Harnessing Age-Associated B cells for a Universal Influenza Vaccine for the Aged

利用与年龄相关的 B 细胞开发针对老年人的通用流感疫苗

• 批准号: 10573680
• 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: 2022
• 资助国家: 美国
• 起止时间: 2022-11-03 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10573680
• 关键词: Age; Aging; Antibodies; Antibody Affinity; Antibody titer measurement; Antibody-mediated protection; Antigens; B-Lymphocyte Subsets; B-Lymphocytes; Body Weight decreased; Bone Marrow; Bronchial Lavages; CD4 Positive T Lymphocytes; COVID-19; Cause of Death; Cell Lineage; Cell secretion; Cells; Development; Dose; Effector Cell; Elderly; Exposure to; Generations; Germ-Free; Immune; Immunity; Immunize; Immunoglobulin A; Immunoglobulin D; Immunoglobulin M; Immunoglobulin-Secreting Cells; Inactivated Vaccines; Infection; Influenza; Learning; Life; Location; Longevity; Lower respiratory tract structure; Lung; Lymphoid Tissue; Mediating; Memory; Memory B-Lymphocyte; Messenger RNA; Mus; Nasal Lavage Fluid; Nose; Pathway interactions; Phase; Phenotype; Population; Predisposition; Property; RNA; Residencies; Respiratory System; Rest; Role; Route; Serum; Signal Transduction; Site; Spleen; Structure of germinal center of lymph node; Subunit Vaccines; T-Lymphocyte; TLR7 gene; Testing; Time; Tissues; Upper respiratory tract; Vaccines; Viral; Virus; Weights and Measures; aged; aging population; combat; commensal microbes; emerging pathogen; influenza infection; influenza outbreak; influenza virus vaccine; influenzavirus; insight; migration; neutralizing antibody; novel; pandemic influenza; pathogen; programs; residence; respiratory; respiratory pathogen; response; seasonal influenza; secondary lymphoid organ; stem cells; universal influenza vaccine; universal vaccine; vaccination strategy; vaccine strategy

ABSTRACT: Harnessing Age-Associated B Cells for a Universal Influenza Vaccine for the Aged. With age, the generation of T follicular helpers from naive CD4 T cells, and germinal center B cells from follicular B cells, that are both needed for the generation of high affinity antibody (Ab), become highly compromised. Most current vaccines for influenza in the elderly are not effective at inducing these critical responses. Thus, the elderly, though protected by Ab already in place for pathogens encountered earlier in life, are highly susceptible to new strains of virus (e.g. influenza) and newly emerged pathogens (e.g. pandemic influenzas, COVID-19). We described the generation of an unusual population of Ab-secreting B cells that developed to live influenza infection in aged mice. We found they were derived from stimulation of recently described "age-associated B cells" (ABC) of a naïve sIgD+ phenotype. In the aged, these influenza-induced ABC (iABC) are generated independently of CD4 T cell help, but strictly depend on stimulation by pathogen-associated "danger" signals and thus they are generated well in aged infected mice. Notably, ABC are the predominant naïve B cells that respond in aged mice. Here we will determine the potential of IgD ABC to respond to influenza infection and generate Ab-secreting cells (AbSC) effector iABC that are either recirculating or are tissue resident. We will determine if they give rise to B cell memory, both resting memory and long-lived Ab-secreting cells, and if these are found in the lower respiratory tract (lung) and upper respiratory tract (URT):nasal tissues and nasal associated lymphoid tissue- NALT), as well as the spleen and BM. We will determine the contribution of ABC-derived effector and memory subsets and the Ab they produce in these the different sites to protection from reinfection. We will ask how long- lived are the memory cells in distinct sites. We will compare the ability of live influenza virus, whole inactivated virus, and mRNA-LNP HA vaccine to generate the recirculating and tissue resident effector and memory subsets and to induce protective immunity. These results will give us new insights into this novel age-associated immune pathway and give us important new insights into whether harnessing the aged ABC response can provide superior protection in the aged. It will provide indications of what general vaccine strategies are likely to be needed to immunize the ABC in the elderly. These findings could lead to a more Universal vaccines that can provide robust protection to the elderly, who are currently highly vulnerable.

摘要： 利用与流感相关的B细胞作为老年人通用流感疫苗。随着年龄的增长， 从初始CD 4 T细胞产生T滤泡辅助细胞，从滤泡B细胞产生生发中心B细胞， 两者都是产生高亲和力抗体（Ab）所需的，变得高度受损。最新 老年人的流感疫苗不能有效诱导这些关键反应。故长者， 虽然已经有抗体对生命早期遇到的病原体进行保护，但它们对新的 病毒株（如流感）和新出现的病原体（如大流行性流感，COVID-19）。我们 描述了一种不寻常的分泌抗体的B细胞群的产生，这种细胞群发展成活的流感病毒 感染老年小鼠。我们发现它们来源于刺激最近描述的“年龄相关B 幼稚sIgD+表型的“细胞”（ABC）。在老年人中，这些流感诱导的ABC（iABC） 独立于CD 4 T细胞帮助，但严格依赖于病原体相关的“危险”信号的刺激 因此它们在年老的感染小鼠中很好地产生。值得注意的是，ABC是主要的幼稚B细胞， 老年小鼠的反应。 在这里，我们将确定免疫球蛋白ABC的潜力，以应对流感感染，并产生抗体分泌细胞 （AbSC）效应物iABC，其是再循环的或组织驻留的。我们将确定它们是否会产生B 细胞记忆，包括静息记忆和长寿的Ab分泌细胞，如果这些细胞在较低的水平上被发现， 呼吸道（肺）和上呼吸道（URT）：鼻组织和鼻相关淋巴组织- NALT），以及脾和BM。我们将确定ABC衍生的效应器和记忆的贡献 亚群和抗体，他们在这些不同的网站，以保护免受再感染。我们会问多久- 不同部位的记忆细胞存活。我们将比较活流感病毒的能力， 病毒和mRNA-LNP HA疫苗，以产生再循环和组织驻留效应子和记忆子亚群 并诱导保护性免疫。这些结果将使我们对这种新的年龄相关免疫系统有新的认识。 途径，并为我们提供重要的新见解，以了解利用老年ABC反应是否可以提供 对老年人的上级保护。它将提供什么样的一般疫苗策略的迹象可能是 需要在老年人中接种ABC。这些发现可能会导致更普遍的疫苗， 为目前非常脆弱的老年人提供强有力的保护。