Design and optimization of DL-NLTs and molecular adjuvants to increase potency and promote NAb formation in vivo

DL-NLT 和分子佐剂的设计和优化，以提高效力并促进体内 NAb 形成

• 批准号: 10589587
• 负责人: DAVID B. WEINER
• 金额: $ 142.76万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-08 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589587
• 关键词: Adjuvant; Antibodies; Antibody Response; Antigens; Apical; Automobile Driving; B-Lymphocytes; Benchmarking; Binding Sites; CCL27 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Lineage; Cells; Cellular Immunity; Clinic; Clinical; Clinical Trials; Complex; Conceptions; DNA; DNA Vaccines; Development; Dose; Epitopes; Evaluation; Formulation; Frequencies; Genetic; Goals; HIV; HIV Vaccine Trials Network; HIV vaccine; HIV-1; HIV-1 vaccine; Human; Humoral Immunities; Immune response; Immunity; Immunization; Interleukin-12; Knock-in Mouse; Laboratories; Mediating; Molecular; Mucous Membrane; Mus; Plasmids; Population; Property; Regimen; Reporting; Selection Criteria; Surface; T cell response; T-Lymphocyte; Tissues; Vaccinated; Vaccines; design; effector T cell; immune function; immunogenicity; in vivo; interleukin-21; nanoparticle; neutralizing antibody; novel; programs; response; self assembly; synthetic construct; vaccine candidate; vaccine-induced immunity

Project 1 Summary Extensive efforts have been carried out over the years to design a HIV-1 vaccine candidate which elicits robust immune responses supporting broad neutralization and effector T cell responses. Recently the Weiner and Kulp laboratories reported the development of novel DNA-launched, in vivo, self-assembling immunogens, including both DNA launched native like trimers (DL-NLTs) and DNA-launched nanoparticle immunogens (DLNPs). Both DNA launched NLTs and NPs assemble and display appropriate epitopes for neutralizing antibodies while occluding epitopes for non-neutralizing antibodies in vivo. Additionally, they drive robust T cell immunity. These vaccine candidates are being moved to the clinic under studies HVTN-304 and HVTN-305. synDNA facilitates rapid immunogen design, co-delivery of molecular adjuvants, supports expression and assembly of complex structural antigens in vivo, has a safe clinical track record, and maintains boost-ability. Building on progress from our previous IPCAVD, combining these designs, we will be working with Dr. Kulp under Project 2 to formulate DLNPs bearing NLTs displaying Apex and CD4 binding-site B cell lineage targeting Epitopes (DLNP-ACEs). Furthermore, we have designed and characterized several synDNA-encoded molecular adjuvants to support enhanced humoral immunity, cell-mediated immunity, and direct antigen-specific responses to mucosal surfaces. The overarching goal of Project 1 is to combine these novel immunogens with DNA-delivered genetic adjuvant combinations and/or heterologous adjuvant regimens, in dual expressing plasmids developed with Project 3 to support vaccine-induced immunity and represents a great leap forward in the design of HIV-1 vaccines.

项目1摘要 多年来，已经进行了广泛的努力，以设计HIV-1疫苗候选者 引起支持广泛中和和效应T细胞反应的强大免疫反应。 最近，韦纳（Weiner）和库尔普（Kulp）实验室报告了新型DNA启动的发展， 体内，自组装免疫原，包括两个DNA都启动了像三聚体（DL-NLTS） 和DNA推出的纳米颗粒免疫原（DLNP）。 DNA都启动了NLT和NP 组装并显示适当的表位，以中和抗体，同时阻塞表位 用于体内的非中和抗体。此外，它们驱动稳健的T细胞免疫力。这些 根据研究HVTN-304和HVTN-305，候选疫苗的候选物正在转移到诊所。 SynDNA促进了快速的免疫原设计，分子佐剂的共同传递，支持 体内复杂结构抗原的表达和组装具有安全的临床记录， 并保持增强性。以我们以前的IPCAVD的进展为基础 设计，我们将在项目2下与Kulp博士合作，以制定NLT的DLNP 显示顶点和CD4结合位点B细胞谱系靶向表位（DLNP-aces）。 此外，我们设计并表征了几个联合编码的分子佐剂 为了支持增强的体液免疫，细胞介导的免疫和直接抗原特异性 对粘膜表面的反应。项目1的总体目标是结合这些小说 具有DNA传递的遗传佐剂组合和/或异源佐剂的免疫原子 在用项目3开发的双重表达质粒中，方案以支持疫苗诱导的 免疫力，代表了HIV-1疫苗设计中的巨大飞跃。