A new mucosal adjuvant for augmenting influenza vaccines in elderly

一种用于增强老年人流感疫苗接种效果的新型粘膜佐剂

• 批准号: 10409833
• 负责人: Mei X Wu
• 金额: $ 46.4万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-24 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10409833
• 关键词: Address; Adjuvant; Adjuvanticity; Age; Aging; Agonist; Air; Alveolar Macrophages; Alveolus; Antigen Targeting; Antigen-Presenting Cells; Attenuated; Biological Response Modifiers; Biomimetics; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; COVID-19; COVID-19 pandemic; Cause of Death; Cell Aging; Cells; Cellular Immunity; Cessation of life; Clinical; Cyclic GMP; Cytosol; Defect; Dendritic Cells; Disease; Distant; Effectiveness; Elderly; Encapsulated; Endocytosis; Engineering; Epithelial Attachment; Epithelial Cells; Excision; Face; Ferrets; Gene Activation; Genes; H1N1 vaccine; Health; Healthcare Systems; Hospitalization; Humoral Immunities; ITGAM gene; Immune; Immune response; Immune system; Immunity; Immunization; Immunization Programs; Infection; Inflammaging; Inflammation; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H7N9 Subtype; Influenza vaccination; Inhalation; Interferons; Invaded; Learning; Liposomes; Longevity; Lung; Mediating; Medical; Membrane; Memory; Middle East Respiratory Syndrome; Modeling; Monitor; Mucous Membrane; Mus; Names; Nature; Organ; Persons; Phospholipase A2; Play; Population; Predisposition; Production; Public Health; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactants; Respiratory System; Role; Science; Severe Acute Respiratory Syndrome; Single Nucleotide Polymorphism; Structure of parenchyma of lung; T cell response; T memory cell; T-Lymphocyte; Tissues; Tsunami; Vaccination; Vaccines; Viral Respiratory Tract Infection; Viral Vaccines; Virus; Virus Diseases; aged; aging population; alveolar epithelium; base; cost; cross immunity; flu; immunopathology; improved; influenza virus vaccine; interest; memory CD4 T lymphocyte; mortality; novel; particle; prevent; recruit; respiratory; response; universal influenza vaccine; vaccination strategy; young adult

Abstract This proposal is to investigate a newly developed mucosal adjuvant for its effectiveness in bolstering influenza (flu) vaccines in the elderly. Current flu vaccines are inefficacious in the elderly owing to the aged immune system and their poor stimulation of cell-mediated immunity (CMI). A powerful adjuvant capable of stimulating both humoral and cell immune responses in the elderly should greatly augment existing flu vaccines, better safeguarding this aging and growing population. We recently engineered a powerful mucosal adjuvant by encapsulating a natural STING agonist with pulmonary surfactant (PS)- biomimetic liposomes, named PS-GAMP, based on recent findings that activation of STING, the stimulator of IFN genes, can vigorously stimulate CMI and humoral immunity. PS-GAMP alongside inactivated H1N1 vaccine induced a wide spectrum of cross-protection against distant H1N1 and heterosubtypic H3N2, rgH5N1, and H7N9 viruses as early as 2 days after a single immunization. The cross-protection lasted for at least 6 months, concurrent with durable lung tissue resident memory (TRM) CD8+ T cells in young adult mice. We will extend the study to aged mice in this proposal and determine whether strong CD8+ T-cells (and perhaps CD4+ T cells as well) can be quickly induced by PS-GAMP/flu vaccine in aged mice. We will monitor a longevity of the heterosubtypic immunity, humoral immune responses, and lung TRM CD8+ and CD4+ memory T cells as mice age. Because the vaccination does not involve any replicating vaccine, pre-exiting immunity should have little effect on the efficacy of PS- GAMP/flu vaccination, which will be investigated to demonstrate significant advantages of the vaccine over live-attenuated intranasal flu vaccine that is ineffective in the elderly. Secondly, distinguished from most prominent adjuvants primarily targeting antigen-presenting cells (APCs) or professional immune cells, PS-GAMP activates both alveolar epithelial cells (AEC) and APCs. It would be interested to learn whether PS-GAMP-mediated AEC activation can offset the defects of aged APCs, eliciting strong heterosubtypic immunity in aged mice. The pivotal role for AEC will be also substantiated in ferret model. Aim 3 will investigate whether PS-GAMP/flu vaccination can be further improved in aged mice by suppressing inflammaging and/or removing senescence cells. Moreover, a novel, much more potent, and pan-STING agonist will be explored to enhance PS-GAMP’s adjuvanticity and strengthen its clinical potential. The study, if successful, would have significant impact on the overall health and quality of the aged population not only for influenza but also for other respiratory viral infections like Covid-19.

抽象的 该建议是调查新开发的粘膜调整，以调整其在增强的有效性 流感（流感）疫苗在较早的情况下。当前的流感疫苗在最古老的 老化的免疫免疫系统及其对细胞介导的免疫增强（CMI）的刺激不良。强大的调整 能够刺激旧的体液和细胞免疫反应，应大大增加 现有的流感疫苗，更好地保护这种老龄化和人口增长。我们最近设计了 强大的粘膜通过用肺表面活性剂（PS） - 基于最近发现的刺激性脂质体，称为PS-GAMP IFN基因的刺激器可以剧烈刺激CMI和体液免疫。 PS-GAMP旁边 灭活的H1N1疫苗诱导了针对遥远H1N1的广泛交叉保护和 单次免疫抑制后2天，杂型H3N2，RGH5N1和H7N9病毒。 跨保护持续至少6个月，并发与耐用的肺组织居民记忆（TRM）同时进行 年轻小鼠的CD8+ T细胞。我们将在此提案中将研究扩展到老年小鼠并确定 PS-GAMP/流感是否可以迅速诱导强CD8+ T细胞（也许还有CD4+ T细胞）（也许还有CD4+ T细胞） 老年小鼠的疫苗。我们将监视异源性免疫史的寿命 反应，随着小鼠的年龄，肺TRM CD8+和CD4+记忆T细胞。因为疫苗确实 不涉及任何复制疫苗，预先审查的免疫对PS-的有效性影响不大 GAMP/流感疫苗，将研究以证明疫苗的显着优势 过多的活体内鼻内流感疫苗在较早的情况下无效。其次，与众不同 最突出的调节器主要靶向抗原呈递细胞（APC）或专业免疫 细胞，PS-GAMP激活肺泡上皮细胞（AEC）和APC。学习很感兴趣 PS-GAMP介导的AEC激活是否可以抵消老化APC的缺陷，从而引起强烈 老年小鼠的杂型免疫学。 AEC的关键作用也将在雪貂模型中得到证实。 AIM 3将研究PS-GAMP/流感疫苗接种是否可以通过老年小鼠进一步改善 抑制炎症和/或去除感应细胞。而且，一种小说，更多的潜力，并且 将探索泛刺激动剂，以增强PS-GAMP的可调性并增强其临床 潜在的。该研究，如果成功的话，将对整体健康和质量产生重大影响 年龄的人口不仅是影响力的人群，而且对其他呼吸道病毒感染（如Covid-19）。