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.

抽象的： 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。随着年龄的增长， 从幼稚 CD4 T 细胞产生滤泡辅助 T 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) 所必需的，但都变得高度受损。最新 老年人的流感疫苗不能有效诱导这些关键反应。因此，老年人， 尽管已经受到针对生命早期遇到的病原体的抗体的保护，但仍然非常容易受到新的病原体的影响 病毒株（例如流感）和新出现的病原体（例如大流行性流感、COVID-19）。我们 描述了异常的抗体分泌 B 细胞群的产生，这些细胞发育成活流感病毒 老年小鼠的感染。我们发现它们源自最近描述的“与年龄相关的 B 初始 sIgD+ 表型的细胞”(ABC)。在老年人中，会产生这些流感诱导的 ABC (iABC) 独立于 CD4 T 细胞的帮助，但严格依赖于病原体相关“危险”信号的刺激 因此，它们在老年感染小鼠中可以很好地产生。值得注意的是，ABC 是主要的幼稚 B 细胞， 老年小鼠中有反应。 在这里，我们将确定 IgD ABC 对流感感染做出反应并产生抗体分泌细胞的潜力 (AbSC) 效应子 iABC 要么是再循环的，要么是组织驻留的。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命的抗体分泌细胞，如果这些细胞存在于下层细胞中， 呼吸道（肺）和上呼吸道（URT）：鼻组织和鼻相关淋巴组织- NALT），以及脾脏和 BM。我们将确定 ABC 衍生效应器和记忆的贡献 子集及其在这些不同位点产生的抗体，以防止再次感染。我们会问多久- 活着的是不同地点的记忆细胞。我们将比较活流感病毒、全灭活流感病毒的能力 病毒和 mRNA-LNP HA 疫苗产生再循环和组织驻留效应子和记忆子集 并诱导保护性免疫。这些结果将为我们提供对这种新型年龄相关免疫的新见解 途径，并为我们提供重要的新见解，了解利用老化的 ABC 反应是否可以提供 为老年人提供卓越的保护。它将提供一般疫苗策略可能是什么的指示 老年人需要接种 ABC 疫苗。这些发现可能会导致更通用的疫苗 为目前高度脆弱的老年人提供强有力的保护。