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性病原体。糖蛋白B(Gb)是发现于CMV表面的一种蛋白，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中和抗体，但尚不清楚此类抗体是否能预防CMV感染。移植患者代表了一个独特的群体，因为他们面临着捐赠器官中存在的CMV的挑战，或者是内源性的重新激活。我们在自然史研究中跟踪了大量的移植患者，结果表明：1)聚合酶链式反应检测到的CMV DNA的数量是CMV病的主要决定因素；2)预先存在的自然免疫可以减缓病毒载量的增加速度；3)CMV病可以通过在病毒载量达到高值之前进行预防性治疗来预防。我们现在提议一项为期3年的研究，用CMV GB疫苗免疫等待移植的患者，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。共有140名患者将按照安慰剂控制的时间表接受CMV GB疫苗接种，给予单剂(正常研究中为20 MU/g)、双剂和加强剂量。将对疫苗接受者进行跟踪，以确定GB疫苗诱导的中和抗体效价的持久性。那些继续进行移植的患者(估计105人)将接受一系列的CMV负荷测量。将对接种疫苗的人和分配了安慰剂的人的病毒载量增加速度进行比较。如果能够确定控制病毒载量的疫苗时间表，这将被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.