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确定诱导的佐剂和免疫原 持续的高强度的 HIV 抗原特异性全身和粘膜体液反应。我们最近的 研究评估 3M Pharmaceuticals 的新型 TLR7/8 配体 (3M052)，采用可生物降解配方配制 RMs中的合成聚合物纳米粒子首次产生了HIV包膜特异性长寿命浆细胞 最终疫苗接种后，（LLPC）在猕猴骨髓中保存了近一年。有限责任公司的存在 与带有抗体反应的结合、中和和 ADCC 活性显着相关， 持续了一年的高强度。强大且持久的生发中心、滤泡 T 辅助细胞和 在这些猕猴的引流淋巴结中也观察到了淋巴结驻留浆细胞。最后， 据观察，持续反应依赖于单独使用新型 3M052 佐剂，并且 与我们的观察结果相反，与 TLR4 激动剂结合并没有进一步增强免疫反应 老鼠。然而，我们在转化我们内部开发的聚合物颗粒时面临着相当大的挑战 工业规模的制剂可供人类使用。因此，在我们的概念验证研究的基础上，目标 当前提案的目的是： a) 系统地评估临床制剂（cGMP 可扩展油乳剂 基于纳米粒子）与 3M 制药公司和传染病研究中心合作开发 研究所 (IDRI) 能够在猕猴中诱导这些有效的 Env 特异性 LLPC，以加快翻译速度 b) 仔细剖析 3M052 的先天分子机制和基于 B 细胞的分子机制 佐剂能够促进 Env 特异性 LLPC 和长效抗体反应。