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。尽管 疫苗是预防感染的有效措施，但一个关键问题是与衰老相关的变化 免疫系统的影响导致大多数目前使用的疫苗的免疫原性和临床功效下降。小说 提高疫苗接种效力并专门针对衰老免疫系统的策略势在必行。一个 这些努力的一个重要方面是使用组合佐剂，以协同增强更有效的效果 疫苗诱导的针对各种病原体的免疫反应。在这个项目中，我们将定义以下机制： 独特的寄生虫蛋白佐剂 rASP-1 与三个孔中的每一个的组合的作用（MOA） 特征性先天佐剂：STING、TLR7/8 和 RIG-I 激动剂，已知可激活细胞质模式 识别受体和 I 型干扰素信号传导，这些信号在老年人群中特别受到抑制。我们 已表明 rASP-1 是一种强大的佐剂，因为它可以激活人和小鼠树突状细胞以增强 幼稚 CD4+ T 细胞分化为 Th1、Th17 和 Tfh 样细胞。 rASP-1- 的转录组分析 激活的 hMoDC 揭示了 MyD88 独立激活途径的上调和干扰素相关 基因。在小鼠中，rASP-1 引发平衡的 Th1/Th2 抗体反应、偏向 Th1 的细胞免疫，以及 与疫苗共同施用时增强反应，从而提高微生物感染后的存活率 挑战。重要的是，我们的初步数据表明 rASP-1 与 2'3'-cGAMP (STING) 结合， R848 (TLR7/8) 或 5'3p-hpRNA (RIG-I) 在激活的成年和老年小鼠 BMDC 中可以显着协同作用 不仅仅是累加效应；它增强 IL-12p40、IP-10 和/或 IL-10 的分泌。协同作用是 当它用 STING 配体激活衰老的小鼠 BMDC 时，效果尤为明显。因此，我们假设 rASP-1 与 STING、TLR7/8 或 RIG-I 激动剂组合将协同激活早期先天免疫 对免疫反应的建立和性质以及持续时间和免疫反应至关重要的信号传导 免疫激活的强度。我们认为这将有助于恢复关键领域与衰老相关的缺陷 抗病毒反应的调节途径。通过综合免疫学和转录组学 分析表明，rASP-1 与这三种 PRR 激动剂组合通过 MOA 产生最佳效果 驱动体液和细胞抗病毒反应的辅助 T 细胞的激活将在小鼠体内建立 （目标 1）和人类（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（IIV3）作为模型在成年和老年小鼠体内的功效 抗原（目标 3）。该项目汇集了一支充满活力的团队，具有合作和互补的历史 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。 我们将提供一种新颖、有效的先天细胞质 PRR 佐剂与 rASP-1 的组合， 促进保护性长期适应性反应并提高疫苗对老年人群的功效。