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.

摘要 SARS-CoV-2大流行造成了巨大的生命损失，并在一个子集中造成了长期的健康后遗症 康复期的病人。关于SARS-CoV-2感染对原发性高血压患者的影响知之甚少。 免疫缺陷病（PIDD）。此外，还缺乏关于将残疾人纳入社会的指导方针。 SARS-CoV-2疫苗接种工作中的PIDD。 在PIDD中，主要抗体缺乏症最为普遍。X连锁无丙种球蛋白血症（XLA）是一种遗传性 一种由布鲁顿酪氨酸激酶突变引起的疾病，估计每200，000个新生儿中有1个发生 (BTK)导致B细胞发育停滞。因此，XLA患者不能产生抗体应答， 需要终生注射丙种球蛋白来预防感染。然而，这些输注并不 含有最近出现的SARS-CoV-2病毒的抗体，使这些患者容易受到COVID-19的影响。 目前批准的SARS-CoV-2疫苗被认为是通过介导抗感染的保护作用。 中和抗体的诱导。然而，目前所有的SARS-CoV-2候选疫苗都有可能 引发体液和T细胞反应。虽然T细胞反应不能保护免受病毒感染，但抗病毒T细胞反应可以预防病毒感染。 细胞反应在控制病毒复制和传播中是至关重要的。在XLA患者中， 被认为是正常的。因此，我们假设目前批准的SARS-CoV-2 mRNA疫苗 将引发持续的刺突蛋白特异性T细胞应答，具有保护免受以下疾病的潜力： 疫苗株和变异株的问题。支持我们的假设的数据记录， 接受灭活流感疫苗的XLA患者可以产生保护性流感特异性T细胞应答 与免疫活性个体的数量和质量相似。拟议研究的目标1将评估 XLA患者中SARS-CoV-2特异性T细胞应答的幅度、功能、持久性和广度 以及在接种疫苗和/或加强接种两种已批准的SARS之一后第1周、第3周、4个月和1年- CoV-2刺突蛋白mRNA疫苗。然而，XLA患者可以包括广谱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引发和活化中都是重要的。 特异性T细胞因此，拟议研究的目标2将评估单核细胞和树突状细胞的功能。 细胞，并将这些功能参数与XLA参与者中疫苗诱导的T细胞应答相关联。 同一个病人为了进行研究，我们将利用杜克大学的XLA患者的成熟队列， 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疫苗接种工作中的应用，并为其他PIDD人群的更大规模研究提供基础。