Alu dsRNAs as adjuvants for influenza vaccines

Alu dsRNA 作为流感疫苗佐剂

• 批准号: 10605272
• 负责人: Thomas M. Aune
• 金额: $ 25.34万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-07 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605272
• 关键词: Adaptive Immune System; Address; Adjuvant; Agonist; Alu Elements; Antigens; Attenuated Live Virus Vaccine; Attenuated Vaccines; Autoantigens; Autoimmune; Autoimmune Diseases; B-Cell Antigen Receptor; B-Lymphocytes; Cause of Death; Cell Differentiation process; Cellular Immunity; Chemical Structure; Clinical; Clinical Trials; Clonal Expansion; Communicable Diseases; Complex; Dendritic Cells; Disease; Double-Stranded RNA; Elements; Emulsions; Eukaryotic Cell; Exhibits; Formulation; Gene Chips; Gene Expression; Generations; Genes; Genetic Transcription; Human; I Kappa B-Alpha; Immune response; Immune system; Immunity; Immunization; Immunologic Memory; In Vitro; Inactivated Vaccines; Infection; Inflammatory; Inflammatory Response; Influenza; Influenza vaccination; Innate Immune Response; Innate Immune System; Interferon Type I; Interferons; Longevity; Macrophage; Medical; Minerals; Molecular; Multiple Sclerosis; Mus; Natural Immunity; Nuclear; Nucleic Acids; Oils; Patients; Pattern; Pattern recognition receptor; Play; Production; Property; Proteins; RNA; Relapsing-Remitting Multiple Sclerosis; Research; Role; Safety; Salts; Signal Pathway; Signal Transduction; Sodium Chloride; Subunit Vaccines; T-Lymphocyte; TLR3 gene; TLR4 gene; Testing; Toxic effect; Vaccination; Vaccine Adjuvant; Vaccines; Validation; Viral Proteins; Viral Vaccines; Virus Diseases; Water; Work; adaptive immune response; aluminum sulfate; arm; clinically relevant; combat; cost; design; gene induction; immunogenicity; improved; in vivo; influenza virus vaccine; influenzavirus; nanoparticle; novel; novel vaccines; nucleic acid detection; pathogen; pre-clinical; prevent; response; sensor; success; systemic inflammatory response; systemic toxicity; tool; tumor; vaccine delivery; vaccine efficacy

Despite medical progress, infectious diseases remain one of the leading causes of death worldwide. Vaccines are one of the most effective tools to prevent infectious diseases. Generation of immunity has two components. The first is the unique chemical structure of the antigen recognized by T and B cell receptors allowing clonal expansion and differentiation of cells of the adaptive immune system. The second is a ‘danger signal’ that stimulates the innate immune system via pattern recognition receptors (PRRs) that recognize conserved pathogen-associated molecular patterns (PAMPS) absent from eukaryotic cells. In general, the most effective viral vaccines are live attenuated viruses. Inactivated virus vaccines also confer immunity but offer less protection and require multiple immunizations. Subunit vaccines, such as viral protein antigens, are less useful due to poor immunogenicity. However, there are clear advantages to subunit vaccines in terms of cost, uniformity of production, stability, ability to control the type of immunity that is generated, and far superior safety profiles, but subunit vaccines require effective adjuvants to generate strong immunity. Examples in clinical use include mineral salts (Alum), oil-in-water emulsions, and a mineral salt-TLR4 agonist combination. Other PRR agonists as components of adjuvants are in various stages of clinical trials. A limitation to use of PAMPS as vaccine adjuvants is toxicity. In general terms, signaling through PRRs activates two major transcriptional cascades, interferon regulatory factor (IRF) and nuclear factor-kappa B (NF-kB) signaling culminating in expression of genes encoding proteins to both inhibit pathogen replication and strongly activate the immune system. Recent evidence argues that it may be possible to retain adjuvant activity of a PAMP and alleviate toxicity by combining a PAMP (CpG) with an inhibitor of the NF-kB signaling path. A limitation to this strategy derives from inherent serious mechanism-based toxicity of systemic inhibition of NF-kB signaling. Autoimmune disease generates a kind of ‘danger signal’; referred to as an ‘interferon signature’ in which many genes induced by interferons are elevated in patients in apparent absence of infection. We found that the ‘interferon signature’ in multiple sclerosis (MS) results from markedly increased levels of endogenous double-stranded Alu elements (Alu dsRNA) and showed that Alu dsRNAs stimulate strong IRF and NF-kB activation. Alu dsRNAs complexed with nanoparticles (AluJb/NP) have potent anti-tumor activity, in vivo, demonstrating their immunostimulatory activity. We identified Alu dsRNA elements that are strong activators of both IRF and NF-kB signaling and those that are strong activators of only IRF signaling but not NF-kB. Thus, our hypothesis to test is that we can design and deliver RNA adjuvants that mimic endogenous Alu elements that preferentially activate IRF responses and minimally agonize NF-kB signaling to enhance immune responses and improve tolerability of influenza subunit vaccines.

尽管有医疗进展，但传染病仍然是全球死亡的主要原因之一。疫苗是预防传染病的最有效工具之一。免疫组织化学的产生有两个组成部分。首先是T和B细胞受体识别的抗原的独特化学结构，允许克隆膨胀和自适应免疫系统细胞的分化。第二个是一个“危险信号”，该信号通过模式识别接收器（PRR）刺激先天免疫系统，该系统识别出与真核细胞中没有病原体相关的分子模式（PAMP）。通常，最有效的病毒疫苗是活病毒。灭活的病毒疫苗还赋予免疫史，但提供更少的保护，需要多种免疫抑制。亚基疫苗，例如病毒蛋白抗原，由于免疫原性差而有用。但是，在成本，生产的统一，稳定性，控制生成的免疫学类型的能力以及更高的安全性概况方面，亚基疫苗具有明显的优势，但是亚基疫苗需要有效的调节器来产生强大的免疫学。临床用途的例子包括矿物质盐（明矾），水中乳液和矿物质盐-TLR4激动剂组合。其他PRR激动剂作为调节器的组成部分处于临床试验的各个阶段。用作疫苗调节器的限制是毒性。一般而言，通过PRR的信号传导激活两个主要的转录级联反应，干扰素调节因子（IRF）和核因子-KAPPA B（NF-KB）信号传导最终导致编码蛋白质表达的蛋白质表达，以抑制病原体的复制并强烈激活免疫学系统。最近的证据论证表明，有可能通过将PAMP（CPG）与NF-KB信号通路的抑制剂相结合来保留调整症状的活性并减轻毒性。该策略的局限性来自继承基于严重机制的NF-KB信号传导系统性抑制的毒性。自身免疫性疾病会产生一种“危险信号”；被称为“干扰素签名”，其中在没有感染的情况下，患者在患者中诱导的许多基因升高。我们发现，多发性硬化症（MS）中的“干扰素特征”是由于内源性双链Alu元素（Alu dsRNA）显着升高的结果，并表明Alu DSRNA刺激了强的IRF和NF-KB激活。与纳米颗粒（Alujb/np）复合的Alu DSRNA具有潜在的抗肿瘤活性，体内证明了它们的免疫刺激活性。我们确定了Alu dsRNA元素，它们是IRF和NF-KB信号的强激活剂，以及仅具有IRF信号（而不是NF-KB）的强激活剂的元素。这是我们测试的假设是，我们可以设计和传递RNA调节器，以模仿内源性的ALU元素，这些元素优先激活IRF响应，并最小化NF-KB信号传导，以增强免疫反应并提高影响力的耐受性。