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Serological response to three alternative series of hepatitis B revaccination (Fendrix, Twinrix, and HBVaxPro-40) in healthy non-responders: a multicentre, open-label, randomised, controlled, superiority trial.
The Lancet Infectious Diseases ( IF 56.3 ) Pub Date : 2019-10-16 , DOI: 10.1016/s1473-3099(19)30417-7
Stijn F H Raven 1 , Christian J P A Hoebe 2 , Ann C T M Vossen 3 , Leo G Visser 4 , Jeannine L A Hautvast 5 , Anna H E Roukens 4 , Jim E van Steenbergen 6
Affiliation  

BACKGROUND Serological non-response can be present after hepatitis B vaccination in healthy adults. We aimed to establish which of three revaccination regimens is most effective at inducing protective immunity METHODS: Healthy adults (aged 18-80 years) from 16 Dutch centres (13 public health services, two university hospitals, and one travel clinic) were included in this multicentre, parallel group, randomised, controlled, superiority trial. The inclusion criterion was vaccine non-response (hepatitis B surface antibody [anti-HBs] titre <10 IU/L) after a primary series with three doses of one type of recombinant vaccine against hepatitis B virus (either HBVaxPro-10 or Engerix-B at months 0, 1, and 6). Participants were individually randomly assigned (1:1:1:1) to a vaccination series of repeated initial vaccination (HBVaxPro 10 μg or Engerix-B 20 μg) as the control, or to Twinrix 20 μg, Fendrix 20 μg, or HBVaxPro 40 μg. We used a web-based randomisation programme, stratified by centre, with a block size of four. Participants and centres were unmasked to assignment after randomisation. Laboratory staff and investigators were masked to vaccine-group assignment. All revaccination schedules were identical, with intramuscular vaccinations at 0, 1, and 2 months. Anti-HBs was measured at 0, 1, 2, and 3 months. The primary outcome was the percentage of responders (anti-HBs titres ≥10 IU/L) at 3 months. Immunogenicity and safety analyses were based on an intention-to-vaccinate analysis, the immunogenicity analysis with last observation carried forward for missing data, and the Bonferroni and the Benjamini-Hochberg method were applied to correct for multiple testing. The trial was registered in the Dutch National Trial Register and inclusion has been stopped (identifier NL3011; EudraCT-number 2011-005627-40). FINDINGS The participants were recruited between Nov 1, 2012, and Sept 1, 2017. 480 participants were randomly assigned and included in intention-to-vaccinate analyses: 124 (26%) to control, 118 (25%) to Twinrix, 114 (24%) to HBVaxPro-40, and 124 (26%) to Fendrix. At month 3 the percentage of responders was 83 (67%) of 124 (95% CI 57·9-75·1 in the control group, 94 (80%) of the 118 (71·3-86·5) in the Twinrix group, 95 (83%) of 114 (75·2-89·7) in the HBVaxPro-40 group, and 108 (87%) of 124 (79·9-92·4) in the Fendrix group. Compared with the control group, the percentage of responders was superior for the HBVaxPro-40 group (adjusted difference 21·6% [95% CI 10·4-32·7], p=0·0204 [Bonferroni corrected p value]) and the Fendrix group (26·3% [15·4-37·3], p=0·0006), but not the Twinrix group (25·0% [13·0-37·0]; p=0·0846). One serious adverse event occurred (herpes zoster ophthalmicus) in the Fendrix group, which was not attributed to the vaccine. INTERPRETATION Revaccinating healthy non-responders with Fendrix or HBVaxPro-40 resulted in significantly higher proportions of responders and therefore indication for these vaccines should be expanded to enable revaccination of non-responders. FUNDING National Institute for Public Health and the Environment.

