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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的该提案旨在研究一种新开发的粘膜佐剂在支持方面的有效性目前的流感疫苗对老年人的债务无效。老化的免疫系统及其对细胞介导免疫（CMI）的刺激作用较差。能够刺激老年人的体液和细胞免疫反应，应该会大大增强我们最近设计了一种现有的流感疫苗，可以更好地保护老龄化和不断增长的人口。通过将天然 STING 激动剂与肺表面活性剂 (PS) 封装在一起，形成强大的粘膜佐剂 - 仿生脂质体，命名为 PS-GAMP，基于最近的发现，即 STING 的激活， IFN 基因的刺激剂，可与 PS-GAMP 一起强烈刺激 CMI 和体液免疫。灭活 H1N1 疫苗可诱导针对远距离 H1N1 流感的广谱交叉保护，最早在单次免疫后 2 天发现异亚型 H3N2、rgH5N1 和 H7N9 病毒。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) 在本提案中，我们将把研究扩展到老年小鼠，并确定年轻成年小鼠的 CD8+ T 细胞。 PS-GAMP/flu 是否可以快速诱导强 CD8+ T 细胞（也许还有 CD4+ T 细胞）我们将监测老年小鼠的异亚型免疫、体液免疫的寿命。随着小鼠年龄的增长，反应和肺 TRM CD8+ 和 CD4+ 记忆 T 细胞会发生变化。不涉及任何复制疫苗，预退出免疫对 PS- 的功效影响不大 GAMP/流感疫苗接种，将进行研究以证明疫苗的显着优势二是与鼻内注射流感减毒活疫苗相区别。主要针对抗原呈递细胞 (APC) 或专业免疫的最著名佐剂细胞，PS-GAMP 激活肺泡上皮细胞 (AEC) 和 APC，这将是有兴趣了解的。 PS-GAMP介导的AEC激活是否可以抵消老化APC的缺陷，从而引发强烈的 AEC 的关键作用也将在雪貂模型中得到证实。目标 3 将研究是否可以通过以下方法进一步改善老年小鼠的 PS-GAMP/流感疫苗接种：此外，抑制炎症和/或去除衰老细胞。将探索pan-STING激动剂增强PS-GAMP的佐剂作用并加强其临床该研究如果成功，将对整体健康和质量产生重大影响。老年人不仅感染流感，还感染 Covid-19 等其他呼吸道病毒感染。