Restoring age-dependent vaccine unresponsiveness by a novel ASP-1 adjuvant combination

通过新型 ASP-1 佐剂组合恢复年龄依赖性疫苗无反应

• 批准号: 10220588
• 负责人: Sara Lustigman
• 金额: $ 73.71万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10220588
• 关键词: Adjuvant; Adult; Aging; Agonist; Antibody Response; Antigens; Antiviral Response; Automobile Driving; B-Lymphocytes; Biochemistry; Bioinformatics; Biological Assay; Biology; Bone Marrow; CD4 Positive T Lymphocytes; CD8B1 gene; CXCL10 gene; Cells; Cellular Immunity; Cellular Immunology; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Communicable Diseases; Data; Dendritic Cells; Engineered Gene; Engineering; Ensure; Genes; Goals; Helminths; Helper-Inducer T-Lymphocyte; Human; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunologics; Immunology; Individual; Infection prevention; Interferons; Interleukin-10; Lead; Ligands; Measures; Memory; Modeling; Molecular Profiling; Morbidity - disease rate; Mus; Nature; Older Population; Onchocerca volvulus; Parasites; Pathway interactions; Pattern recognition receptor; Peptides; Proteins; Receptor Cell; Recording of previous events; Regulatory Pathway; Signal Pathway; Signal Transduction; Societies; Stimulator of Interferon Genes; Structure of germinal center of lymph node; T cell response; T-Lymphocyte; TLR7 gene; Testing; Up-Regulation; Vaccination; Vaccines; age related; aged; aging population; asparaginase; base; cell type; clinical efficacy; healthy aging; human model; immune activation; immunogenicity; immunosenescence; in vivo; induced pluripotent stem cell; influenza infection; influenza virus vaccine; knockout gene; lymph nodes; microbial; monocyte; mortality; mouse model; novel; novel strategies; pathogen; recruit; response; synergism; transcriptomics; vaccine efficacy; vaccinology

PROJECT ABSTRACT Infectious diseases are a major cause of morbidity and mortality in the expanding older population. While vaccines are efficient measures to prevent infections, a critical problem is that aging-associated changes in the immune system lead to decreased immunogenicity and clinical efficacy of most currently used vaccines. Novel strategies that increase vaccination efficacy and specifically target the aged immune system are imperative. An essential facet of these efforts is the use of combinatory adjuvants that synergistically potentiate more effective vaccine-induced immune responses against various pathogens. In this project we will define the mechanism of action (MOA) of a combination of a unique parasite protein adjuvant, rASP-1 with each of three well- characterized innate adjuvants: STING, TLR7/8 and RIG-I agonists, known to activate cytoplasmic pattern recognition receptors and Type I IFN signaling, which are specifically dampened in the aged population. We have shown that rASP-1 is a powerful adjuvant as it activates human and mouse dendritic cells to potentiate the differentiation of naïve CD4+ T cells into Th1, Th17 and Tfh-like cells. Transcriptomic analyses of rASP-1- activated hMoDCs revealed upregulation of the MyD88-independent activation pathway and interferon related genes. In mice, rASP-1 elicits a balanced Th1/Th2 antibody response, Th1-biased cellular immunity, and enhanced responses when co-administered with vaccines leading to increased survival following microbial challenge. Importantly, our preliminary data indicate that rASP-1 in combination with 2’3’-cGAMP (STING), R848 (TLR7/8) or 5’3p-hpRNA (RIG-I) in activated adult and aged mouse BMDCs can dramatically synergize beyond merely additive effects; it enhanced secretion of IL-12p40, IP-10 and/or IL-10. The synergy is exceptionally evident when it activates aged mouse BMDCs with the STING ligand. Therefore, we hypothesize that combining rASP-1 with STING, TLR7/8 or RIG-I agonists will synergistically activate early innate immune signaling that critically contributes to the establishment and nature of immune responses, and the duration and intensity of immune activation. We posit that this will help restore the aging-associated deficits in the critical regulatory pathways of the antiviral responses. Through comprehensive immunologic and transcriptomic analyses, the MOA through which rASP-1 in combination with these three PRR agonists leads to optimal activation of helper T cells driving humoral and cellular antiviral responses will be established in both mouse (Aim 1) and human (Aim 2) DCs (adult and aged), to establish that they are conserved, and then test their efficacy in vivo in adult and aged mice using the trivalent inactivated influenza vaccine (IIV3) as a model antigen (Aim 3). This project brings together a dynamic team with a history of collaboration and complementary expertise in vaccinology, immunology, biochemistry, innate cell receptor biology, adjuvants, and bioinformatics. We will deliver a novel, efficacious combination of innate cytoplasmic PRR adjuvants with rASP-1 that promotes protective long-lived adaptive responses and boosts efficacy of vaccines in aged populations.

项目摘要 传染病是不断扩大的老年人口发病和死亡的主要原因。而 疫苗是预防感染的有效措施，但关键问题是， 免疫系统缺陷导致大多数目前使用疫苗的免疫原性和临床效力降低。小说 提高疫苗接种效力和专门针对老年人免疫系统的战略是必要的。一个 这些努力的基本方面是使用组合佐剂， 疫苗诱导的针对各种病原体的免疫应答。在本项目中，我们将定义 作用（MOA）的独特的寄生虫蛋白佐剂，rASP-1与三个孔- 表征的先天性佐剂：STING、TLR 7/8和RIG-I激动剂，已知激活细胞质模式 识别受体和I型IFN信号传导，其在老年人群中特异性减弱。我们 已经表明rASP-1是一种强大的佐剂，因为它激活人类和小鼠树突状细胞， 幼稚CD 4 + T细胞分化为Th 1、Th 17和Tfh样细胞。rASP-1的转录组学分析- 活化的hMoDCs显示了MyD 88非依赖性活化途径和干扰素相关的上调。 基因.在小鼠中，rASP-1能平衡Th 1/Th 2抗体应答，Th 1偏向细胞免疫， 当与疫苗共同施用时，增强的应答导致微生物感染后的存活率增加， 挑战.重要的是，我们的初步数据表明，rASP-1与2 '3'-cGAMP（STING）组合， R848（TLR 7/8）或5 '3 p-hpRNA（RIG-I）在活化的成年和老年小鼠BMDCs中可显著协同 除了仅仅是累加效应之外，它还增强了IL-12 p40、IP-10和/或IL-10的分泌。协同作用是 当它用STING配体激活老化小鼠BMDC时，这是特别明显的。因此，我们假设 将rASP-1与STING、TLR 7/8或RIG-I激动剂组合将协同激活早期先天免疫， 信号传导对免疫应答的建立和性质以及持续时间和 免疫激活强度。我们认为，这将有助于恢复与衰老相关的赤字， 抗病毒反应的调节途径。通过全面的免疫学和转录组学 分析中，通过MOA，rASP-1与这三种PRR激动剂的组合导致最佳的PRR。 将在两种小鼠中建立驱动体液和细胞抗病毒应答的辅助性T细胞的激活 (Aim 1）和人（目标2）DC（成人和老年人），以确定它们是保守的，然后测试它们的 使用三价灭活流感疫苗（IIV 3）作为模型在成年和老年小鼠中的体内有效性 抗原（Aim 3）。这个项目汇集了一个充满活力的团队，具有合作和互补的历史 在疫苗学、免疫学、生物化学、先天细胞受体生物学、佐剂和生物信息学方面的专业知识。 我们将提供一种新的，有效的先天性细胞质PRR佐剂与rASP-1的组合， 促进保护性长期适应性反应，提高疫苗在老年人群中的效力。