emulsions; Evaluation; Failure; Formulation; Goals; HIV; HIV Antigens; HIV Envelope Protein gp120; HIV envelope protein; HIV vaccine; HIV-1; Helper-Inducer T-Lymphocyte; Housing; Human; Humoral Immunities; Immune response; Immunity; Immunologic Memory; In Vitro; Infectious Diseases Research; Intramuscular; Learning; Life; Ligands; Macaca; Macaca mulatta; Mediating; Molecular; Mus; Oils; Outcome; Pharmacologic Substance; Phase III Clinical Trials; Plasma Cells; Plasmablast; Polymers; Population; Proteins; Recombinants; Recruitment Activity; Research Institute; Route; Serinus; Serological; Signal Transduction; Skin; Smallpox; Structure of germinal center of lymph node; T-Lymphocyte; TLR4 gene; TLR7 gene; Time; Toll-like receptors; Translating; Translations; Vaccinated; Vaccination; Vaccine Adjuvant; Vaccines; Viral Vector; Virus; Work; Yellow Fever; aluminum sulfate; base; deep sequencing; design; improved; innovation; lymph nodes; nanoparticle; next generation; nonhuman primate; novel; novel vaccines; particle; pathogen; programs; prophylactic; protective effect; protective efficacy; receptor; response; scale up; subcutaneous; transcriptomics

One of the major obstacles to developing a HIV vaccine is defining adjuvants and immunogens that induce persistent HIV antigen specific systemic and mucosal humoral responses of high magnitude. Our recent studies evaluating a novel TLR7/8 ligand (3M052) from 3M Pharmaceuticals formulated in biodegradable synthetic polymer nanoparticles in RMs has for the first time yielded HIV Env specific long-lived plasma cells (LLPCs) in the macaque bone marrow for close to one year post final vaccination. The presence of LLPCs correlated significantly with binding, neutralizing and ADCC activity bearing antibody responses that also persisted at high magnitude for a year. Robust and persistent germinal center, follicular t helper cells and lymph node resident plasma cells were also observed in draining lymph nodes in these macaques. Finally, the persistent response was observed to be dependent on the presence of the novel 3M052 adjuvant alone and combining with a TLR4 agonist did not further enhance immune responses in contrast to our observations in mice. However, we have faced considerable challenges in translating our in house developed polymer particle formulations in industrial scale up for human use. Therefore, building on our proof of concept studies, the goal of the current proposal is to: a) systematically evaluate a clinical formulation (cGMP scalable oil emulsion based nanoparticle) developed in partnership with 3M pharmaceuticals and the Infectious Disease Research Institute (IDRI) in its ability to induce these potent Env specific LLPCs in macaques for expedited translation for use in humans and b) carefully dissect the innate and B cell based molecular mechanisms by which the 3M052 adjuvant is capable of promoting Env specific LLPCs and long lived antibody responses.

开发艾滋病毒疫苗的主要障碍之一是定义辅助和免疫原子，以诱导 持续的HIV抗原特异性全身性和粘膜体液反应。我们最近 评估来自3M药品的新型TLR7/8配体（3M052）的研究 RMS中的合成聚合物纳米颗粒首次产生HIV特定的长期浆细胞 （LLPC）在最终疫苗接种后在猕猴的骨髓中接近一年。 LLPC的存在 与结合，中和和ADCC活性具有显着相关的抗体反应 持续一年。稳健和持续的生发中心，卵泡T辅助细胞和 在这些猕猴中的排水淋巴结中，还观察到淋巴结常见的浆细胞。最后， 观察到持续反应取决于单独的3M052佐剂的存在，并且 与我们的观察结果相比，与TLR4激动剂结合并未进一步增强免疫反应 老鼠。但是，我们在翻译房屋开发的聚合物粒子方面面临着巨大的挑战 工业规模的配方供人使用。因此，以我们的概念研究证明为基础 当前的建议是：a）系统评估临床配方（CGMP可伸缩油乳液 基于纳米粒子）与3M药物和传染病研究合作开发 Institute（IDRI）能够在猕猴中诱导这些有效的ENV特定LLPC进行快速翻译 在人类中使用，b）仔细剖析了3M052的先天和B细胞分子机制 佐剂能够促进ENV特定的LLPC和长期生存的抗体反应。