中文翻译:

在健康无反应者中,对三种替代性乙肝疫苗接种(Fendrix,Twinrix和HBVaxPro-40)的血清学反应:一项多中心,开放标签,随机,对照,优越性试验。

背景在健康成年人中,乙肝疫苗接种后可能会出现血清学无反应。我们旨在确定三种再接种方案中哪一种最有效地诱导保护性免疫。方法:本研究纳入了来自16个荷兰中心(13个公共卫生服务机构,两所大学医院和一家旅行诊所)的健康成年人(18-80岁)多中心,平行分组,随机,对照,优势试验。纳入标准是在三剂一剂针对乙型肝炎病毒的重组疫苗(HBVaxPro-10或Engerix- B在第0、1和6个月)。参与者被随机分配(1:1:1:1)接种一系列重复的初始疫苗(HBVaxPro 10μg或Engerix-B 20μg)作为对照,或Twinrix 20μg,Fendrix 20μg或HBVaxPro 40μg。我们使用了一个基于网络的随机程序,按中心分层,每个程序块为四个。随机分配后,参与者和中心均未分配任务。实验室工作人员和研究人员对疫苗组的工作不了解。所有的重新接种时间表都相同,分别在0、1、2个月进行肌肉注射。在0、1、2和3个月时测量抗HBs。主要结局是3个月时应答者的百分比(抗HBs滴度≥10IU / L)。免疫原性和安全性分析基于意向性疫苗分析,而免疫原性分析以及最近观察到的遗漏数据会继续进行,并使用Bonferroni和Benjamini-Hochberg方法校正多次测试。该试验已在荷兰国家试验注册局进行了注册,并且已经停止纳入(标识NL3011; EudraCT-number 2011-005627-40)。结果在2012年11月1日至2017年9月1日之间招募了参与者。随机分配了480位参与者,并将其包括在意向性疫苗分析中:对照组为124(26%),Twinrix为118(25%),114( HBVaxPro-40为24%)和Fendrix为124(26%)。在第3个月,对照组的124人(95%CI 57·9-75·1)中有83人(67%),对照组的118人(71·3-86·5)中94人(80%)。 Twinrix组在HBVaxPro-40组中为114(75·2-89·7)的95(83%),在Fendrix组中为124(79·9-92·4)的108(87%)。对照组 HBVaxPro-40组(校正后差异21·6%[95%CI 10·4-32·7],p = 0·0204 [Bonferroni校正后的p值])和Fendrix组(26 ·3%[15·4-37·3],p = 0·0006),但不是Twinrix组(25·0%[13·0-37·0]; p = 0·0846)。Fendrix组发生了一次严重的不良事件(眼带状疱疹),这与疫苗无关。解释用Fendrix或HBVaxPro-40对健康无反应者进行重新接种可导致较高的反应者比例,因此应扩大这些疫苗的适应症,以使无反应者能够再次接种。资助国立公共卫生与环境研究所。p = 0·0006),但不是Twinrix组(25·0%[13·0-37·0]; p = 0·0846)。Fendrix组发生了一次严重的不良事件(眼带状疱疹),这与疫苗无关。解释用Fendrix或HBVaxPro-40对健康无反应者进行重新接种可导致更高比例的反应者,因此应扩大这些疫苗的适应症,以使无反应者能够再次接种。资助国立公共卫生与环境研究所。p = 0·0006),但不是Twinrix组(25·0%[13·0-37·0]; p = 0·0846)。Fendrix组发生了一次严重的不良事件(眼带状疱疹),这与疫苗无关。解释用Fendrix或HBVaxPro-40对健康无反应者进行重新接种可导致较高的反应者比例,因此应扩大这些疫苗的适应症,以使无反应者能够再次接种。资助国立公共卫生与环境研究所。解释用Fendrix或HBVaxPro-40对健康无反应者进行重新接种可导致较高的反应者比例,因此应扩大这些疫苗的适应症,以使无反应者能够再次接种。资助国立公共卫生与环境研究所。解释用Fendrix或HBVaxPro-40对健康无反应者进行重新接种可导致较高的反应者比例,因此应扩大这些疫苗的适应症,以使无反应者能够再次接种。资助国立公共卫生与环境研究所。
更新日期:2019-12-25
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