背景:戊型肝炎病毒(HEV)导致低收入国家孕妇的高死亡率。我们旨在评估HEV疫苗的安全性及其在怀孕期间预防戊型肝炎的有效性。
方法:在此阶段4,双盲,集群随机试验,Matlab中的67个村庄,孟加拉国,以1:1的比例随机分配接受HEV239(重组HEV疫苗)或对照疫苗(Hepa-B,乙肝疫苗),使用带有随机数表和大小为8的块的块随机化,按集群人口规模分层。符合条件的非孕妇(16-39岁)在第0天,在1个月,6个月时,并在最后一次免疫接种后随访2年。主要终点是孕妇的戊型肝炎,符合方案的人群(在预定日期的2天内接受所有三种剂量的人),虽然安全性是次要终点,在意向治疗(ITT)人群(接受至少一次剂量的参与者)中进行评估。每个剂量后的前7天记录诱发的不良事件,和未经请求的事件,直到参与者的最终剂量后2年。在妊娠ITT人群中评估妊娠相关的安全性结果。本研究在ClinicalTrials.gov(NCT02759991)注册。
结果:在2017年10月2日至2019年2月28日之间,有19460名参与者注册并接受了HEV239(9478[48·7%]名参与者,33个集群)或Hepa-B(9982[51·3%]参与者,34个集群),其中17937例(92·2%)参与者接受了三剂,17613例(90·5%)参与者按照方案接种了疫苗(HEV239组8524例[48·4%],对照组9089例[51·6%]).在任一治疗组中,均未确认怀孕参与者患有戊型肝炎。HEV239显示出轻微的安全性,类似于Hepa-B,两组间征询不良事件的比例无差异,无严重征询事件。疼痛是最常见的局部症状(1215[12·8%]HEV239受体和1218[12·2%]Hepa-B受体),发热是最常见的全身症状(141[1·5%]HEV239受体和145[1·5%]Hepa-B受体)。没有严重不良事件或死亡与疫苗相关。在怀孕的参与者中,与对照组(2604人中有102人[3·9%];校正后比值比1·54[95%CI1·15-2·08])相比,HEV239组的流产风险较高(2407例孕妇中的136人[5·7%]).
结论:HEV239在孕妇中的有效性仍不确定。HEV239在非孕妇中是安全且耐受性良好的,但是关于流产的调查结果需要进一步调查。
背景:挪威研究委员会;Innovax。
BACKGROUND: Hepatitis E virus (HEV) leads to high mortality in pregnant women in low-income countries. We aimed to evaluate the safety of a HEV vaccine and its effectiveness in preventing hepatitis E during pregnancy.
METHODS: In this phase 4, double-blind, cluster-randomised
trial, 67 villages in Matlab, Bangladesh, were randomised 1:1 to receive HEV239 (a recombinant HEV vaccine) or a control vaccine (Hepa-B, a hepatitis B vaccine), using block randomisation with random number tables and blocks of size eight, stratified by cluster population size. Eligible non-pregnant women (aged 16-39 years) were vaccinated intramuscularly on day 0, at 1 month, and at 6 months, and followed up for 2 years after the last immunisation. The primary endpoint was hepatitis E in the pregnant, per-protocol population (those who received all three doses within 2 days of the scheduled dates), while safety was a secondary endpoint, assessed in the intention-to-treat (ITT) population (participants who received at least one dose). Solicited adverse events were recorded for the first 7 days after each dose, and unsolicited events until 2 years after a participant\'s final dose. Pregnancy-related safety outcomes were assessed in the pregnant ITT population. This
study is registered with ClinicalTrials.gov (NCT02759991).
RESULTS: Between Oct 2, 2017, and Feb 28, 2019, 19 460 participants were enrolled and received either HEV239 (9478 [48·7%] participants, 33 clusters) or Hepa-B (9982 [51·3%] participants, 34 clusters), of whom 17 937 (92·2%) participants received three doses and 17 613 (90·5%) were vaccinated according to protocol (8524 [48·4%] in the HEV239 group and 9089 [51·6%] in the control group). No pregnant participants were confirmed to have hepatitis E in either treatment group. HEV239 showed a mild safety profile, similar to Hepa-B, with no difference in the proportion of solicited adverse events between groups and no severe solicited events. Pain was the most common local symptom (1215 [12·8%] HEV239 recipients and 1218 [12·2%] Hepa-B recipients) and fever the most common systemic symptom (141 [1·5%] HEV239 recipients and 145 [1·5%] Hepa-B recipients). None of the serious adverse events or deaths were vaccine related. Among pregnant participants, the HEV239 group had a higher risk of miscarriage (136 [5·7%] of 2407 pregnant participants) compared with the control group (102 [3·9%] of 2604; adjusted odds ratio 1·54 [95% CI 1·15-2·08]).
CONCLUSIONS: The effectiveness of HEV239 in pregnant women remains uncertain. HEV239 was safe and well tolerated in non-pregnant women, but findings regarding miscarriage warrant further investigation.
BACKGROUND: Research Council of Norway; Innovax.