PHASE IB TRIAL OF CYTOMEGALOVIRUS GLYCOPROTEIN B VACCINE

描述（申请人提供）：巨细胞病毒（CMV）是移植受者、艾滋病患者和孕妇中重要的机会性病原体。糖蛋白B （gB）是在巨细胞病毒表面发现的一种蛋白质，含有该病毒的主要中和表位。一种gB疫苗制剂已被证明能诱导出与自然感染个体相当的中和抗体水平，但尚不清楚这种抗体是否能预防巨细胞病毒感染。移植患者是一个独特的群体，因为他们受到捐赠器官中存在的巨细胞病毒的挑战或内源性的再激活。我们在自然史研究中对大量移植患者进行了跟踪研究，结果表明：1)聚合酶链反应检测到的巨细胞病毒DNA数量，即“巨细胞病毒载量”是巨细胞病毒疾病的主要决定因素；2)预先存在的自然免疫可以调节病毒载量的增加速度；(3)在病毒载量达到高值之前进行先发制人的治疗可以预防巨细胞病毒病。我们现在提议进行一项为期3年的研究，用CMV gB疫苗对等待移植的患者进行免疫，并确定诱导的抗体是否能减缓移植后病毒载量的增加速度。总共140名患者将根据安慰剂对照计划接受巨细胞病毒gB疫苗接种，给予单剂量（正常人研究中为20 μ /g）、双剂量和加强剂量。将对疫苗接种者进行跟踪，以确定gb疫苗诱导的中和抗体滴度的持久性。那些进行移植的患者（估计105例）将进行一系列的巨细胞病毒载量测量。将比较接种疫苗者与分配安慰剂者的病毒载量增加率。如果可以确定控制病毒载量的疫苗时间表，将推荐用于临床疗效的II期安慰剂对照试验。

DESCRIPTION (provided by applicant): Cytomegalovirus (CMV) is an important opportunistic pathogen in transplant recipients, AIDS patients and pregnant women. Glycoprotein B (gB) is a protein found on the surface of CMV which contains the major neutralizing epitopes for this virus. A gB vaccine preparation has been shown to induce levels of neutralizing antibody comparable to those found in naturally infected individuals, but it is not known if such antibodies can protect against CMV infection. Transplant patients represent a unique population because they are challenged with CMV present in the donated organ or reactivated endogenously. We have followed substantial numbers of transplant patients in natural history studies to show that: 1) the quantity of CMV DNA detected by polymerase chain reaction, "CMV load" is the major determinant of CMV disease; 2) preexisting natural immunity can moderate the rate of increase of viral load; 3) CMV disease can be prevented by giving pre-emptive therapy before the viral load reaches high values. We now propose a 3-year study to immunize patients awaiting transplantation with CMV gB vaccine and determine if the antibodies induced can moderate the rate of increase of viral load seen post-transplantation. A total of 140 patients will receive CMV gB vaccination according to a placebo-controlled schedule giving single doses (20 mu/g as studied in normals), double doses and booster doses. Vaccine recipients will be followed to determine the durability of gB-vaccine-induced neutralizing antibody titers. Those patients (estimate 105) who proceed to transplant will be followed with serial measures of CMV load. The rate of increase in viral load will be compared for those who receive vaccine versus those allocated placebo. If a vaccine schedule can be identified which controls viral load, this will be recommended for a phase II placebo-controlled trial of clinical efficacy.