Safety and immunogenicity of 2-dose heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola vaccination in healthy and HIV-infected adults: A randomised, placebo-controlled Phase II clinical trial in Africa

Abstract

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.gov NCT02564523

Safety and immunogenicity of 2-dose heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola vaccination in children and adolescents in Africa: A randomised, placebo-controlled, multicentre Phase II clinical trial

“…Robust EBOV GP-specific binding and neutralising antibody levels were observed in these younger age groups, consistent with those reported in adults [ 11 – 16 ], with higher responses observed with a longer time interval between the 2 doses (56 versus 28 days). Although not statistically significant, greater responses in the younger age cohort were also detected, in line with our previous observations in an Ad26.ZEBOV, MVA-BN-Filo study in Sierra Leone [ 21 , 22 ].…”

“…We have previously reported that in adults, the heterologous 2-dose Ad26.ZEBOV, MVA-BN-Filo vaccine regimen against EVD is safe, well tolerated, and immunogenic in several Phase I and II trials [ 11 – 16 ]. The present report confirms those observations in 12- to 17-year-old and 4- to 11-year-old participants.…”

“…Blood samples were taken on day 1, day 29 or 57, day 50 or 78, day 209 or 237, and day 365. EBOV GP-specific total IgG binding antibody concentrations were measured in sera by the Filovirus Animal Nonclinical Group (FANG) ELISA at Q 2 Solutions (San Juan Capistrano, CA, US) [ 14 , 16 , 19 ] and were expressed as group geometric mean concentrations (GMCs) of ELISA units (EU)/mL with 95% confidence intervals (CIs). EBOV GP-specific neutralising antibody titres were measured using a pseudovirion neutralisation assay (psVNA) at Monogram (San Francisco, CA, US) [ 14 , 16 ] and expressed as group geometric mean titres (GMTs) of the half maximal inhibitory titre (IC 50 ) with 95% CIs.…”

“…This regimen comprises Ad26.ZEBOV (Zabdeno) and MVA-BN-Filo (Mvabea) administered approximately 8 weeks apart. Phase I/II studies in European and African adults established acceptable safety, tolerability, and robust immunogenicity of the 2-dose regimen with intervals of 28 or 56 days between vaccinations [ 11 – 16 ]. Both vaccines are recommended by SAGE in outbreak settings for infants and children from birth to 17 years of age [ 17 ].…”

“…We previously reported a Phase II study in healthy and HIV-infected adult African participants to assess the safety and immunogenicity of different timing intervals between vaccinations in a heterologous regimen [ 16 ]. This report presents the safety and immunogenicity results in 12- to 17-year-old adolescents and 4- to 11-year-old children from the same study.…”