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

基本信息

批准号：
10620718
负责人：
Sara Lustigman
金额：
$ 71.94万
依托单位：
NEW YORK BLOOD CENTER
依托单位国家：
美国
项目类别：
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/10620718
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 CXCR3 gene Cells Cellular Immunity Cellular Immunology Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Communicable Diseases Cytoplasm Data Dendritic Cells Engineered Gene Engineering Ensure Genes Goals Helminths Helper-Inducer T-Lymphocyte Human Immune response Immune signaling Immune system Immunity Immunologics Immunology Individual Infection prevention Interferon Type I 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 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 clinical efficacy healthy aging human model immune activation immunogenicity immunoregulation 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 type I interferon receptor vaccine efficacy vaccinology

项目摘要

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.

项目摘要传染病是扩大老年人群发病率和死亡率的主要原因。尽管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可改善当前使用的疫苗的免疫原性和临床效率。小说必须采取提高疫苗接种效力并特别针对老年免疫系统的策略。一个这些努力的基本方面是使用组合性调节器，这些调节器具有协同潜在的有效性疫苗诱导的针对各种病原体的免疫反应。在这个项目中，我们将定义独特的寄生虫蛋白可调节的RASP-1组合的作用（MOA）与三个井中的每一个具有先天调节器的特征：Sting，TLR7/8和Rig-i激动剂，已知会激活细胞质模式识别受体和I型IFN信号传导，这些信号在老年人群中特异性抑制。我们已经表明，RASP-1是一种强大的调整，因为它激活了人和小鼠树突状细胞幼稚的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揭示了非依赖MyD88的激活途径和与干扰相关的上调基因。在小鼠中，RASP-1引起平衡的Th1/Th2抗体反应，Th1偏见的细胞免疫（and）和当与疫苗共同管理导致微生物后生存率增加时，反应增强挑战。重要的是，我们的初步数据表明RASP-1与2'3'-cgamp（sting）相结合，激活的成年和老鼠BMDC中的R848（TLR7/8）或5'3P-HPRNA（RIG-I）可以显着协同不仅仅是上瘾的影响；它增强了IL-12P40，IP-10和/或IL-10的分泌。协同作用是当它用刺激配体激活老年小鼠BMDC时，它具有异常的证据。因此，我们假设将RASP-1与STING，TLR7/8或RIG-I激动剂结合起来，将协同激活早期先天免疫信号对免疫反应的建立和性质以及持续时间和持续时间和免疫激活的强度。我们指出，这将有助于恢复与衰老相关的定义抗病毒反应的调节途径。通过全面的免疫和转录组学分析，RASP-1与这三种PRR激动剂结合使用的MOA导致最佳在两只小鼠（目标1）和人类（目标2）DCS（成人和老年），以确定它们是保守的，然后测试他们的使用三价灭活的影响疫苗（IIV3）作为模型的成人和老年小鼠的体内功效抗原（AIM 3）。该项目汇集了一个具有协作历史和完成历史的动态团队疫苗学，免疫学，生物化学，先天细胞受体生物学，辅助和生物信息学方面的专业知识。我们将提供一种新颖，有效的结合，将先天性细胞质PRR调节器与RASP-1结合在一起，促进保护性的长期自适应反应，并提高老年人群中疫苗的效率。