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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结