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

基本信息

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
项目类别：
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

项目摘要

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 细胞免疫力以广泛预防流感目前使用的流感疫苗主要是为了产生中和抗体来包裹蛋白质和必须每年重新配制并给予，它们只能部分有效，而活感染则具有很高的效果。保护性 T 细胞介导的免疫提供了多种额外的保护机制，也是至关重要的用于产生持久的中和抗体。我们最近的研究表明，保护性 CD4 T 细胞免疫的产生需要病毒的强烈呈递。抗原和感染介导的信号持续至少一周，这是因为效应器需要接收。这些信号在明确的检查点完成向记忆的过渡，目前很少提供疫苗。 Ag 或相关病原体识别信号 (PRS) 在这段时间内处于最佳水平。反应通常取决于已经生成的记忆 T 细胞，目前尚不清楚记忆 CD4 T 细胞是否必须经过类似的检查点才能重新生成辅助 (20) 记忆响应。这里我们将比较灭活的全流感产生的记忆CD4 T细胞的体内20反应疫苗与活感染，并确定 20 个 CD4 效应器是否也需要 Ag 和病原体信号类似的“效应检查点”，通过类似的机制，重新生成20个CD4记忆，如果这样的记忆确实可以针对多种甲型流感病毒提供强大的异亚型保护。如果是这样，应该有可能增强疫苗以提供最初的抗原和病原体信号。检查点，这应该为新一代更有效的流感疫苗创建一个框架具有更广泛的保护作用并提供持久的免疫力此外，很可能采用相同的策略。可应用于针对其他病原体的疫苗。