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、艾滋病患者和孕妇的重要机会致病菌。糖蛋白 B (gB) 是在 CMV 表面发现的一种蛋白质，含有该病毒的主要中和表位。 gB 疫苗制剂已被证明可诱导与自然感染个体中发现的中和抗体水平相当的水平，但尚不清楚此类抗体是否可以预防 CMV 感染。移植患者代表了一个独特的群体，因为他们受到捐赠器官中存在的巨细胞病毒或内源性重新激活的挑战。我们对大量移植患者的自然史研究表明：1）聚合酶链式反应检测到的CMV DNA数量，“CMV载量”是CMV疾病的主要决定因素； 2）预先存在的自然免疫力可以减缓病毒载量的增加速度； 3）巨细胞病毒病可以通过在病毒载量达到高值之前进行先发制人的治疗来预防。 我们现在提出一项为期 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可以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时间表接受 CMV gB 疫苗接种，给予单剂量（正常人研究中为 20 mu/g）、双剂量和加强剂量。将跟踪疫苗接种者以确定 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 名）将接受一系列 CMV 负荷测量。将比较接受疫苗的患者与分配安慰剂的患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，将建议将其用于临床疗效的 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.