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

Abstract

Background: Reoccurring Ebola outbreaks in West and Central Africa have led to serious illness and death in thousands of adults and children. The objective of this study was to assess safety, tolerability, and immunogenicity of the heterologous 2-dose Ad26.ZEBOV, MVA-BN-Filo vaccination regimen in adolescents and children in Africa.

Methods and findings: In this multicentre, randomised, observer-blind, placebo-controlled Phase II study, 131 adolescents (12 to 17 years old) and 132 children (4 to 11 years old) were enrolled from Eastern and Western Africa and randomised 5:1 to receive study vaccines or placebo. Vaccine groups received intramuscular injections of Ad26.ZEBOV (5 × 1010 viral particles) and MVA-BN-Filo (1 × 108 infectious units) 28 or 56 days apart; placebo recipients received saline. Primary outcomes were safety and tolerability. Solicited adverse events (AEs) were recorded until 7 days after each vaccination and serious AEs (SAEs) throughout the study. Secondary and exploratory outcomes were humoral immune responses (binding and neutralising Ebola virus [EBOV] glycoprotein [GP]-specific antibodies), up to 1 year after the first dose. Enrolment began on February 26, 2016, and the date of last participant last visit was November 28, 2018. Of the 263 participants enrolled, 217 (109 adolescents, 108 children) received the 2-dose regimen, and 43 (20 adolescents, 23 children) received 2 placebo doses. Median age was 14.0 (range 11 to 17) and 7.0 (range 4 to 11) years for adolescents and children, respectively. Fifty-four percent of the adolescents and 51% of the children were male. All participants were Africans, and, although there was a slight male preponderance overall, the groups were well balanced. No vaccine-related SAEs were reported; solicited AEs were mostly mild/moderate. Twenty-one days post-MVA-BN-Filo vaccination, binding antibody responses against EBOV GP were observed in 100% of vaccinees (106 adolescents, 104 children). Geometric mean concentrations tended to be higher after the 56-day interval (adolescents 13,532 ELISA units [EU]/mL, children 17,388 EU/mL) than the 28-day interval (adolescents 6,993 EU/mL, children 8,007 EU/mL). Humoral responses persisted at least up to Day 365. A limitation of the study is that the follow-up period was limited to 365 days for the majority of the participants, and so it was not possible to determine whether immune responses persisted beyond this time period. Additionally, formal statistical comparisons were not preplanned but were only performed post hoc.

Conclusions: The heterologous 2-dose vaccination was well tolerated in African adolescents and children with no vaccine-related SAEs. All vaccinees displayed anti-EBOV GP antibodies after the 2-dose regimen, with higher responses in the 56-day interval groups. The frequency of pyrexia after vaccine or placebo was higher in children than in adolescents. These data supported the prophylactic indication against EBOV disease in a paediatric population, as licenced in the EU.

Trial registration: ClinicalTrials.gov NCT02564523.

Fig 1. Study disposition of adolescents and children.

Fig 2. Solicited local AEs.

(A) Solicited systemic AEs (B) and unsolicited AEs (C); full analysis set. Percentages reflect n/N where n is the number of participants with one or more AEs and N is the number of participants with available reactogenicity data after the given dose (solicited AEs) or the number of participants who received the given dose (unsolicited AEs). Only unsolicited AEs reported between the dose 1 vaccination and 28 days post-dose 1, and between dose 2 vaccination and 28 days post-dose 2 are included in this table. Different diaries were used in adolescents (12–17 years) and children (4–11 years) to collect solicited systemic AEs. Solicited systemic AEs collected in adolescents: arthralgia, chills, fatigue, headache, myalgia, nausea, and pyrexia; in children: pyrexia, decreased activity, decreased appetite, irritability, and vomiting. ^aPer the DMID Toxicity Tables used in this study, erythema was graded based on the diameter data only. ^bPyrexia mild: 38.0–38.4 °C, moderate: 38.5–38.9 °C, severe: >38.9 °C. ^cN = 54. ^dPyrexia mild: 38.0–38.4 °C, moderate: 38.5–40.0 °C, severe: >40.0 °C. Ad26: Ad26.ZEBOV at a dose of 5 × 10¹⁰ viral particles; MVA: MVA-BN-Filo at a dose of 1 × 10⁸ Inf.U. Ad26, Ad26.ZEBOV; AE, adverse event; DMID, Division of Microbiology and Infectious Diseases; Inf.U, infectious units; MVA, MVA-BN-Filo.

Fig 3. GMCs of EBOV-specific binding antibodies (FANG ELISA, 95% CI) in adolescents and children.

Participants administered with Ad26.ZEBOV or placebo on day 1 and MVA-BN-Filo or placebo 28 or 56 days later as indicated. Responses are expressed as GMCs (EU/mL, 95% CI). Responses in placebo groups are shown as open symbols. Grey dotted line represents the LLOQ. The points (symbols) denote GMCs, and error bars denote 95% CIs. Ad26, Ad26.ZEBOV; CI, confidence interval; EBOV, Ebola virus; EU, ELISA units; FANG ELISA, Filovirus Animal Nonclinical Group enzyme-linked immunosorbent assay; GMC, geometric mean concentration; LLOQ, lower limit of quantification; MVA, MVA-BN-Filo; Pbo, placebo.