Heterologous two-dose Ebola vaccine regimen in pregnant women in Rwanda: a randomized controlled phase 3 trial

Abstract

Risk of death for both mother and fetus following Ebola virus infection is extremely high. In this study, healthy women in Rwanda aged ≥18 years were randomized to two-dose Ebola vaccination (Ad26.ZEBOV, MVA-BN-Filo) during pregnancy (group A) or postpartum (group B). Unvaccinated pregnant group B women served as control. This was a parallel, randomized, controlled, open-label, single-center trial to evaluate the safety (primary endpoint-outcomes of interest and serious adverse events (SAEs)) and immunogenicity (secondary endpoint) of the two-dose Ebola vaccination. Among 3,484 women screened, 2,013 were randomized, and 2,012 women and 1,945 infants born alive were descriptively analyzed. Adverse outcomes of interest occurred in women (5.2% in group A and 7.3% in group B) and infants (26.0% in group A and 25.6% in group B). The most common maternal outcome of interest was pathways to preterm birth (3.2% in group A and 3.4% in group B), and the most common infant outcome of interest was small for gestational age (14.3% in group A and 11.8% in group B). Maternal/fetal and neonatal/infant SAE frequencies were comparable between groups (9.8% in group A, 9.0% in group B and 21.9% in group A, 15.9% in group B, respectively). Anti-Ebola virus glycoprotein-specific binding antibody response (secondary endpoint) was sustained in ≥90% of women at 1 year postdose 1. In group A, binding antibodies were detected in cord blood (99%) and infant serum (95%) samples 14 weeks postbirth. The trial met all primary and secondary objectives. Ad26.ZEBOV, MVA-BN-Filo did not raise concerns regarding adverse maternal/fetal or neonatal/infant outcomes, had no unexpected safety issues, and induced binding antibody responses in women and offspring through passive transfer. ClinicalTrials.gov registration: NCT04556526 .

Fig. 1. Trial profile.

Infant deaths were captured from birth to 14 weeks. A single asterisk indicates primary analysis datasets for baseline demographic characteristics and safety analyses. Dagger indicates primary analysis datasets for immunogenicity analyses. Main reasons for discontinuation among the randomized women were withdrawal by participant (72/2,013 (3.6%)), loss to follow-up (14/2,013 (0.7%)) and new pregnancy during the study (8/2,013 (0.4%)). Double asterisk indicates data from group C (n = 5) were analyzed separately and are not included in this paper.

Fig. 2. Vaccine-induced EBOV GP-binding antibody concentrations.

a, Anti-EBOV GP-specific binding antibody concentrations in vaccinated women over time. GMCs with 95% CI are shown in the figure. Group A, pregnant women randomized to be vaccinated during pregnancy; group B, pregnant women randomized to be vaccinated after pregnancy. Enrollment of first-trimester pregnant women was opened after the immunogenicity subset was fully enrolled. As a result, no first-trimester pregnant women were included in the immunogenicity subset. b, Correlation between mother anti-EBOV GP-specific binding antibody concentration at postpartum day 1 and mother cord blood anti-EBOV GP-specific binding antibody concentration at postpartum day 1. c, Correlation between mother anti-EBOV GP-specific binding antibody concentration at postpartum day 1 versus infant anti-EBOV GP-specific binding antibody concentration at 14 weeks of age. d, Correlation between mother cord blood anti-EBOV GP-specific binding antibody concentration at postpartum day 1 versus infant anti-EBOV GP-specific binding antibody concentration at 14 weeks of age. For b–d, the Spearman correlation coefficients calculated are partial Spearman correlation coefficients that control for the trimester of the mother at randomization. For a–d, trimester refers to the trimester at randomization. First trimester, 0–12 weeks; second trimester, >12–24 weeks; third trimester, >24 weeks. EU, enzyme-linked immunosorbent assay units. N/A, not applicable.

Extended Data Fig. 1. Percentage of women with adverse maternal/fetal outcomes of interest with at least 3% frequency in any group by trimester of randomization.

The exact Clopper–Pearson 95% CI is shown for the percentage of each specific outcome in each group. This figure presents select (≥3% for any trimester) of adverse maternal/fetal outcomes of interest by group and by trimester of randomization. The bars represent the percentage of participants. Percentages reflect n/N, where n is the number of participants with at least one of the given outcomes, N is the number of participants with available maternal/fetal outcomes and the error bars denote the 95% Clopper–Pearson exact confidence interval.

Extended Data Fig. 2. Percentage of infants with adverse neonatal/infant outcomes of interest with at least 3% frequency in any group by trimester of randomization.

The exact Clopper–Pearson 95% CI is shown for the percentage of each specific outcome in each group. This figure presents select (≥3% in any trimester) adverse neonatal/infant outcomes of interest by group and by trimester of randomization. The bars represent the percentage of participants. Percentages reflect n/N, where n is the number of participants with at least one of the given outcomes, N is the number of participants available and error bars denote the 95% Clopper–Pearson exact confidence interval.