Seasonal and universal Vaccination in aged populations with pre-existing immunity

对已有免疫力的老年人群进行季节性和普遍的疫苗接种

• 批准号: 10313001
• 负责人: SANG-MOO KANG
• 金额: $ 50.2万
• 依托单位: GEORGIA 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: 2021-05-21 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10313001
• 关键词: Adjuvant; Adult; Affinity; Age; Aging; Animal Model; Animals; Antibodies; Antibody Affinity; Antigen Targeting; Avian Influenza; B-Lymphocytes; Cells; Cessation of life; Chemicals; Chickens; Collaborations; Complex; Consensus; Data; Development; Elderly; Epitopes; Exposure to; Extracellular Domain; Ferrets; Flu virus; Generations; Hemagglutinin; Human; Immune; Immune Sera; Immune response; Immunity; Immunization Programs; Immunoglobulin G; Individual; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H7N9 Subtype; Influenza A Virus, H9N2 Subtype; Influenza vaccination; Knockout Mice; Length; Link; Mus; Mutate; Neuraminidase; Outcome; Phylogenetic Analysis; Play; Preparation; Proteins; Public Health; RHOA gene; Recombinants; Reporting; Role; Structure of germinal center of lymph node; Surface; T-Lymphocyte; Tandem Repeat Sequences; Testing; Translational Research; Vaccination; Vaccines; Virus; Virus Diseases; Virus-like particle; aged; aging population; base; design; efficacy testing; flu; human old age (65+); immunogenic; immunogenicity; improved; influenza infection; influenza virus vaccine; mouse model; nanoparticle; novel; particle; protective efficacy; response; seasonal influenza; senescence; translation to humans; universal influenza vaccine; universal vaccine; vaccination strategy; vaccine candidate; vaccine evaluation; young adult

PROJECT SUMMARY Current influenza (flu) vaccination based on hypervariable hemagglutinin (HA) protein fails to provide effective cross protection. The efficacy of vaccination is low in the aged populations even with pre-existing immunity. The impacts of pre-existing immunity on the immunogenicity and efficacy of universal and seasonal vaccination largely remain not well understood in the aged populations. Development of new flu vaccines and vaccination strategies improving cross protective efficacy in young naïve and aged hosts with pre-existing immunity is of high priority. Mono conserved antigenic targets inducing cross protection tested in naïve animal models include the flu A virus M2 extracellular domain (M2e), HA-stalk domains, and neuraminidase (NA) were reported but insufficient for translation to humans. The multi-target universal vaccines in naïve and aged hosts with pre-existing immunity remain to be developed. We developed heterologous tandem repeat of M2e (5xM2e) presented on immunogenic virus-like particles (5xM2e VLP). Vaccination with 5xM2e VLP was effective in broadening cross protection but suboptimal. A further improved universal vaccine should be developed. Our preliminary studies found synergistic effects on improving cross protection by both M2e and NA immunity. Therefore, as a new universal vaccine candidate, we developed a multi NA + 5xM2e VLP vaccine containing multi-subtype NA and 5xM2e on the same VLP particle. In addition, we newly designed genetically linked novel recombinant M2e-stalk universal protein vaccines effectively inducing both M2e and HA-stalk immunity and conferring broad cross- group protection. Adjuvanted universal vaccination will overcome the aging-related immune senescence by activating T and B immune cells in naïve hosts or aged populations under pre-existing immunity. In this project, we will test the hypothesis that new universal vaccination inducing multi immunity (M2e, Stalk, NA) will enhance the breadth and efficacy of cross protection in adult and aged populations with or without pre-existing immunity. Under Aim 1, we will determine the efficacy of multi-target universal vaccines in young adult mice and ferrets under naïve and pre-existing immune conditions. In Aim 2 studies, we will determine the durability of cross protective immunity by multi targeting new universal vaccines and test a vaccination strategy enhancing cross protection in aged mouse and ferret animal models. In the Aim 3, we will investigate cross protective immune mechanisms of multi targeting universal vaccination in young and aged mouse models. The outcomes in this project will be highly significant in the aspect of translational science and relevance to improve the cross protective efficacy of flu vaccination.

项目摘要 基于高变量血凝蛋白（HA）蛋白的当前流感（流感）疫苗接种未能提供 有效的交叉保护。即使先前存在的疫苗效率也很低 免疫。预先存在免疫对通用和季节性免疫原性和效率的影响 在老年人群中，疫苗接种在很大程度上尚未得到很好的了解。开发新的流感疫苗和 疫苗接种策略提高了年轻的幼稚和老年宿主的交叉保护效率 免疫力很高。单声道保守的抗原靶标诱导了在幼稚的动物中测试的横向保护 模型包括流感A病毒M2细胞外结构域（M2E），HA - stalk结构域和神经瘤酶（NA）为 报告但不足以翻译为人类。幼稚和老年宿主中的多目标通用疫苗 预先存在的免疫力仍有待发展。 我们开发了M2E（5xM2E）的异源串联重复 颗粒（5xm2e VLP）。使用5xM2E VLP疫苗接种可有效扩大交叉保护，但 次优。应开发进一步改进的通用疫苗。我们的初步研究发现 M2E和NA免疫对改善交叉保护的协同作用。因此，作为一个新的通用 候选疫苗，我们开发了一个多NA + 5xM2E VLP疫苗，其中含有多含量Na和5xm2e 相同的VLP粒子。此外，我们新设计的一般连接的新型重组M2E stalk 通用蛋白质疫苗有效诱导M2E和HA stalk免疫组织化学和会议广泛的交叉 团体保护。调整的通用疫苗接种将通过 在预先存在的免疫细胞下，在幼稚的宿主或老年人群中激活T和B免疫球。 在这个项目中，我们将检验以下假设：新的通用疫苗接种诱导的多免疫协会（M2E，，M2E， Stalk，Na）将通过OR或 没有预先存在的免疫力。在AIM 1下，我们将确定多目标通用疫苗的效率 年轻的成年小鼠和雪貂在幼稚且先前存在的免疫条件下。在AIM 2研究中，我们将 通过多个靶向新的通用疫苗来确定交叉保护免疫的耐用性并测试 疫苗接种策略增强了老鼠和雪貂动物模型的交叉保护。在目标3中，我们将 研究年轻人和老年的多靶向通用疫苗接种的跨保护免疫机制 鼠标模型。在转化科学方面，该项目的结果将非常重要 相关性，以提高流感疫苗的交叉保护效率。