A new mucosal adjuvant for augmenting influenza vaccines in elderly

摘要 这项建议是为了研究一种新开发的粘膜佐剂在支持支持方面的有效性 老年人接种流感(流感)疫苗。目前的流感疫苗对老年人无效，因为 免疫系统老化及其对细胞免疫(CMI)刺激作用差。一种强有力的佐剂 能够刺激老年人体液和细胞免疫反应的能力应该大大增强 现有的流感疫苗，更好地保护这一老龄化和不断增长的人口。我们最近设计了一种 通过将天然刺痛激动剂与肺表面活性物质(PS)包裹在一起而产生强大的粘膜佐剂- 仿生脂质体，名为PS-GAMP，基于最近的发现，激活刺痛， 干扰素基因的刺激物，可大力刺激CMI和体液免疫。PS-GAMP旁边 甲型H1N1灭活疫苗诱导了对远距离H1N1和 H3N2、rgH5N1和H7N9异亚型病毒最早在单次免疫后2天。这个 交叉保护持续至少6个月，与耐久的肺组织常驻记忆(TRM)同时进行 幼年小鼠的CD8T细胞。在这项建议中，我们将把这项研究扩展到老龄小鼠，并确定 PS-GAMP/Flu能否快速诱导强大的CD8 T细胞(可能还有CD4T细胞) 为老龄小鼠接种疫苗。我们将监测一种长寿的异亚型免疫，体液免疫 随着小鼠年龄的增长，肺组织TRM CD8和CD4记忆T细胞的变化。因为接种疫苗会 不涉及任何复制疫苗，退出前的免疫应该对PS-1的疗效影响不大。 GAMP/流感疫苗接种，将进行调查，以证明疫苗的显著优势 对老年人无效的过多减毒鼻腔流感疫苗。第二，区别于 最突出的佐剂主要针对抗原提呈细胞(APC)或专业免疫 PS-GAMP可激活肺泡上皮细胞(AEC)和APC。它会很感兴趣地了解 PS-GAMP介导的AEC活化能否弥补衰老APC的缺陷 老龄小鼠的异亚型免疫。AEC的关键作用也将在雪貂模型中得到证实。 目标3将调查PS-GAMP/Flu疫苗能否通过以下方式进一步改善老龄小鼠的接种 抑制炎症和/或去除衰老细胞。此外，一部小说，更有说服力， 将开发PAN-STING激动剂以增强PS-GAMP的佐剂作用并加强其临床应用 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 老年人口不仅是流感，而且还有其他呼吸道病毒感染，如新冠肺炎。

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.