Biomimetic nanoparticles to enhance the breadth of influenza vaccines

仿生纳米颗粒可增强流感疫苗的广度

• 批准号: 10455053
• 负责人: Mei X Wu
• 金额: $ 56.23万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-07 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10455053
• 关键词: Address; Adjuvant; Adjuvanticity; Adverse effects; Adverse event; Affect; Agonist; Alveolar Macrophages; Alveolus; Animal Model; Antigen-Presenting Cells; Antigens; Binding; Biological Response Modifiers; Biomimetics; Body Temperature; Body Weight; Bone Marrow Cells; CD8-Positive T-Lymphocytes; Cause of Death; Cells; Cessation of life; Cholera Toxin; Clinical; Cyclic GMP; Cytosol; Dendritic Cells; Distant; Dose; Dreams; Encapsulated; Endocytosis; Epithelial Cells; Exhibits; Flu virus; Gap Junctions; Gene Activation; Generations; H1N1 vaccine; Hemagglutinin; ITGAM gene; Immune response; Immunity; Immunization; Immunologic Surveillance; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H7N9 Subtype; Innate Immune System; Licensing; Lipids; Liposomes; Lung; Mediating; Medical; Membrane; Membrane Proteins; Mucous Membrane; Mus; Names; Neuraminidase; Pathologic; Pathway interactions; Phase; Phospholipase A2; Poly I-C; Population; Probability; Production; Pulmonary Inflammation; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactants; Respiratory System; Role; Seasons; Stimulator of Interferon Genes; Surface; T cell response; Time; Uncertainty; Update; Vaccination; Vaccines; Viral; Viral Vaccines; Virus; Virus Diseases; Wild Type Mouse; alveolar epithelium; cell type; cross immunity; cross reactivity; experience; flu; global health; high risk; human model; influenza virus strain; influenza virus vaccine; lung histology; nanoparticle; neutralizing antibody; novel; pandemic disease; pandemic influenza; pandemic potential; pandemic virus; pre-pandemic; prevent; recruit; response; seasonal influenza; universal influenza vaccine; vaccine efficacy

Abstract Current influenza (flu) vaccines are effective only for closely matched flu viral strains and must be updated annually to address constant antigenic shift/drifts of surface hemagglutinin (HA) and/or neuraminidase (NA) of the virus. Even with annual update, there have been years in which flu vaccines were ineffective due to significant differences in antigenicity of HA and/or NA between the strains used for preparing the vaccines and the circulating ones, leaving us at high risk of pandemics in case a new and highly pathological virus emerges. It is without any doubt that a “Universal” flu vaccine that can protect against both seasonal (matched or mismatched) and pandemic flu viruses is urgently needed, but it remains “an alchemist’s dream” so far. We developed a novel adjuvant by encapsulation of cGAMP, an agonist of the stimulator of interferon (IFN) gene (STING), into pulmonary surfactant (PS)-biomimetic liposomes (PS-GMNP). The adjuvant, alongside an inactivated flu vaccine, robustly stimulated humoral and CD8+ T cell immune responses that resemble those ocurring during the early phase of viral infection both in magnitude and in dynamics. Strikingly, a single dose of PS-GMNP-adjuvant flu vaccine elicited strong cross-protection against a lethal challenge of diverse heterosubtypic flu A viruses as early as 2 days after immunization. While stimulating robust heterosubtypic immunity, the adjuvant did not cause any adverse events in lung histology, body weight or temperature, in sharp contrast to the severe lung inflammation and death caused by flu viral infection. In this proposal, we will investigate the cellular and humoral immune responses essential to the cross-protection induced by PS- GMNP-adjuvanted flu vaccines. Specifically, we will determine whether PS-GMNP can expand cross-reactive CD8+ T cells and induce broadly neutralizing antibodies (bnAbs), pivotal to PS-GMNP-induced cross- protection. In Aim 2, we will preclude any adverse effects of pre-existing immunity on the adjuvanticity of PS- GMNP and extend the cross-protection to pre-pandemic wild type H5N1 and H7N9 viruses to establish its clinical potentials. Distinguished from conventional adjuvants that activate primarily antigen-presenting cells (APCs), cGAMP delivered by PS-GMNP activated both alveolar macrophages (aMɸ) and alveolar epithelial cells (AEC), which can be crucial since similar activation of these two types of cells is also observed during flu viral infection. Two alternative approaches will be employed in Aim 3 to corroborate indispensable function of AEC and/or aMɸ in PS-GMNP-mediated heterosubtypic immunity, including a blockade of cell-gap junctions and generation of chimeric mice of wild type and STING-deficient bone marrow (BM) cells. The study, if successful, could provide invaluable information about clinical potentials for PS-GMNP to widen the breadth of existing flu vaccines toward a “Universe” one, which will have a huge and immediate impact on global health.

抽象的 当前的影响力（流感）疫苗仅对紧密匹配的流感病毒菌株有效，必须进行更新 单向解决表面血凝素（HA）和/或神经瘤酶（Na）的恒定抗原移位/漂移 病毒。即使有年度更新，由于多年的流感疫苗由于 用于制备疫苗的菌株之间HA和/或NA的抗原性差异显着差异 循环的人，如果出现了一种新的，高度病毒的病毒，就会使我们面临大流行的高风险。 毫无疑问，可以防止这两种季节性的“通用”流感疫苗（匹配或 迫切需要不匹配的）和大流血病毒，但到目前为止，它仍然是“炼金术士的梦想”。我们 通过封装CGAMP（IFN）基因刺激剂的激动剂（IFN）基因的激动剂，开发了一种新颖的调整 （sting），进入肺表面活性剂（PS） - 生物映射脂质体（PS-GMNP）。调整，与 失活的流感疫苗，强烈刺激的体液和CD8+ T细胞免疫反应类似于这些反应 在病毒感染的早期阶段，无论是在大小还是动力学中。令人惊讶的是，一剂 PS-GMNP-Adjuvant流感疫苗引起了潜水员的致命挑战的强跨保护 免疫后2天，杂型流感A病毒。同时刺激强大的异质型 免疫力，调整不会引起肺组织学，体重或温度的任何不良事件， 与流感病毒感染引起的严重肺部感染和死亡形成鲜明对比。在此提案中，我们将 研究对PS-诱导的跨保护必不可少的细胞和体液免疫反应 gmnp辅助流感疫苗。特别是，我们将确定PS-GMNP是否可以扩展交叉反应性 CD8+ T细胞并影响广泛中和抗体（BNAB），对PS-GMNP诱导的跨 保护。在AIM 2中，我们将排除预先存在免疫对PS-辅助性的任何不利影响 GMNP并将交叉保护扩展到流行前野生型H5N1和H7N9病毒以建立其 临床潜力。与激活原代抗原细胞的常规调节器区分开 （APC），PS-GMNP传递的CGAMP激活了肺泡巨噬细胞（AMɸ）和肺泡上皮 细胞（AEC），这是至关重要的，因为在流感中也观察到这两种类型的细胞的类似激活 病毒感染。 AIM 3将进行两种替代方法，以证实 PS-GMNP介导的异源性免疫史的AEC和​​/或AMɸ，包括封锁细胞间隙连接 以及野生型和缺陷骨骨髓（BM）细胞的嵌合小鼠的产生。该研究，如果 成功，可以提供有关PS-GMNP临床潜力的宝贵信息，以扩大广度 现有的流感疫苗对一种“宇宙”，这将对全球健康产生巨大而直接的影响。