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 在不断扩大的老年人口中，传染病是发病率和死亡率的主要原因。而当 疫苗是预防感染的有效措施，一个关键的问题是与衰老相关的变化 免疫系统导致目前使用的大多数疫苗的免疫原性和临床疗效降低。小说 提高疫苗接种效力并特别针对老年免疫系统的战略势在必行。一个 这些努力的基本方面是使用能够协同增强更有效的组合佐剂 疫苗诱导对各种病原体的免疫反应。在本项目中，我们将定义 一种独特的寄生虫蛋白佐剂rasp-1与三个孔-1的组合的作用(MOA) 固有佐剂：STING、TLR7/8和RIG-I激动剂，已知激活细胞质模式 识别受体和I型干扰素信号，这在老年人中特别受到抑制。我们 已经证明rasp-1是一种强大的佐剂，因为它激活了人和小鼠的树突状细胞，增强了 单纯CD4+T细胞向Th1、Th17和Tfh样细胞的分化Rasp-1-基因的转录转录分析 活化的hMoDC显示MyD88非依赖性激活途径上调和干扰素相关 基因。在小鼠中，rasp-1诱导平衡的Th1/Th2抗体反应，偏向Th1的细胞免疫，以及 与疫苗联合使用时的增强反应，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)结合， R848(TLR7/8)或5‘3P-hpRNA(RIG-I)在激活的成年和老年小鼠BMDCs中可以显著协同作用 除相加作用外，还可促进IL-12p40、IP-10和/或IL-10的分泌。协同效应是 当它用刺配体激活老化的小鼠骨髓细胞时，尤为明显。因此，我们假设 Rasp-1与STING、TLR7/8或RIG-I激动剂联合使用将协同激活早期先天免疫。 对免疫反应的建立和性质起关键作用的信号，以及持续时间和 免疫激活的强度。我们假设，这将有助于恢复与老龄化相关的赤字 抗病毒反应的调控途径。通过全面的免疫学和转录本 分析，rasp-1与这三种PRR激动剂联合使用的MOA导致最佳 将在两只小鼠中建立驱动体液和细胞抗病毒反应的辅助T细胞的激活 (目标1)和人类(目标2)DC(成人和老年)，以确定它们是保守的，然后测试它们的 三价流感灭活疫苗(IIV3)对成年和老龄小鼠的体内免疫效果 抗原(目标3)。这个项目将一个充满活力的团队聚集在一起，具有合作和互补的历史 疫苗学、免疫学、生物化学、天然细胞受体生物学、佐剂和生物信息学方面的专业知识。 我们将提供一种新颖、有效的天然细胞质PRR佐剂与rasp-1的组合， 促进保护性长寿适应性反应，提高疫苗在老年人口中的效力。