University of Chicago, Department of Medicine, Chicago, IL, USA.
University of Minnesota, Hennepin County Medical Center, Minneapolis, MN, USA.
Lancet Infect Dis. 2019 Sep;19(9):1001-1012. doi: 10.1016/S1473-3099(19)30310-X. Epub 2019 Aug 6.
Patients who are immunocompromised because of malignancy have an increased risk of herpes zoster and herpes zoster-related complications. We aimed to investigate the efficacy and safety of an inactivated varicella zoster virus (VZV) vaccine for herpes zoster prevention in patients with solid tumour or haematological malignancies.
This phase 3, two-arm, randomised, double-blind, placebo-controlled, multicentre trial with an adaptive design was done in 329 centres across 40 countries. The trial included adult patients with solid tumour malignancies receiving chemotherapy and those with haematological malignancies, either receiving or not receiving chemotherapy. Patients were randomly assigned (1:1) to receive four doses of VZV vaccine inactivated by γ irradiation or placebo approximately 30 days apart. The patients, investigators, trial site staff, clinical adjudication committee, and sponsor's clinical and laboratory personnel were masked to the group assignment. The primary efficacy endpoint was herpes zoster incidence in patients with solid tumour malignancies receiving chemotherapy, which was assessed in the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of inactivated VZV vaccine or placebo). The primary safety endpoint was serious adverse events up to 28 days after the fourth dose in patients with solid tumour malignancies receiving chemotherapy. Safety endpoints were assessed in all patients who received at least one dose of inactivated VZV vaccine or placebo and had follow-up data. This trial is registered (NCT01254630 and EudraCT 2010-023156-89).
Between June 27, 2011, and April 11, 2017, 5286 patients were randomly assigned to receive VZV vaccine inactivated by γ irradiation (n=2637) or placebo (n=2649). The haematological malignancy arm was terminated early because of evidence of futility at a planned interim analysis; therefore, all prespecified haematological malignancy endpoints were deemed exploratory. In patients with solid tumour malignancies in the modified intention-to-treat population, confirmed herpes zoster occurred in 22 of 1328 (6·7 per 1000 person-years) VZV vaccine recipients and in 61 of 1350 (18·5 per 1000 person-years) placebo recipients. Estimated vaccine efficacy against herpes zoster in patients with solid tumour malignancies was 63·6% (97·5% CI 36·4 to 79·1), meeting the prespecified success criterion. In patients with solid tumour malignancies, serious adverse events were similar in frequency across treatment groups, occurring in 298 (22·5%) of 1322 patients who received the vaccine and in 283 (21·0%) of 1346 patients who received placebo (risk difference 1·5%, 95% CI -1·7 to 4·6). Vaccine-related serious adverse events were less than 1% in each treatment group. Vaccine-related injection-site reactions were more common in the vaccine group than in the placebo group. In the haematological malignancy group, VZV vaccine was well tolerated and estimated vaccine efficacy against herpes zoster was 16·8% (95% CI -17·8 to 41·3).
The inactivated VZV vaccine was well tolerated and efficacious for herpes zoster prevention in patients with solid tumour malignancies receiving chemotherapy, but was not efficacious for herpes zoster prevention in patients with haematological malignancies.
Merck & Co, Inc.
由于恶性肿瘤而免疫功能低下的患者罹患带状疱疹和带状疱疹相关并发症的风险增加。我们旨在研究灭活水痘带状疱疹病毒（VZV）疫苗对接受化疗的实体瘤或血液恶性肿瘤患者预防带状疱疹的疗效和安全性。
这是一项在 40 个国家的 329 个中心进行的、具有适应性设计的、两臂、随机、双盲、安慰剂对照的 3 期临床试验。试验纳入了正在接受化疗的实体瘤恶性肿瘤患者和接受或未接受化疗的血液恶性肿瘤患者。患者以 1:1 的比例随机分配（1:1）接受 4 剂 γ 照射灭活的 VZV 疫苗或安慰剂，大约间隔 30 天。患者、研究者、试验现场工作人员、临床裁决委员会以及赞助商的临床和实验室人员对分组均不知情。主要疗效终点是接受化疗的实体瘤恶性肿瘤患者的带状疱疹发病率，在改良意向治疗人群中评估（定义为所有接受至少一剂灭活 VZV 疫苗或安慰剂的随机分配患者）。主要安全性终点是接受化疗的实体瘤恶性肿瘤患者在接种第四剂疫苗后 28 天内发生的严重不良事件。在至少接受一剂灭活 VZV 疫苗或安慰剂且有随访数据的所有患者中评估安全性终点。这项试验已在 ClinicalTrials.gov（NCT01254630 和 EudraCT 2010-023156-89）注册。
2011 年 6 月 27 日至 2017 年 4 月 11 日，5286 名患者被随机分配接受 γ 照射灭活的 VZV 疫苗（n=2637）或安慰剂（n=2649）。由于计划的中期分析显示无效证据，血液恶性肿瘤组提前终止；因此，所有预先指定的血液恶性肿瘤终点均被视为探索性的。在改良意向治疗人群中，接受化疗的实体瘤恶性肿瘤患者中，经确认的带状疱疹发生率为疫苗组 1328 例患者中有 22 例（每 1000 人年 6.7 例），安慰剂组 1350 例患者中有 61 例（每 1000 人年 18.5 例）。接受化疗的实体瘤恶性肿瘤患者的疫苗有效性估计为 63.6%（97.5%CI 36.4 至 79.1），达到了预设的成功标准。在接受化疗的实体瘤恶性肿瘤患者中，两组间严重不良事件的发生频率相似，接受疫苗的 1322 例患者中有 298 例（22.5%）和接受安慰剂的 1346 例患者中有 283 例（21.0%）（风险差 1.5%，95%CI-1.7 至 4.6）。每组中疫苗相关的严重不良事件少于 1%。疫苗相关的注射部位反应在疫苗组比安慰剂组更常见。在血液恶性肿瘤组中，VZV 疫苗耐受良好，预防带状疱疹的疫苗有效性估计为 16.8%（95%CI-17.8 至 41.3）。
灭活的 VZV 疫苗对接受化疗的实体瘤恶性肿瘤患者预防带状疱疹是安全且有效的，但对预防血液恶性肿瘤患者的带状疱疹无效。
默克公司。
