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.

项目概要 目前基于高变血凝素 (HA) 蛋白的流感 (flu) 疫苗无法提供 有效的交叉保护。即使已有疫苗接种，老年人口的疫苗接种效果也较低 免疫。预先存在的免疫力对通用和季节性疫苗的免疫原性和功效的影响 老年人口对疫苗接种的了解在很大程度上仍不明确。开发新的流感疫苗和 疫苗接种策略可提高年轻幼稚宿主和老年宿主的交叉保护功效 免疫力是重中之重。在幼稚动物中测试诱导交叉保护的单保守抗原靶标 模型包括甲型流感病毒 M2 胞外结构域 (M2e)、HA 茎结构域和神经氨酸酶 (NA) 已报道但不足以翻译给人类。适用于幼稚宿主和老年宿主的多靶点通用疫苗 与预先存在的免疫力仍有待开发。 我们开发了在免疫原性病毒样上呈现的 M2e (5xM2e) 异源串联重复序列 颗粒（5xM2e VLP）。 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 候选疫苗中，我们开发了一种含有多亚型 NA 和 5xM2e 的多 NA + 5xM2e VLP 疫苗 相同的VLP颗粒。此外，我们新设计了基因连锁的新型重组M2e-stalk 通用蛋白疫苗可有效诱导 M2e 和 HA 茎免疫并赋予广泛的交叉免疫 群体保护。辅助性普遍疫苗接种将通过以下方式克服与衰老相关的免疫衰老： 在已有免疫力的情况下激活幼稚宿主或老年人群中的 T 和 B 免疫细胞。 在这个项目中，我们将测试新的通用疫苗诱导多重免疫（M2e， Stalk，NA）将增强成人和老年人群交叉保护的广度和功效，或 没有预先存在的免疫力。在目标 1 下，我们将确定多靶点通用疫苗的功效 处于幼稚和预先存在的免疫条件下的年轻成年小鼠和雪貂。在目标 2 研究中，我们将 通过多目标新通用疫苗确定交叉保护免疫的持久性并测试 疫苗接种策略增强老年小鼠和雪貂动物模型的交叉保护。在目标 3 中，我们将 研究青少年和老年人多靶点通用疫苗接种的交叉保护免疫机制 鼠标模型。该项目的成果在转化科学和 提高流感疫苗接种交叉保护功效的相关性。