Vaccine-induced SARS-CoV-2-specific T cell responses in patients with X-linked Agammaglobulinemia

X 连锁无丙种球蛋白血症患者中疫苗诱导的 SARS-CoV-2 特异性 T 细胞反应

• 批准号: 10593523
• 负责人: Kristina De Paris
• 金额: $ 24.99万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-09 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10593523
• 关键词: 2019-nCoV; APC Vaccine; Activities of Daily Living; Adult; Affect; Agammaglobulinaemia tyrosine kinase; Age; Antibodies; Antibody Response; Antigen-Presenting Cells; Antigens; Authorization documentation; B-Cell Development; B-Lymphocytes; Bacterial Infections; Birth; CD8-Positive T-Lymphocytes; COVID-19; COVID-19 pandemic; COVID-19 vaccination; COVID-19 vaccine; Cell physiology; Cells; Child; Data; Deficiency Diseases; Dendritic Cells; Development; Disease; Face; Foundations; Gamma globulin; Genetic Diseases; Goals; Guidelines; Health; Health Personnel; Health Policy; Human; Immune; Immune response; Immunization; Immunocompetent; Immunocompromised Host; Immunologic Deficiency Syndromes; Impairment; In Vitro; Individual; Infection; Infection prevention; Influenza; Infusion procedures; Life; Ligands; Link; Lung infections; Mature B-Lymphocyte; Measures; Mediating; Memory; Messenger RNA; Mutation; Organ; Outcome; Participant; Patients; Persons; Pfizer-BioNTech COVID-19 vaccine; Play; Population; Production; Proteins; RNA vaccination; RNA vaccine; Receptor Signaling; Role; SARS-CoV-2 infection; SARS-CoV-2 spike protein; SARS-CoV-2 variant; Signal Transduction; T cell response; T-Cell Development; T-Lymphocyte; Toll-like receptors; United States; Vaccination; Vaccine Clinical Trial; Vaccines; Variant; Viral; Virus; Virus Activation; Virus Diseases; Virus Replication; Vulnerable Populations; X-Linked Agammaglobulinemia; age group; antigen-specific T cells; authority; cohort; congenital immunodeficiency; cross reactivity; cytokine; influenza virus vaccine; lung injury; male; monocyte; neutralizing antibody; prevent; recurrent infection; severe COVID-19; sex; vaccine candidate; vaccine distribution; vaccine hesitancy; variants of concern

ABSTRACT The SARS-CoV-2 pandemic has resulted in enormous loss of life and in long-lasting health sequalae in a subset of convalescent patients. Little is known about the impact of SARS-CoV-2 infection on people with primary immune deficiency diseases (PIDD). There is also a lack of guidelines regarding the inclusion of people with PIDD in SARS-CoV-2 vaccination efforts. Among PIDD, primary antibody deficiencies are most prevalent. X-linked agammaglobulinemia (XLA) is a genetic disorder that is estimated to occur in 1 of 200,000 births and is caused by a mutation in Bruton tyrosine kinase (BTK) that leads to an arrest in B cell development. Thus, XLA patients cannot mount antibody responses and require lifelong therapy with gammaglobulin infusions to prevent infections. These infusions, however, do not contain antibodies to the recently emerged SARS-CoV-2 virus leaving these patients vulnerable to COVID-19. The currently approved SARS-CoV-2 vaccines are thought to mediate protection against infection through the induction of neutralizing antibodies. However, all current SARS-CoV-2 vaccine candidates have the potential to elicit humoral and T cell responses. Although T cell responses cannot protect against viral infection, anti-viral T cell responses are critical in the control of virus replication and dissemination. In XLA patients, T cell responses are considered to be normal. Thus, we hypothesize that the currently approved SARS-CoV-2 mRNA vaccines will elicit persistent Spike protein-specific T cell responses with the potential to protect against disease against the vaccine strain and variants of concerns. Support for our hypothesis is provided by data documenting that XLA patients receiving the inactivated influenza vaccine can mount protective influenza-specific T cell responses at a similar magnitude and quality as immunocompetent individuals. Aim 1 of the proposed studies will assess magnitude, function, durability, and breadth of SARS-CoV-2 specific T cell responses in XLA patients prior to and at week 1, week 3, 4 months and 1 year after vaccination and/or boost with one of the two approved SARS- CoV-2 Spike protein mRNA vaccines. XLA patients, however, can encompass a broad spectrum of BTK mutations. Some BTK mutations can inhibit Toll-like receptor signaling and other innate functions in monocytes and dendritic cells. Both monocytes and dendritic cells are important in the priming and activation of antigen- specific T cells. Therefore, Aim 2 of the proposed studies, will assess the function of monocytes and dendritic cells in XLA participants and correlate these functional parameters to vaccine-induced T cell responses in the same patient. To perform the studies, we will leverage well-established cohorts of XLA patients at Duke, UNC, and USF. The results of our study are expected to inform health policies regarding the inclusion of XLA patients in SARS-CoV-2 vaccination efforts and provide the foundation for larger studies with other PIDD populations.

抽象的 SARS-COV-2大流行导致了巨大的生命损失，并在子集中持续持久的健康序列 康复患者。关于SARS-COV-2感染对主要患者的影响很少 免疫缺陷疾病（PIDD）。关于包括 SARS-COV-2疫苗接种工作中的PIDD。 在PIDD中，主要抗体缺陷最为普遍。 X连锁的Agammaglobulobulinemia（XLA）是一种遗传 据估计，疾病发生在200,000个出生中的1例中，是由布鲁顿酪氨酸激酶突变引起的 （BTK）导致B细胞发育逮捕。因此，XLA患者无法安装抗体反应，并且 需要用γ球蛋白输注终身治疗以防止感染。但是，这些注入不会 含有与最近出现的SARS-COV-2病毒的抗体，使这些患者容易受到COVID的影响。 当前批准的SARS-COV-2疫苗被认为可以通过 诱导中和抗体。但是，所有当前的SARS-COV-2疫苗候选者都有可能 引起体液和T细胞反应。尽管T细胞反应无法预防病毒感染，但抗病毒T 细胞反应对于控制病毒复制和传播至关重要。在XLA患者中，T细胞反应 被认为是正常的。因此，我们假设当前批准的SARS-COV-2 mRNA疫苗 将引起持续的尖峰蛋白特异性T细胞反应，以防止疾病免受 疫苗应变和关注的变体。数据记录提供了对我们假设的支持 接受灭活流感疫苗的XLA患者可以安装保护性流感特异性T细胞反应 与免疫能力的个体相似。拟议研究的目标1将评估 在XLA患者中，SARS-COV-2特异性T细胞反应的大小，功能，耐用性和广度 在接种疫苗接种后第1周，第3周，第4个月零1年和/或提升两个批准的SARS- COV-2尖峰蛋白mRNA疫苗。但是，XLA患者可以涵盖一大批BTK 突变。一些BTK突变可以抑制单核细胞中的Toll样受体信号传导和其他先天功能 和树突状细胞。单核细胞和树突状细胞在抗原的启动和激活中都很重要 特定的T细胞。因此，拟议的研究的目标2将评估单核细胞和树突状的功能 XLA参与者中的细胞并将这些功能参数与疫苗诱导的T细胞反应相关联 同一个病人。为了进行研究，我们将利用杜克大学UNC，UNC， 和USF。我们的研究结果有望为纳入XLA患者的卫生政策提供信息 在SARS-COV-2疫苗接种工作中，并为其他PIDD人群提供了大型研究的基础。