Safety and immunogenicity of the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in children in Sierra Leone: a randomised, double-blind, controlled trial

Abstract

Background: Children account for a substantial proportion of cases and deaths from Ebola virus disease. We aimed to assess the safety and immunogenicity of a two-dose heterologous vaccine regimen, comprising the adenovirus type 26 vector-based vaccine encoding the Ebola virus glycoprotein (Ad26.ZEBOV) and the modified vaccinia Ankara vector-based vaccine, encoding glycoproteins from the Ebola virus, Sudan virus, and Marburg virus, and the nucleoprotein from the Tai Forest virus (MVA-BN-Filo), in a paediatric population in Sierra Leone.

Methods: This randomised, double-blind, controlled trial was done at three clinics in Kambia district, Sierra Leone. Healthy children and adolescents aged 1-17 years were enrolled in three age cohorts (12-17 years, 4-11 years, and 1-3 years) and randomly assigned (3:1), via computer-generated block randomisation (block size of eight), to receive an intramuscular injection of either Ad26.ZEBOV (5 × 10¹⁰ viral particles; first dose) followed by MVA-BN-Filo (1 × 10⁸ infectious units; second dose) on day 57 (Ebola vaccine group), or a single dose of meningococcal quadrivalent (serogroups A, C, W135, and Y) conjugate vaccine (MenACWY; first dose) followed by placebo (second dose) on day 57 (control group). Study team personnel (except for those with primary responsibility for study vaccine preparation), participants, and their parents or guardians were masked to study vaccine allocation. The primary outcome was safety, measured as the occurrence of solicited local and systemic adverse symptoms during 7 days after each vaccination, unsolicited systemic adverse events during 28 days after each vaccination, abnormal laboratory results during the study period, and serious adverse events or immediate reportable events throughout the study period. The secondary outcome was immunogenicity (humoral immune response), measured as the concentration of Ebola virus glycoprotein-specific binding antibodies at 21 days after the second dose. The primary outcome was assessed in all participants who had received at least one dose of study vaccine and had available reactogenicity data, and immunogenicity was assessed in all participants who had received both vaccinations within the protocol-defined time window, had at least one evaluable post-vaccination sample, and had no major protocol deviations that could have influenced the immune response. This study is registered at ClinicalTrials.gov, NCT02509494.

Findings: From April 4, 2017, to July 5, 2018, 576 eligible children or adolescents (192 in each of the three age cohorts) were enrolled and randomly assigned. The most common solicited local adverse event during the 7 days after the first and second dose was injection-site pain in all age groups, with frequencies ranging from 0% (none of 48) of children aged 1-3 years after placebo injection to 21% (30 of 144) of children aged 4-11 years after Ad26.ZEBOV vaccination. The most frequently observed solicited systemic adverse event during the 7 days was headache in the 12-17 years and 4-11 years age cohorts after the first and second dose, and pyrexia in the 1-3 years age cohort after the first and second dose. The most frequent unsolicited adverse event after the first and second dose vaccinations was malaria in all age cohorts, irrespective of the vaccine types. Following vaccination with MenACWY, severe thrombocytopaenia was observed in one participant aged 3 years. No other clinically significant laboratory abnormalities were observed in other study participants, and no serious adverse events related to the Ebola vaccine regimen were reported. There were no treatment-related deaths. Ebola virus glycoprotein-specific binding antibody responses at 21 days after the second dose of the Ebola virus vaccine regimen were observed in 131 (98%) of 134 children aged 12-17 years (9929 ELISA units [EU]/mL [95% CI 8172-12 064]), in 119 (99%) of 120 aged 4-11 years (10 212 EU/mL [8419-12 388]), and in 118 (98%) of 121 aged 1-3 years (22 568 EU/mL [18 426-27 642]).

Interpretation: The Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen was well tolerated with no safety concerns in children aged 1-17 years, and induced robust humoral immune responses, suggesting suitability of this regimen for Ebola virus disease prophylaxis in children.

Funding: Innovative Medicines Initiative 2 Joint Undertaking and Janssen Vaccines & Prevention BV.

Figure 1. Trial profiles for the 12–17 years (A), 4–11 years (B), and 1–3 years (C) age cohorts

Ad26.ZEBOV=adenovirus type 26 vector-based vaccine encoding the Ebola virus glycoprotein. MenACWY=meningococcal quadrivalent (serogroups A, C, W135, and Y) conjugate vaccine. MVA-BN-Filo=modified vaccinia Ankara vector-based vaccine, encoding glycoproteins from the Ebola virus, Sudan virus, and Marburg virus, and the nucleoprotein from the Tai Forest virus. *One participant received Ad26.ZEBOV followed by placebo and was therefore excluded from further analyses.

Figure 2. Solicited local and systemic AEs in the paediatric cohorts

Solicited local (A) and systemic (B) AEs during 7 days after the first dose, and solicited local (C) and systemic (D) AEs during 7 days after the second dose in the 12–17 years age cohort. Solicited local (E) and systemic (F) AEs during 7 days after the first dose, and solicited local (G) and systemic (H) AEs during 7 days after the second dose in the 4–11 years age cohort. Solicited local (I) and systemic (J) AEs during 7 days after the first dose, and solicited local (K) and systemic (L) AEs during 7 days after the second dose in the 1–3 years age cohort. Ad26.ZEBOV=adenovirus type 26 vector-based vaccine encoding the Ebola virus glycoprotein. AE=adverse event. MenACWY=meningococcal quadrivalent (serogroups A, C, W135, and Y) conjugate vaccine. MVA-BN-Filo=modified vaccinia Ankara vector-based vaccine, encoding glycoproteins from the Ebola virus, Sudan virus, and Marburg virus, and the nucleoprotein from the Tai Forest virus.

Figure 3. Geometric mean concentrations of Ebola virus glycoprotein-specific binding antibodies before and after each vaccination

Figure 4. Ebola virus glycoprotein-specific neutralising antibody responses before and after each vaccination

The response profile for each group is shown as geometric mean titres, measured by use of the pseudovirion neutralisation assay. The error bars show the 95% CIs. The black dotted line represents the LLOQ. Day 1 is baseline, day 57 is 56 days after the first dose, day 78 is 21 days after the second dose, day 240 is 179 days after the second dose, and day 360 is 359 days after the first dose. Ad26.ZEBOV=adenovirus type 26 vector-based vaccine encoding the Ebola virus glycoprotein. IC₅₀=half maximal inhibitory concentration. LLOQ=lower limit of quantification. MenACWY=meningococcal quadrivalent (serogroups A, C, W135, and Y) conjugate vaccine. MVA-BN-Filo=modified vaccinia Ankara vector-based vaccine, encoding glycoproteins from the Ebola virus, Sudan virus, and Marburg virus, and the nucleoprotein from the Tai Forest virus.