A Self-Adjuvanting Virus Like Particle Vaccine Platform for Emerging Viruses

针对新兴病毒的自我佐剂病毒样颗粒疫苗平台

• 批准号: 10711617
• 负责人: VICTOR Robert DEFILIPPIS
• 金额: $ 76.76万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-08 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711617
• 关键词: Acceleration; Address; Adjuvant; Alphavirus; Animals; Antibodies; Antigen-Presenting Cells; Antigens; Arboviruses; Biological; Cell Line; Cell physiology; Cells; Cellular Immunity; Chemicals; Chikungunya virus; Clinical; Cyclic GMP; DNA; Dinucleoside Phosphates; Disparity; Encapsulated; Enzymes; Exhibits; Flavivirus; Genes; Genome; Goals; Growth; Human; Immune; Immune response; Immune signaling; Immunity; Immunologic Stimulation; Immunological Models; Immunologics; Immunotherapeutic agent; In Vitro; Injections; Innate Immune Response; Ligands; Link; Macaca mulatta; Mammals; Mediating; Methods; Microbe; Modeling; Molecular; Mus; Outcome; Pattern recognition receptor; Periodicity; Phenotype; Predisposition; Process; Proteins; Purines; RNA; Reaction; Role; Safety; Signaling Protein; Site; Stimulator of Interferon Genes; Structure; System; Technology; Vaccination; Vaccine Adjuvant; Vaccines; Viral; Virion; Virus; Virus Replication; Virus-like particle; Zika Virus; adaptive immune response; adaptive immunity; clinical development; draining lymph node; efficacy evaluation; exosome; extracellular; gene induction; immune function; immunogenic; immunoregulation; improved; in vitro Model; in vivo; in vivo Model; mouse model; nonhuman primate; novel; novel vaccines; pathogenic microbe; pharmacologic; recruit; response; small molecule; transcriptomics; vaccination outcome; vaccine efficacy; vaccine platform

Project Summary The goals of this R01 proposal include the molecular and immunological characterization of vaccine adjuvant activity associated with processes mediated by the protein Stimulator of Interferon Genes (STING). Vaccines comprised of inert antigen are often only weakly immunogenic and thus require co-administration of adjuvants to augment immunostimulation. Unfortunately, very few adjuvants are approved for clinical use and the mechanisms of adjuvant-associated enhancement are poorly understood. STING is a pattern recognition receptor that detects purine-containing cyclic dinucleotides (CDN) synthesized by either bacterial cyclases or the host enzyme cyclic GMP-AMP (cGAMP) synthase (cGAS) following its sensing of cytosolic DNA. Pharmacologic activation of STING greatly enhances vaccine efficacy as indicated by antibody and cell-mediated protection against diverse microbial pathogens. Furthermore, endogenously synthesized cGAMP is naturally released from cells in exosomes and virus particles. We exploited this phenomenon by constructing cell lines that express constitutively active cyclases that we then used to produce immunogenic virus-like particles (VLP). We now show that VLP derived from unrelated emerging flavi- and alphaviruses efficiently encapsulate bioactive CDN and stimulate STING-dependent activity in vivo. Since extracellular CDNs are highly susceptible to degradation and disperse quickly from the site of injection, we hypothesize that this simple approach represents a transformative technological improvement for harnessing STING-directed adjuvant effects in the draining lymph node. We also predict this will be a highly adaptable platform and propose to explore the extent to which it is applicable to potentially emerging virus types. Experimentally, this also represents a unique investigative model that will allow in vivo characterization of the innate and molecular correlates of adaptive immunity that are potentiated by targeted STING activity. We thus hypothesize that the enhancement of antigen-directed immune responses by STING-based adjuvants is functionally linked to key molecular and cellular processes that are discernable using our proposed vaccines and experimental systems. We plan to explore this using an integrated approach that uses molecular transcriptomic analysis, mouse models of immune profiling, and nonhuman primate models of viral growth and protective immunity devised by our group.

项目概要 该 R01 提案的目标包括疫苗佐剂的分子和免疫学表征 与干扰素基因刺激蛋白 (STING) 介导的过程相关的活性。疫苗 由惰性抗原组成的免疫原性通常较弱，因此需要同时施用佐剂 以增强免疫刺激。不幸的是，很少有佐剂被批准用于临床，并且 佐剂相关的增强机制尚不清楚。 STING 是一种模式识别 检测由细菌环化酶或合成的含嘌呤的环状二核苷酸（CDN）的受体 宿主酶环 GMP-AMP (cGAMP) 合酶 (cGAS) 感知胞质 DNA。 抗体和细胞介导的结果表明，STING 的药理学激活大大增强了疫苗功效 抵御多种微生物病原体。此外，内源合成的 cGAMP 是天然的 从外泌体和病毒颗粒中的细胞中释放出来。我们通过构建细胞系来利用这种现象 表达组成型活性环化酶，然后我们用它来产生免疫原性病毒样颗粒（VLP）。 我们现在表明，源自不相关的新兴黄病毒和甲病毒的 VLP 有效地封装了生物活性 CDN 并刺激体内 STING 依赖性活性。由于细胞外 CDN 非常容易受到 降解并从注射部位快速分散，我们假设这种简单的方法代表 利用 STING 引导的引流辅助效应的革命性技术改进 淋巴结。我们还预测这将是一个高度适应性的平台，并建议探索在多大程度上 它适用于潜在新出现的病毒类型。在实验上，这也代表了一种独特的调查 该模型将允许体内表征适应性免疫的先天和分子相关性 通过针对性的 STING 活动增强。因此，我们假设抗原定向免疫的增强 基于 STING 的佐剂的反应在功能上与关键分子和细胞过程相关 使用我们提出的疫苗和实验系统可以辨别。我们计划使用集成的 使用分子转录组分析、免疫分析小鼠模型和非人类 我们小组设计的病毒生长和保护性免疫的灵长类动物模型。