Comparison of High vs. Standard Dose Flu Vaccine in Pediatric Stem Cell Transplant Recipients

项目摘要 流感病毒是免疫功能低下者，尤其是造血干细胞缺乏者的重要病原体 移植（HSCT）受者。然而，这些个体对三价灭活流感的反应较差 TIV疫苗。高剂量（HD）-TIV在>65岁的成人中具有增加的免疫原性和功效。是 尚不清楚HD-TIV在严重免疫功能低下患者中是否安全有效。的 TIV免疫原性标准量度是血凝抑制（HAI）滴度。核心假设 我们的建议是，与标准剂量四价灭活相比，HD-TIV的免疫原性更强 流感疫苗（QIV）在儿科HSCT接受者中的应用，如对流感的较高HAI抗体应答所证实 A抗原。该研究是一项多中心、II期免疫原性和安全性试验， 在儿科HSCT接受者中，将HD-TIV剂量改为标准剂量QIV。共200例儿科患者（3-17岁 接受同种异体HSCT且移植后3-35个月的受试者将在 以下临床研究中心：范德比尔特大学（牵头研究中心）;贝勒医学院，德克萨斯州儿童医院; 费城儿童医院;儿童慈善医院;辛辛那提儿童医院 儿童医院、西雅图儿童医院、圣裘德儿童研究医院和UCSF贝尼奥夫 儿童医院具体目的是：1）确定HD-TIV是否与标准剂量相比 QIV将增加HAI滴度升高≥4倍、HAI滴度≥1：40或更高的可能性 儿科HSCT受者中甲型流感抗原的几何平均滴度（GMT）; 2）确定频率 征集性局部注射部位不良事件和征集性全身不良事件的严重程度 在儿科HSCT受者中，HD-TIV与标准剂量QIV的比较; 3）确定关系 在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， 接受HD-TIV或标准剂量QIV的儿科HSCT受者。受试者将以1：1的比例随机分配 接受2剂2016-2017 HD- TIV（每种流感抗原60µg）或2剂 标准剂量QIV（每种流感抗原15µg）。流感病毒的HAI和微量中和滴度 抗原、表型B和T细胞应答、B和T细胞特异性流感应答、全血细胞计数， 在给药前，将测量定量CD 4 +/CD 8 +/CD 19+水平和定量血清IgG浓度。 第一次和第二次疫苗接种后28-42天，以及第二次疫苗接种后约7个月， 第二种疫苗征集性不良事件将由父母/受试者在以下7天内记录 疫苗接种和研究人员的电话随访。这项研究的结果将填补知识上的空白 关于儿科HSCT接受者的流感疫苗反应，并将指导疫苗建议， 这个弱势群体。

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.