Receipt of hepatitis E vaccine and fetal loss in rural Bangladesh: further analysis of a double-blind, cluster-randomised, controlled trial.

BACKGROUND: 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. METHODS: 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). FINDINGS: 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. INTERPRETATION: 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. FUNDING: Research Council of Norway and Innovax.

Impact of vaccination on the risk factors for acute rotavirus diarrhea: An analysis of the data of a cluster randomized trial conducted in a rural area of Bangladesh.

BACKGROUND: Rotavirus is one of the causes of severe diarrhea and death in young children. To control the disease, safe and effective vaccines are being used in several countries. We assessed the impact of vaccination on the risk factors for acute rotavirus diarrhea (ARD) in Bangladesh. METHODS: We used the data of a cluster-randomized trial. The clusters were 142 villages, 71 in each of the two arms of study. The infants were offered human rotavirus vaccine (HRV), Rotarix, over three-year period. We divided the time period into two equal periods (T1 and T2). A generalized estimating equation with logit-link function was used to evaluate the risk factors by arm and by period. RESULTS: Among 10,917 children, 5,759 (53%) were in the HRV villages. We had 359 cases; 44% in the HRV villages. Mean age of attack was similar between the arms of study in T1, but significantly higher in HRV villages than that in the non-HRV villages in T2. In HRV villages, males were at a higher risk of having ARD than females in T1, but not in T2. In contrast, males were at a higher risk of having ARD in both the time periods in non-HRV villages. In HRV-villages, children having literate mother were at significantly higher risk of having ARD in T1 but not in T2; whereas children in the non-HRV villages had a higher risk of having ARD in T2. Children living in an area with higher phone users had more cases than their counterpart in non-HRV villages, but not in HRV villages. CONCLUSION: Our study illustrates that several risk factors for ARD varied between the two arms of study as well as between the two periods of study. Assessing post-vaccination risk factors is, therefore, important for understanding the impact of vaccination and undertaking post-vaccination control measures.