Novel nanoparticulate adjuvants to enhance HIV-1 Env specific mucosal antibody responses

新型纳米颗粒佐剂增强 HIV-1 Env 特异性粘膜抗体反应

基本信息

批准号：
10657401
负责人：
Sudhir Pai Kasturi
金额：
$ 88.28万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-03 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10657401
关键词：
Address Adjuvant Adsorption Affinity Agonist Animals Antibodies Antibody Affinity Antibody Response Antigens B-Lymphocytes B-cell receptor repertoire sequencing Binding Bone Marrow Cells Clinic Clinical Collaborations Color Disease Flow Cytometry Formulation Frequencies Gene Expression Profile Genes Genital Genitalia HIV-1 HIV-1 vaccine Helper-Inducer T-Lymphocyte Human Immune Immune response Immunity Immunoglobulin G Immunoglobulins Immunologics Industrialization Infection Infection Control Infectious Diseases Research Investigation Knowledge Ligands Link Lymph Node Drainage Macaca Macaca mulatta Manuscripts Methodology Molecular Mucosal Immunity Mucous Membrane Outcome Pharmacologic Substance Plasma Cells Pre-Clinical Model Preparation Proteomics Rectum Reporting Research Institute Resolution Safety Secretory Immunoglobulin A Serum Source Structure of germinal center of lymph node T-Lymphocyte TLR7 gene Testing Time Toll-like receptors Vaccination Vaccine Clinical Trial Vaccines Viral Virus Work aluminum sulfate clinically relevant cost effective design draining lymph node env Gene Products experience improved innovation insight lymph nodes manufacturability nano nanoparticle nanoparticulate nanopolymer neutralizing antibody nonhuman primate novel preclinical study prevent protective efficacy rectal response simian human immunodeficiency virus subcutaneous synergism transcriptome sequencing vaccination strategy vaccine candidate vaccine evaluation vaccine response

项目摘要

Abstract One of the key obstacles to developing an effective HIV-1 vaccine is identifying adjuvants and immunogens that induce persistent HIV-1 envelope (Env) antigen specific antibody responses of high magnitude. Alum has been the choice of adjuvant for use in humans for almost a century now and also used in most HIV-1 vaccine clinical trials. However, Alum fails to induce persistent HIV-1 Env specific antibody responses of the appropriate quality (neutralizing activity or effector functions). Nanoparticulate adjuvants are known to enhance immune responses by rapidly draining and targeting key immune cells in lymph nodes. Our recently completed studies evaluating a novel TLR-7/8 ligand (3M-052) from 3M Pharmaceuticals by itself or in combination with a TLR-4 agonist GLA formulated in biodegradable synthetic polymer nanoparticles in rhesus macaques has for the first time successfully induced HIV-1 Env specific long-lived plasma cells (LLPCs) in the bone marrow. Robust and persistent antibody responses with binding, neutralizing and ADCC activity were also observed at high magnitude in addition to high frequencies of germinal center B cells and follicular T helper cells in draining lymph nodes. However, our polymer nanoparticles have faced challenges with manufacturability for use in humans. Hence, building on our proof of concept studies, in collaboration with the Infectious Disease Research Institute (IDRI) and 3M Pharmaceuticals, we now propose to a) evaluate a NanoAlum, novel clinically relevant Alum based nanoparticulate adjuvant with HIV-1 Env immunogens in combination with the 3M-052 molecule, b) establish new methodology that uses novel serum proteomics and BCR sequencing to rigorously investigate vaccine induced responses by defining key subsets of LLPCs in RMs and finally c) evaluate vaccine based protective efficacy upon virus challenge when combining sub-cutaneous vaccinations with such new adjuvants with intranasal vaccinations (IN) to improve mucosal immunity at genital mucosa.

抽象的开发有效的HIV-1疫苗的关键障碍之一是识别佐剂和免疫原子诱导持续的HIV-1包膜（ENV）抗原特异性抗体反应。明矾一直是现在将佐剂在人类中使用了将近一个世纪，也用于大多数HIV-1疫苗临床试验。但是，明矾无法诱导适当质量的持续性HIV-1 ENV特定抗体反应（中和活性或效应子功能）。已知纳米尖锐佐剂可以增强免疫反应通过快速排水和靶向淋巴结中的关键免疫细胞。我们最近完成的研究评估了来自3M Pharmaceuticals的新型TLR-7/8配体（3M-052）本身或与TLR-4激动剂GLA组合在恒河猕猴中的可生物降解合成聚合物纳米颗粒中配制成功诱导了骨髓中的HIV-1 ENV特异性长浆细胞（LLPC）。坚固和还观察到具有结合，中和和ADCC活性的持续性抗体反应除了发芽中心B细胞的高频率和排水淋巴中的滤泡T辅助细胞外节点。但是，我们的聚合物纳米颗粒面临着在人类中的生产性的挑战。因此，基于我们的概念研究证明，与传染病研究所合作（IDRI）和3M药品，我们现在建议a）评估纳米，新型临床相关明矾基于HIV-1 ENV免疫原的纳米核心佐剂与3M-052分子相结合，B）建立使用新型血清蛋白质组学和BCR测序进行严格研究的新方法疫苗通过在RMS中定义LLPC的关键子集并最终c）评估疫苗基于疫苗将皮下疫苗接种与这种新佐剂相结合时，对病毒挑战的保护效果鼻内疫苗接种（IN）可改善生殖器粘膜的粘膜免疫。