A novel therapeutic cytomegalovirus DNA vaccine in allogeneic haemopoietic stem-cell transplantation: a randomised, double-blind, placebo-controlled, phase 2 trial
A novel therapeutic cytomegalovirus DNA vaccine in allogeneic haemopoietic stem-cell transplantation: a randomised, double-blind, placebo-controlled, phase 2 trial
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DOI：
10.1016/s1473-3099(11)70344-9
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发表时间：
2012-04-01
影响因子：
56.3
通讯作者：
Kenney, Richard T.
中科院分区：
文献类型：
--
作者：
Kharfan-Dabaja, Mohamed A.;Boeckh, Michael;Kenney, Richard T.
背景：同种异体造血干细胞移植（HSCT）后，60-70%巨细胞病毒血清阳性患者在6个月内发生巨细胞病毒再激活，主要是由于该手术相关的免疫抑制。先发制人的抗病毒治疗可降低巨细胞病毒病的发病率，但可能有毒性。为了减少疾病的可能性和随后对此类抗病毒药物的需求，我们旨在评估巨细胞病毒治疗性DNA疫苗与安慰剂相比的安全性和有效性。在这项探索性双盲、安慰剂对照、平行组2期试验中，计划在美国16个移植中心招募多达80对供体受体和80对未配对的受体接受同种异体造血干细胞移植。符合条件的受者为巨细胞病毒血清阳性，年龄18-65岁，无高危原发疾病、t细胞衰竭、既往巨细胞病毒疫苗接种或自身免疫性疾病。我们将两个平行组的参与者按1:1的比例随机分配，分别在治疗前和移植后1、3和6个月接受巨细胞病毒治疗性DNA疫苗（TransVax; Vical, San Diego， CA， USA）或安慰剂。该疫苗含有编码巨细胞病毒糖蛋白B和磷酸蛋白65的质粒，由poloxamcrl1005和苯扎氯铵配制。随机化是基于Pocock和Simon的方法进行顺序分配，并根据地点、供体受体HLA匹配状况和供体巨细胞病毒血清状态进行分层。主要结果是临床显著病毒血症的发生率，导致在按方案可评估的人群中开始巨细胞病毒特异性抗病毒治疗。我们评估了所有接受至少一剂疫苗或安慰剂的参与者的不良事件发生率。本研究已在ClinicalTrials.gov注册，注册号NCT00285259。我们在2006年6月29日至2009年12月11日期间随机分配了108名参与者（94名HSCT受者和14名配对供者）。由于后勤原因，配对手臂的登记于2008年2月停止。对所有参与者进行安全性评估；有效人群限定为74名未配对受者。根据人口统计学和临床变量平衡各组。40名疫苗接种者中有19人（48%）需要巨细胞病毒特异性抗病毒治疗，而34名对照组中有21人（62%）需要（p=0.145）。然而，在随访期间，与安慰剂相比，疫苗显著减少了巨细胞病毒血症的发生和复发，并缩短了病毒血症发作的时间。疫苗耐受性良好；只有一名参与者在过敏反应后停药。移植后常见不良事件（如移植物抗宿主病或继发感染）的发生率在两组之间没有差异。我们展示了免疫治疗巨细胞病毒疫苗（TransVax）在HSCT环境中治疗临床显著病毒血症的概念证明。报告的安全性和有效性结果支持在3期试验中进一步开发，尽管在2期试验中与安慰剂相比，巨细胞病毒特异性抗病毒治疗的使用缺乏显着减少。资助维克斯和美国国家过敏和传染病研究所。
Background Cytomegalovirus reactivation occurs within 6 months in 60-70% of cytomegalovirus-seropositive patients after allogeneic haemopoietic stem-cell transplantation (HSCT), mainly due to immunosuppression associated with the procedure. Pre-emptive antiviral therapy reduces incidence of cytomegalovirus disease but can be toxic. To reduce the potential for disease and subsequent need for such antiviral drugs, we aimed to assess safety and efficacy of a cytomegalovirus therapeutic DNA vaccine compared with placebo.Methods In this exploratory double-blind, placebo-controlled, parallel group, phase 2 trial, up to 80 donor recipient pairs and 80 unpaired recipients undergoing allogeneic HSCT were planned for enrolment at 16 transplant centres in the USA. Eligible recipients were cytomegalovirus-seropositive, 18-65 years old, without high-risk primary disease, T-cell depletion, previous vaccination for cytomegalovirus, or autoimmune diseases. We randomly allocated participants in both parallel groups in a 1:1 ratio to receive a cytomegalovirus therapeutic DNA vaccine (TransVax; Vical, San Diego, CA, USA) or placebo before conditioning and at 1, 3, and 6 months after transplantation. The vaccine contains plasmids encoding cytomegalovirus glycoprotein B and phosphoprotein 65 formulated with poloxamer CRL1005 and benzalkonium chloride. Randomisation was done by sequential allocation based on Pocock and Simon's method, and stratified by site, donor recipient HLA matching status, and donor's cytomegalovirus serostatus. The primary outcome was the occurrence rate of clinically significant viraemia resulting in initiation of cytomegalovirus-specific antiviral therapy in the per-protocol assessable population. We assessed rates of adverse events in all participants who received at least one dose of vaccine or placebo. This study is registered with ClinicalTrials.gov, number NCT00285259.Findings We randomly allocated 108 participants (94 HSCT recipients and 14 paired donors) between June 29, 2006, and Dec 11, 2009. Enrolment of the paired arm was halted in February 2008 for logistical reasons. Safety was assessed in all participants; the efficacy population was restricted to 74 unpaired recipients. Groups were balanced for demographic and clinical variables. 19 (48%) of 40 vaccine recipients required cytomegalovirus-specific antiviral therapy, compared with 21 (62%) of 34 controls (p=0.145). However, during follow-up vaccine significantly reduced the occurrence and recurrence of cytomegalovirus viraemia and improved the time-to-event for viraemia episodes compared with placebo. The vaccine was well-tolerated; only one participant discontinued after an allergic reaction. Incidence of common adverse events after HSCT (eg, graft-versus-host disease or secondary infections) did not differ between groups.Interpretation We show proof of concept for an immunotherapeutic cytomegalovirus vaccine (TransVax) for clinically significant viraemia in the HSCT setting. The reported safety and efficacy outcomes support further development in a phase 3 trial, notwithstanding a lack of significant reduction in the use of cytomegalovirus-specific antiviral therapy compared with placebo in this phase 2 trial.Funding Vical and US National Institute of Allergy and Infectious Diseases.