High vs. Standard Dose Flu Vaccine in Adult Stem Cell Transplant Recipients

项目总结 流感病毒是一种严重的病原体，对免疫功能低下的人，尤其是造血干细胞。 移植(HSCT)受者。然而，这些人对三价灭活流感的反应很差。 疫苗(TIV)。大剂量(HD)-TIV提高了65岁成年人的免疫原性和疗效。它是 尚不清楚HD-TIV对免疫功能严重受损的人是否安全和具有免疫原性。这个 TIV免疫原性的标准测量是血凝抑制(HAI)滴度。中心假说 我们建议的方案之一是，与标准剂量四价灭活相比，HD-TIV将具有更强的免疫原性 成人HSCT受者的流感疫苗(QIV)对甲型流感的高HAI抗体应答 抗原。拟议的研究是一项多中心、二期免疫原性和安全性试验，比较两种剂量。 成人HSCT受者HD-TIV与标准剂量QIV的比较。共有138名患者(18岁的≥) 接受异基因造血干细胞移植，并在移植后3-23个月将在以下临床站点登记： 范德比尔特大学医学中心(主要站点)；西北大学范伯格医学院，弗雷德 哈钦森癌症研究中心；阿拉巴马大学伯明翰医学院。具体的 目标如下：具体目标1)确定HD-TIV与标准剂量QIV是否 提高实现HAI滴度增加4倍、HAI滴度≥1：40或更高的可能性 成人造血干细胞移植受者甲型流感抗原的几何平均滴度(GMT)；特定目标2)至 确定征集的局部注射部位不良事件和征集的不良事件的频率和严重程度 成人HSCT中HD-TIV与标准剂量QIV的全身不良事件比较 明确HAI滴度、体内T细胞和B细胞表型之间的关系， 接受HD-TIV的成人HSCT受者的体外流感特异性T和B细胞反应 或标准剂量QIV。受试者将以1：1的方式随机接受2017-2018年的两剂 HD-TIV(每种流感抗原60微克)或2剂标准剂量QIV(每种流感抗原15微克)。 流感病毒抗原的HAI和微量中和效价、表型B和T细胞反应、B和T细胞 特异性流感反应、全血细胞计数、定量的CD4+/CD8+/CD19+水平和定量 在第一次和第二次接种疫苗前，即28-42天，将检测血清中的免疫球蛋白和免疫球蛋白。 在第二次接种疫苗后，以及第二次疫苗接种后大约7个月。征集的不良事件将 在接种疫苗和研究人员电话/电子邮件跟踪后七天，受试者将记录下来。 这项研究的结果将填补关于HSCT接受者流感疫苗反应的知识空白 并将指导这一脆弱人群的疫苗建议。

PROJECT SUMMARY Influenza virus is a serious pathogen in immunocompromised persons, especially hematopoietic stem cell transplant (HSCT) recipients. However, these individuals respond poorly to trivalent inactivated influenza vaccine (TIV). High dose (HD)-TIV has increased immunogenicity and efficacy in adults >65 years of age. It is not known whether a HD-TIV will be safe and immunogenic in severely immunocompromised persons. The standard measure of immunogenicity for TIV is hemagglutination inhibition (HAI) titers. The central hypothesis of our proposal is that HD-TIV will be more immunogenic compared to standard dose quadrivalent inactivated influenza vaccine (QIV) in adult HSCT recipients as evident by higher HAI antibody responses to influenza A antigens. The proposed study is a multi-center, phase II immunogenicity and safety trial comparing two doses of HD-TIV to standard dose QIV in adult HSCT recipients. A total of 138 patients (≥18 years of age) who received an allogeneic HSCT and are 3-23 months post-transplant will be enrolled at the following clinical sites: Vanderbilt University Medical Center (lead site); Northwestern University Feinberg School of Medicine, Fred Hutchinson Cancer Research Center; University of Alabama at Birmingham School of Medicine. The specific aims are as follow: Specific Aim 1) to determine whether HD-TIV compared with standard dose QIV will increase the probability of achieving either a ≥4-fold rise in HAI titer, a HAI titer ≥1:40, or a higher geometric mean titer (GMT) to influenza A antigens in adult HSCT recipients; Specific Aim 2) to determine the frequency and severity of solicited local injection site adverse events and solicited systemic adverse events associated with HD-TIV compared with standard dose QIV in adult HSCT recipients; Specific Aim 3) to define the relationship between HAI titers, in vivo T and B cell phenotype, and in vitro influenza-specific T and B cell responses in adult HSCT recipients receiving either HD-TIV or standard dose QIV. Subjects will be randomized in a 1:1 fashion to receive either 2 doses of 2017-2018 HD-TIV (60µg of each influenza antigen) or 2 doses of standard dose QIV (15µg of each influenza antigen). HAI and microneutralization titers to influenza virus antigens, phenotypic B and T cell responses, B and T cell specific influenza responses, complete blood count, quantitative CD4+/CD8+/CD19+ levels, and quantitative serum IgG and IgM concentrations will be measured prior to the first and second vaccine dose, 28-42 days after the second vaccine dose, and approximately 7 months after second vaccine. Solicited adverse events will be recorded by the subject seven days following vaccination and a telephone/email follow-up by study staff. The results of this study will fill a gap in knowledge regarding influenza vaccine responses in HSCT recipients and will guide vaccine recommendations in this vulnerable population.