Comparison of High vs. Standard Dose Flu Vaccine in Pediatric 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有效。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 儿童HSCT受者的流感疫苗(QIV)对流感的HAI抗体应答较高 A类抗原。这项拟议的研究是一项多中心、二期免疫原性和安全性试验，比较了 儿童HSCT受者HD-TIV剂量与标准剂量QIV的比较共有200名儿科患者(3-17名 年龄)，接受异基因造血干细胞移植，并在移植后3-35个月将在 以下临床站点：范德比尔特大学(主要站点)、德州儿童医院贝勒医学院； 费城儿童医院；儿童慈悲医院；辛辛那提儿童医院；全国 儿童医院、西雅图儿童医院、圣犹大儿童研究医院和加州大学伯尼奥夫分校 儿童医院。具体目的是：1)确定HD-TIV是否与标准剂量相比较 QIV将增加实现HAI滴度≥增加4倍、HAI滴度≥1：40或更高的可能性 儿童HSCT受者甲型流感抗原的几何平均滴度(GMT)；2)确定频率 请求的局部注射部位不良事件和与之相关的请求的全身不良事件的严重性 比较HD-TIV与标准剂量QIV在儿童HSCT受者中的应用；3)明确两者之间的关系 HAI滴度、体内T和B细胞表型以及体外流感特异性T和B细胞应答之间的关系 接受HD-TIV或标准剂量QIV的儿童HSCT受者。受试者将以1：1的比例随机分配 2016-2017年度接种2剂HD-TIV(每个流感抗原60微克)或2剂 标准剂量QIV(每种流感抗原15微克)。流感病毒的HAI和微量中和效价 抗原，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+水平和定量的血清免疫球蛋白浓度将在 第一次和第二次接种，第二次接种后28-42天，大约7个月后 第二种疫苗。被请求的不良事件将由家长/受试者在接下来的七天内记录 疫苗接种和研究人员的电话跟踪。这项研究的结果将填补一项知识空白 关于儿童HSCT受者的流感疫苗反应，并将在#年指导疫苗推荐 这些脆弱的人群。

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 effective 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 pediatric 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 pediatric HSCT recipients. A total of 200 pediatric patients (3-17 years of age) who received an allogeneic HSCT and are 3-35 months post-transplant will be enrolled at the following clinical sites: Vanderbilt University (lead site); Baylor School of Medicine, Texas Children's Hospital; Children's Hospital of Philadelphia; Children's Mercy Hospital; Cincinnati Children's Hospital; Nationwide Children's Hospital, Seattle Children's Hospital; St. Jude Children's Research Hospital, and UCSF Benioff Children's Hospital. The specific aims are: 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 pediatric HSCT recipients; 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 pediatric HSCT recipients; 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 pediatric 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 2016-2017 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 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 parent/subject seven days following vaccination and a telephone follow-up by study staff. The results of this study will fill a gap in knowledge regarding influenza vaccine responses in pediatric HSCT recipients and will guide vaccine recommendations in this vulnerable population.