Combination nanovaccine-based immunization against influenza virus in the aged: immunity and protection

基于纳米疫苗的老年人流感病毒联合免疫：免疫与保护

• 批准号: 10553681
• 负责人: Marian L Kohut
• 金额: $ 71.62万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-16 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553681
• 关键词: Adjuvant; Adult; Aging; Antibodies; Antibody Formation; Antibody Response; Antibody titer measurement; Antigen Presentation; Antigens; B-Cell Activation; B-Lymphocytes; Biocompatible Materials; Biology of Aging; Blood; CD8-Positive T-Lymphocytes; Cell physiology; Cellular Immunity; Cellular Metabolic Process; Cessation of life; Characteristics; Clinical Trials; Data; Defect; Dendritic Cells; Development; Dose; Elderly; Formulation; Goals; Health; Helper-Inducer T-Lymphocyte; Hemagglutinin; Human; Immune; Immune response; Immune system; Immunity; Immunization; Impairment; In Vitro; Individual; Infection; Inflammation; Inflammatory; Influenza; Influenza A virus; Influenza vaccination; Lead; Lung; Measures; Memory; Metabolic; Micelles; Mitochondria; Modeling; Mus; Nucleoproteins; Older Population; Outcome; Outcome Measure; Oxidative Phosphorylation; Phenotype; Polyanhydrides; Population; Public Health; Publishing; Recombinants; Research; Respiration; Risk; Role; Route; Serum; Spleen; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Underserved Population; Vaccines; Viral Load result; Virus Diseases; adaptive immunity; age related; aged; amphiphilicity; arm; cell age; cell motility; copolymer; design; draining lymph node; flexibility; hospitalization rates; human old age (65+); immunogenicity; improved; influenza infection; influenza virus vaccine; influenzavirus; insight; lymph nodes; metabolic profile; mortality; nanoparticle; nanopolymer; nanovaccine; nonhuman primate; novel; novel strategies; peripheral blood; preservation; primary outcome; rational design; respiratory; response; safety study; self assembly; vaccine delivery; vaccine efficacy; vaccine formulation; vaccine platform; vaccine response; vaccine-induced immunity; young adult

PROJECT SUMMARY / ABSTRACT Age-related defects of the immune response contribute to reduced efficacy of the influenza vaccine in older adults. Influenza A virus (IAV) infection results in greater risk of complications and higher hospitalization rates in older adults, with approximately 90% of deaths occurring in adults over age 65. Therefore, the development of a safe and effective vaccine that promotes protective immunity for the aged is an urgent public health need. The overall goal of this revised R01 application is to identify the effect of vaccine biomaterials and adjuvants on DC metabolism, and subsequent effects on antibody and T cell memory to develop a nanovaccine to overcome age-related immune impairments. Vaccines for older adults can be further optimized with biomaterials that enhance multiple arms of the immune system and provide a platform to expand antigen selection, broadening protection. Our studies will establish the contribution of specific biomaterials and adjuvants in improving B and T cell outcomes resulting in protection by enhancing vaccine efficacy. The goals are to: 1) develop an efficacious influenza nanovaccine for older populations; and 2) to understand the mechanisms by which rational selection of biomaterials and co-adjuvants in vaccines can enhance immune capabilities of aged individuals. Our two polymeric nanovaccine platforms, polyanhydride nanoparticles and pentablock copolymer micelles, have been shown to increase antibody titers, improve cell-mediated immunity, and prolong antigen delivery resulting in a protective immune response with reduced viral load upon delivery of recombinant hemagglutinin and nucleoprotein in an IAV challenge model. Compelling preliminary data demonstrates that these formulations differentially alter dendritic cell (DC) metabolic profile compared to traditional adjuvants. Aim 1 will identify how nanovaccine biomaterials and adjuvants that promote DC metabolic health augment the immune response in aged mice. Different vaccine formulations will compare adjuvants that produce high glycolytic responses with formulations that retain some oxidative phosphorylation and spare respiratory capacity to optimize DC function. In the second aim, we will optimize the nanovaccine formulation(s) that enhance B cell activation in aged mice and peripheral blood B cells from aged humans. Additionally, we will identify mechanisms by which our nanovaccine improves T follicular helper responses and the induction of protective immunity on an aging background. Traditional inactivated IAV vaccine will be used as a control so as to identify the formulation providing superior protection than the current vaccine. In Aim 3, we will determine how nanovaccine-induced metabolically-optimized DC-T cell priming contributes to T cell memory and heterologous protection against IAV in aged mice. Measures of viral load, serum antibody, and lung T cell responses will be evaluated in homologous and heterosubtypic IAV challenges in aged mice. The long-term goal of this research is to define the mechanisms responsible for induction of protective immune responses in aging populations, thus facilitating the rational design of improved vaccines for this underserved population.

项目摘要/摘要