International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh; International Vaccine Institute, Seoul, South Korea; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Oslo University Hospital, Oslo, Norway.
Lancet Glob Health. 2024 Aug;12(8):e1300-e1311. doi: 10.1016/S2214-109X(24)00193-1.
Vaccination constitutes an attractive control measure for hepatitis E virus (HEV), a major cause of maternal and perinatal mortality globally. Analysis of pregnant participants in an effectiveness trial of the HEV vaccine HEV239 showed possible HEV239-associated fetal losses. We aimed to conduct a detailed analysis of this safety signal.
In a double-blind, cluster-randomised trial, 67 villages in Matlab, Bangladesh, were randomly allocated (1:1) to two vaccine groups, in which non-pregnant women aged 16-39 years received either HEV239 (HEV239 group) or Hepa-B (a hepatitis B vaccine; control group). We implemented weekly surveillance for pregnancy detection, and follow-up of pregnancies once every 2 weeks, using physician-confirmed diagnoses to evaluate fetal loss outcomes (miscarriage [spontaneous abortion], stillbirth, and elective termination). Data from a parallel system of reproductive health surveillance in Matlab were used to clarify study diagnoses when necessary. Miscarriage was assessed only among participants whose first positive pregnancy test and vaccination date (for whichever dose was closest to the date of last menstrual period [LMP]) were before 20 weeks' gestation. We defined the following analysis periods of interest: from 90 days before the LMP until the pregnancy outcome (the proximal period); from the LMP date until the pregnancy outcome (the pregnancy period); from 90 days before the LMP until the LMP date (90 days pre-LMP period); and from enrolment until 90 days before the LMP (the distal period). Both Poisson and Cox regression models were used to assess the associations between receipt of HEV239 and fetal loss outcomes. The trial was registered with ClinicalTrials.gov (NCT02759991).
Among the 19 460 non-pregnant participants enrolled in the trial, 5011 were identified as having pregnancies within 2 years following vaccination and met the criteria for analysis (2407 in the HEV239 group and 2604 in the control group). Among participants vaccinated in the proximal period and evaluated for miscarriage, miscarriage occurred in 54 (8·9%) of 607 in the HEV239 group and 32 (4·5%) of 719 in the control group (adjusted relative risk [aRR] 2·0 [95% CI 1·3-3·1], p=0·0009). Similarly, the risk of miscarriages was increased in the HEV239 group versus the control group among participants inadvertently vaccinated during pregnancy (22 [10·5%] miscarriages among 209 participants in the HEV239 group vs 14 [5·3%] of 266 in the control group; aRR 2·1 [95% CI 1·1-4·1], p=0·036) and among those vaccinated within 90 days pre-LMP (32 [8·0%] of 398 vs 18 [4·0%] of 453; 1·9 [1·1-3·2], p=0·013). No increased risk of miscarriage was observed in those who received HEV239 in the distal period (93 [5·6%] of 1647 vs 80 [4·5%] of 1773; 1·3 [0·8-1·9], p=0·295). Stillbirth and elective termination showed no increased risk among women administered HEV239 versus those administered Hepa-B in any of the analysis periods.
HEV239 given shortly before or during pregnancy was associated with an elevated risk of miscarriage. This association poses a possible safety concern for programmatic use of HEV239 in women of childbearing age.
Research Council of Norway and Innovax.
接种疫苗是戊型肝炎病毒（HEV）的一种有吸引力的控制措施，HEV 是全球孕产妇和围产期死亡的主要原因。对 HEV 疫苗 HEV239 有效性试验中的孕妇参与者进行分析显示，HEV239 可能与胎儿丢失有关。我们旨在对这一安全信号进行详细分析。
在一项双盲、整群随机试验中，孟加拉国 Matlab 的 67 个村庄被随机分配（1:1）到两组疫苗组，其中年龄在 16-39 岁的非孕妇接种了 HEV239（HEV239 组）或乙型肝炎疫苗 Hepa-B（对照组）。我们每周进行妊娠检测监测，并在妊娠每两周进行一次随访，使用医生确诊的诊断来评估胎儿丢失结果（流产[自然流产]、死产和选择性终止妊娠）。Matlab 生殖健康监测平行系统的数据用于必要时澄清研究诊断。仅在第一次阳性妊娠试验和接种日期（距离末次月经周期[LMP]最近的一次）早于 20 周妊娠的参与者中评估流产。我们定义了以下感兴趣的分析期：从末次月经周期前 90 天到妊娠结局（近端期）；从末次月经周期日期到妊娠结局（妊娠期）；从末次月经周期前 90 天到末次月经周期日期（90 天前 LMP 期）；从入组到末次月经周期前 90 天（远端期）。我们使用泊松和 Cox 回归模型评估接受 HEV239 与胎儿丢失结果之间的关联。该试验在 ClinicalTrials.gov （NCT02759991）注册。
在试验中招募的 19460 名非孕妇中，有 5011 名在接种疫苗后 2 年内怀孕，并符合分析标准（HEV239 组 2407 人，对照组 2604 人）。在近端期接种疫苗并评估流产的参与者中，HEV239 组流产 54 例（8.9%），对照组流产 32 例（4.5%）（调整后的相对风险[ARR] 2.0 [95%CI 1.3-3.1]，p=0.0009）。同样，在无意中在怀孕期间接种疫苗的参与者中，HEV239 组与对照组相比，流产风险增加（HEV239 组 209 名参与者中有 22 例[10.5%]流产，对照组 266 名参与者中有 14 例[5.3%]；ARR 2.1 [95%CI 1.1-4.1]，p=0.036）和在接种疫苗后 90 天前 LMP 的参与者中（HEV239 组 398 名参与者中有 32 例[8.0%]流产，对照组 453 名参与者中有 18 例[4.0%]；1.9 [1.1-3.2]，p=0.013）。在远端期接种 HEV239 的参与者中，没有观察到流产风险增加（HEV239 组 1647 名参与者中有 93 例[5.6%]，对照组 Hepa-B 组 1773 名参与者中有 80 例[4.5%]；1.3 [0.8-1.9]，p=0.295）。在任何分析期内，接受 HEV239 接种的女性与接受 Hepa-B 接种的女性相比，死产和选择性终止妊娠的风险均无增加。
在妊娠前或妊娠期间接种 HEV239 与流产风险增加相关。这种关联对在生育年龄的妇女中使用 HEV239 疫苗提出了一个潜在的安全问题。
挪威研究理事会和 Innovax。
