Maintaining Robust T Cell Immunity For Broad Protection Against Influenza

维持强大的 T 细胞免疫力以广泛预防流感

• 批准号: 9806329
• 负责人: SUSAN L SWAIN
• 金额: $ 25.13万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-18 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806329
• 关键词: Adjuvant; Adult; Affinity; Antibodies; Antibody Formation; Antibody titer measurement; Antigen Presentation; Antigens; Antiviral Agents; Attenuated; Automobile Driving; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Capsid Proteins; Cells; Cellular Immunity; Cessation of life; Childhood; Consensus; Core Protein; Death Rate; Development; Disease; Disease Outbreaks; Dose; Epitopes; Exposure to; FluMist; Generations; Health Hazards; Human; Immunity; In Situ; In Vitro; Inactivated Vaccines; Individual; Infection; Infection prevention; Influenza; Influenza A virus; Life; Lung; Mediating; Membrane Glycoproteins; Memory; Memory B-Lymphocyte; Molecular; Mus; Mutate; Natural regeneration; Oils; Pattern; Peptides; Persons; Secondary to; Signal Transduction; Symptoms; T cell response; T memory cell; T-Lymphocyte; Time; Vaccination; Vaccines; Variant; Viral Antigens; Virus; Virus Diseases; Water; Work; aging population; bone; cell injury; cytokine; cytotoxic; design; in vivo; in vivo evaluation; influenza virus vaccine; influenzavirus; memory CD4 T lymphocyte; neutralizing antibody; pandemic disease; pathogen; prevent; repaired; response; universal vaccine

ABSTRACT: Maintaining Robust T Cell Immunity for Broad Protection Against Influenza Influenza vaccines currently in use are designed, primarily to produce neutralizing antibody to coat proteins and must be reformulated and given each year. They are only partially effective, while live infection confers highly protective T cell mediated immunity which provides multiple additional protective mechanisms and also is crucial for generation of long-lasting neutralizing Ab. Our recent studies indicate that generation of protective CD4 T cell immunity requires strong presentation of viral antigen and infection-mediated signals lasting at least a week. This is because the effectors need to receive these signals during a clear-cut checkpoint to complete their transition to memory. Current vaccines rarely supply Ag or the relevant pathogen-recognition signals (PRS) at optimal levels for this long. Moreover, human responses often depend on already generated memory T cells, and it is not known whether memory CD4 T cells must go through a similar checkpoint to re-generate secondary (20) memory responses. Here we will compare the in vivo 20 response of memory CD4 T cells generated by inactivated whole influenza vaccine vs. live infection and determine whether the 20 CD4 effectors also need Ag and pathogen signals at a comparable “effector checkpoint”, via similar mechanisms, to re-generate 20 CD4 memory and if such memory does indeed provide strong heterosubtypic protection against multiple influenza A viruses. If so, it should be possible to augment vaccines to provide the Ag and pathogen signals both initially and at the checkpoint, and this should create a framework for a new generation of more effective vaccines against influenza that are more broadly protective and give long-lasting immunity. Moreover, it is likely that the same strategies could be applied to vaccines against other pathogens.

摘要：维持强大的T细胞免疫，以保护对流感的广泛保护 目前正在使用的流感疫苗是设计的，主要是为了产生蛋白质和蛋白质和 必须进行改革并每年给予。它们仅是部分有效的，而现场感染高度认可 保护性T细胞介导的免疫力，可提供多种额外的保护机制，并且至关重要 用于产生长期中和的AB。 我们最近的研究表明，受保护的CD4 T细胞免疫的产生需要强烈的病毒表现 抗原和感染介导的信号至少持续一周。这是因为效果需要接受 这些信号在清晰的检查点期间完成了其过渡到内存。当前的疫苗很少供应 AG或相关的病原体识别信号（PRS）在最佳水平上长期以来。而且，人类 响应通常取决于已经生成的内存T细胞，尚不清楚存储器CD4 T细胞是否 必须经过类似的检查点才能重新生成次级（20）内存响应。 在这里，我们将比较由灭活整个影响力产生的内存CD4 T细胞的体内20响应 疫苗与实时感染，并确定20个CD4生效器是否还需要在A处的AG和病原体信号 可比较的“效应子检查点”，通过类似的机制重新生成20个CD4内存以及此类内存 确实，确实提供了强烈的异型保护，以防止多种影响。 如果是这样，应该可以增强疫苗以最初和在 检查站，这应该为新一代更有效的疫苗创造一个框架 更广泛地保护并提供持久的免疫力。而且，相同的策略很可能 可以针对其他病原体应用于疫苗。