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Background We investigated safety, tolerability, and immunogenicity of the heterologous 2-dose Ebola vaccination regimen in healthy and HIV-infected adults with different intervals between Ebola vaccinations. Methods and findings In this randomised, observer-blind, placebo-controlled Phase II trial, 668 healthy 18- to 70-year-olds and 142 HIV-infected 18- to 50-year-olds were enrolled from 1 site in Kenya and 2 sites each in Burkina Faso, Cote d’Ivoire, and Uganda. Participants received intramuscular Ad26.ZEBOV followed by MVA-BN-Filo at 28-, 56-, or 84-day intervals, or saline. Females represented 31.4% of the healthy adult cohort in contrast to 69.7% of the HIV-infected cohort. A subset of healthy adults received booster vaccination with Ad26.ZEBOV or saline at Day 365. Following vaccinations, adverse events (AEs) were collected until 42 days post last vaccination and serious AEs (SAEs) were recorded from signing of the ICF until the end of the study. The primary endpoint was safety, and the secondary endpoint was immunogenicity. Anti-Ebola virus glycoprotein (EBOV GP) binding and neutralising antibodies were measured at baseline and at predefined time points throughout the study. The first participant was enrolled on 9 November 2015, and the date of last participant’s last visit was 12 February 2019. No vaccine-related SAEs and mainly mild-to-moderate AEs were observed among the participants. The most frequent solicited AEs were injection-site pain (local), and fatigue, headache, and myalgia (systemic), respectively. Twenty-one days post-MVA-BN-Filo vaccination, geometric mean concentrations (GMCs) with 95% confidence intervals (CIs) of EBOV GP binding antibodies in healthy adults in 28-, 56-, and 84-day interval groups were 3,085 EU/mL (2,648 to 3,594), 7,518 EU/mL (6,468 to 8,740), and 7,300 EU/mL (5,116 to 10,417), respectively. In HIV-infected adults in 28- and 56-day interval groups, GMCs were 4,207 EU/mL (3,233 to 5,474) and 5,283 EU/mL (4,094 to 6,817), respectively. Antibody responses were observed until Day 365. Ad26.ZEBOV booster vaccination after 1 year induced an anamnestic response. Study limitations include that some healthy adult participants either did not receive dose 2 or received dose 2 outside of their protocol-defined interval and that the follow-up period was limited to 365 days for most participants. Conclusions Ad26.ZEBOV, MVA-BN-Filo vaccination was well tolerated and immunogenic in healthy and HIV-infected African adults. Increasing the interval between vaccinations from 28 to 56 days improved the magnitude of humoral immune responses. Antibody levels persisted to at least 1 year, and Ad26.ZEBOV booster vaccination demonstrated the presence of vaccination-induced immune memory. These data supported the approval by the European Union for prophylaxis against EBOV disease in adults and children ≥1 year of age. Trial registration ClinicalTrials.govNCT02564523 Houreratou Barry and co-workers report on safety and immunogenicity of an Ebola vaccine in adults across four African countries. Author summary Why was this study done? With Ebola outbreaks increasing, there is an unmet medical need for a prophylactic vaccine to prevent and mitigate Ebola outbreaks. To address the urgent medical need during the 2014 to 2016 outbreak, the clinical development of the 2-dose vaccine regimen comprising of Ad26.ZEBOV and MVA-BN-Filo was accelerated. This Phase II study was part of this accelerated program, evaluating the safety and immunogenicity of the 2-dose vaccine regimen in healthy and HIV-infected African adults, with 28-, 56-, and 84-day intervals between doses. The study was amended to evaluate safety and immunogenicity of a booster vaccination with Ad26.ZEBOV, administered approximately 1 year after the first vaccination, in healthy adults. What did the researchers do and find? We conducted a randomised trial to assess the safety and the immunogenicity of the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen in 3 different vaccination intervals in healthy and HIV-infected adults. The vaccine regimen was well tolerated and induced marked immune responses; the highest humoral responses were observed after vaccination with 56-day and 84-day intervals. Anamnestic responses were observed in all healthy participants receiving Ad26.ZEBOV as booster at 1 year after the first dose. What do these findings mean? Our results demonstrate that the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen is safe and immunogenic in healthy and HIV-infected adults and induces immune memory that can rapidly be reactivated. Our findings support the prophylactic use of the 2-dose Ad26.ZEBOV, MVA-BN-Filo vaccine regimen against Ebola infection in African adult populations. The 2-dose vaccine regimen comprising of Ad26.ZEBOV and MVA-BN-Filo has received marketing authorisation under exceptional circumstances for prophylactic use against EVD in adults and children ≥1 year old within the European Union.

Objective Although distance has been identified as an important barrier to care, evidence for an effect of distance to care on child mortality is inconsistent. We investigated the association of distance to care with self‐reported care seeking behaviours, neonatal and post‐neonatal under‐five child mortality in rural areas of Burkina Faso. Methods We performed a cross‐sectional survey in 14 rural areas from November 2014 to March 2015. About 100 000 women were interviewed on their pregnancy history and about 5000 mothers were interviewed on their care seeking behaviours. Euclidean distances to the closest facility were calculated. Mixed‐effects logistic and Poisson regressions were used respectively to compute odds ratios for care seeking behaviours and rate ratios for child mortality during the 5 years prior to the survey. Results Thirty per cent of the children lived more than 7 km from a facility. After controlling for confounding factors, there was a strong evidence of a decreasing trend in care seeking with increasing distance to care (P ≤ 0.005). There was evidence for an increasing trend in early neonatal mortality with increasing distance to care (P = 0.028), but not for late neonatal mortality (P = 0.479) and post‐neonatal under‐five child mortality (P = 0.488). In their first week of life, neonates living 7 km or more from a facility had an 18% higher mortality rate than neonates living within 2 km of a facility (RR = 1.18; 95%CI 1.00, 1.39; P = 0.056). In the late neonatal period, despite the lack of evidence for an association of mortality with distance, it is noteworthy that rate ratios were consistent with a trend and similar to or larger than estimates in early neonatal mortality. In this period, neonates living 7 km or more from a facility had an 18% higher mortality rate than neonates living within 2 km of a facility (RR = 1.18; 95%CI 0.92, 1.52; P = 0.202). Thus, the lack of evidence may reflect lower power due to fewer deaths rather than a weaker association. Conclusion While better geographic access to care is strongly associated with increased care seeking in rural Burkina Faso, the impact on child mortality appears to be marginal. This suggests that, in addition to improving access to services, attention needs to be paid to quality of those services.