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.

摘要 目前流行性感冒（流感）疫苗仅对密切匹配的流感病毒株有效，必须更新 每年一次，以解决持续的抗原转移/表面血凝素（HA）和/或神经氨酸酶（NA）的漂移， 病毒即使每年更新一次，也有几年流感疫苗由于以下原因而无效： 用于制备疫苗的菌株之间HA和/或NA的抗原性存在显著差异， 传播的病毒，一旦出现新的和高度病理性的病毒，我们就有很高的流行风险。 毫无疑问，一种“通用”流感疫苗，可以防止季节性（匹配或 错配）和大流行性流感病毒是迫切需要的，但它仍然是“炼金术士的梦想”到目前为止。我们 通过包裹cGAMP，开发了一种新型佐剂，cGAMP是干扰素（IFN）基因刺激物的激动剂 （STING），进入肺表面活性物质（PS）-仿生脂质体（PS-GMNP）中。佐剂，以及 灭活流感疫苗，强烈刺激体液和CD 8 + T细胞免疫反应，类似于那些 发生在病毒感染的早期阶段，无论是在数量上还是在动力学上。令人惊讶的是，一剂 PS-GMNP-佐剂流感疫苗引发了针对多种致命攻击的强交叉保护， 在免疫接种后2天，在刺激强大的异亚型 免疫，佐剂没有引起肺组织学，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炎症和死亡形成鲜明对比。在本提案中，我们将 研究PS诱导的交叉保护所必需的细胞和体液免疫应答， GMNP佐剂流感疫苗。具体地说，我们将确定PS-GMNP是否可以扩大交叉反应， CD 8 + T细胞和诱导广泛中和抗体（bnAbs），这是PS-GMNP诱导的交叉免疫的关键。 保护在目标2中，我们将排除预先存在的免疫对PS的佐剂性的任何不利影响。 GMNP，并将交叉保护扩展到大流行前的野生型H5 N1和H7N9病毒，以建立其 临床潜力区别于主要激活抗原呈递细胞的常规佐剂 在APCs中，由PS-GMNP递送的cGAMP激活肺泡巨噬细胞（aM β）和肺泡上皮细胞（aM β）。 细胞（AEC），这可能是至关重要的，因为在流感期间也观察到这两种类型细胞的类似激活 病毒感染在目标3中，将采用两种不同的方法来证实 在PS-GMNP介导的异亚型免疫中的AEC和/或aM β，包括细胞间隙连接的阻断 以及产生野生型和STING缺陷型骨髓（BM）细胞的嵌合小鼠。这项研究，如果 成功，可以提供关于PS-GMNP的临床潜力的宝贵信息，以扩大 这将对全球健康产生巨大而直接的影响。