A new mucosal adjuvant for augmenting influenza vaccines in elderly

摘要 这项建议是调查一种新开发的粘膜佐剂，其有效性，在支持 老年人接种流感疫苗。目前的流感疫苗对老年人无效， 老化的免疫系统和它们对细胞介导的免疫（CMI）的不良刺激。强效佐剂 能够刺激老年人的体液和细胞免疫反应的药物， 现有的流感疫苗，更好地保护这个老龄化和不断增长的人口。我们最近设计了一个 通过将天然STING激动剂与肺表面活性剂（PS）包封， 仿生脂质体，命名为PS-GAMP，基于最近的发现，STING的激活， IFN基因的刺激因子，能强烈刺激CMI和体液免疫。PS-GAMP与 灭活H1N1疫苗诱导了针对远距离H1N1的广谱交叉保护， H3 N2、rgH 5 N1和H7N9病毒的感染。的 交叉保护持续至少6个月，同时具有持久的肺组织驻留记忆（TRM） 年轻成年小鼠中的CD 8 + T细胞。我们将在本提案中将研究扩展到老年小鼠，并确定 PS-GAMP/流感病毒是否能快速诱导强的CD 8 + T细胞（也许还有CD 4 + T细胞） 老年小鼠的疫苗。我们将监测一个长寿的异型免疫，体液免疫， 随着小鼠年龄的增长，肺TRM CD 8+和CD 4+记忆T细胞的变化。因为接种疫苗 不涉及任何复制疫苗，预先存在的免疫力应该对PS的效力几乎没有影响， GAMP/流感疫苗接种，将对其进行研究，以证明疫苗的显著优势 对老年人无效的鼻内减毒活流感疫苗。其次，区别于 主要靶向抗原呈递细胞（APC）或专职免疫细胞的最突出的佐剂 细胞，PS-GAMP激活肺泡上皮细胞（AEC）和APC。我很想知道 PS-GAMP介导的AEC激活是否可以抵消老化APC的缺陷，引起强烈的免疫反应， 老年小鼠的异亚型免疫。AEC的关键作用也将在雪貂模型中得到证实。 目的3将研究PS-GAMP/流感疫苗接种是否可以通过以下方法在老年小鼠中进一步改善： 抑制炎症和/或去除衰老细胞。此外，一部小说，更有力， 我们将探索一种泛STING激动剂，以增强PS-GAMP的佐剂性，加强其临床应用 潜力这项研究如果成功，将对儿童的整体健康和质量产生重大影响。 老年人不仅是流感，也是其他呼吸道病毒感染，如COVID-19。

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.