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.

项目摘要 该R01提案的目标包括疫苗佐剂的分子和免疫特征 与干扰素基因蛋白刺激剂介导的过程相关的活性（STING）。疫苗 由惰性抗原组成通常仅是弱免疫原性，因此需要佐剂的共同给药 增加免疫刺激。不幸的是，很少有佐剂被批准用于临床用途和 辅助相关增强的机制知之甚少。刺是一种模式识别 检测由细菌循环酶或 宿主循环GMP-AMP（CGAMP）合酶（CGAS）在感知胞质DNA后。 如抗体和细胞介导 保护多种微生物病原体。此外，内源合成的CGAMP自然是 从外泌体和病毒颗粒中释放出来。我们通过构建细胞系来利用这种现象 然后，我们用来产生免疫原性病毒样颗粒（VLP）的组成型活性循环酶。 现在，我们证明，来自无关的新兴黄麻和α病毒的VLP有效地封装了生物活性 CDN并刺激体内刺激依赖性活性。由于细胞外CDN非常容易受到 从注射部位迅速退化和分散，我们假设这种简单的方法代表 用于利用sting指导的佐剂效应的变革性技术改进 淋巴结。我们还预测，这将是一个高度适应的平台，并建议探索多大程度上 它适用于潜在的新兴病毒类型。在实验上，这也代表了一个独特的调查 将允许体内表征自适应免疫的先天和分子相关性的模型 通过靶向刺激活性增强。因此，我们假设增强抗原指导的免疫 通过基于STING的佐剂的反应在功能上与关键分子和细胞过程有关 可以使用我们建议的疫苗和实验系统来辨别。我们计划使用集成的 使用分子转录组分析，免疫分析的小鼠模型和非人类的方法 我们小组设计的病毒生长和保护性免疫力的灵长类动物模型。