Safety, reactogenicity, and immunogenicity of a chimpanzee adenovirus vectored Ebola vaccine in children in Africa: a randomised, observer-blind, placebo-controlled, phase 2 trial

Abstract

Background During the large 2013-16 Ebola virus outbreak caused by the Zaire Ebola virus, about 20% of cases were reported in children. This study is the first, to our knowledge, to evaluate an Ebola vaccine in children younger than 6 years. We aimed to evaluate the safety, reactogenicity, and immunogenicity of a monovalent, recombinant, chimpanzee adenovirus type-3 vectored Zaire Ebola glycoprotein vaccine (ChAd3-EBO-Z) in a paediatric population.Methods This phase 2, randomised, observer-blind, controlled trial was done in a vaccine centre in Mali and a university hospital centre in Senegal. Healthy children were randomly assigned through a web-based system (1:1; stratified by age group, gender, and centre) to receive ChAd3-EBO-Z (day 0) and meningococcal serogroups A,C,W-135,Y tetanus toxoid conjugate vaccine (MenACWY-TT; month 6), or MenACWY-TT (day 0) and ChAd3-EBO-Z (month 6). The study was observer-blind from study start until interim day 30 analysis and became single-blind as of interim analysis. Primary outcomes assessed were serious adverse events (up to study end, month 12), solicited local or general adverse events (7 days post-vaccination), unsolicited adverse events (30 days post-vaccination), haematological or biochemical abnormalities, and clinical symptoms of thrombocytopenia (day 0-6). As secondary endpoints, we evaluated anti-glycoprotein Zaire Ebola virus antibody titres (ELISA) pre-vaccination and 30 days postvaccination. This study is registered with ClinicalTrials.gov, NCT02548078. FindingsFrom Nov 11, 2015, to May 9, 2016, of 776 children screened for eligibility, 600 were randomly assigned (200 [33%] in each age strata: 1-5, 6-12, 13-17 years), 300 (50%) to the ChAd3-EBO-Z/MenACWY-TT group and 300 (50%) to the MenACWY-TT/ChAd3-EBO-Z group; all were included in the total vaccinated cohort. Post-day 0 vaccination, the most common solicited injection site symptom was pain (127 [42%] of 300 in the ChAd3-EBO-Z/ MenACWY-TT group vs 60 [20%] of 300 in the MenACWY-TT/ChAd3-EBO-Z group); the most common solicited general adverse event was fever (95 [32%] of 300 in the ChAd3-EBO-Z/MenACWY-TT group vs 28 [9%] of 300 in the MenACWY-TT/ChAd3-EBO-Z group). Unsolicited adverse events post-day 0 vaccination were reported by 41 (14%) of 300 participants in the ChAd3-EBO-Z/MenACWY-TT group and 24 (8%) of 300 MenACWY-TT/ChAd3-EBO-Z recipients. Serious adverse events were reported for two (1%) of 300 children in each group; none were considered vaccination related. No clinical symptoms of thrombocytopenia were reported. At day 30, anti-glycoprotein Ebola virus antibody geometric mean concentrations (GMC) in the ChAd3-EBO-Z/MenACWY-TT group were 1564 (95% CI 1340-1826) for those aged 13-17 years, 1395 (1175-1655) for 6-12 years, and 2406 (1942-2979) for 1-5 years. Antiglycoprotein Ebola virus IgG antibody responses persisted up to 12 months post-vaccination, with a GMC of 716 (95% CI 619-828) for those aged 13-17 years, 752 (645-876) for 6-12 years, and 1424 (1119-1814) for 1-5 years. Interpretation ChAd3-EBO...

Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial

“…Most of the reported local and systemic adverse events were mild to moderate in severity, in line with our previous phase 1 study of the ChAdOx1 nCoV-19 vaccine 18 and previously reported studies of ChAdOx1-vectored vaccines. [22][23][24] Fewer adverse events were reported after the boost vaccination than after the prime vaccination and reactogenicity reduced with increasing age. The lower dose of vaccine was less reactogenic than the standard dose of vaccine across all age groups.…”

Innate Immune Responses to Chimpanzee Adenovirus Vector 155 Vaccination in Mice and Monkeys

“…Owing to their lower seroprevalence and thus decreased vector neutralization in humans as compared to human Ad5, chimpanzee Ad (ChAd) vectors represent an attractive vaccine platform (3)(4)(5). ChAdvectored candidate vaccines against infectious diseases such as malaria, Ebola, and RSV have shown favorable immunogenicity and tolerability in humans (6)(7)(8)(9)(10)(11). These vaccines drive robust intracellular antigen expression, thus promoting a CD8 + T-cellbiased response, but were also shown to induce antigen-specific CD4 + T-cell responses and antibodies.…”

Is there a role for childhood vaccination against COVID‐19?

“…This antigen is then either secreted, induc- In children, vector-based vaccines have been tested against malaria, 49,50 tuberculosis, 51 and Ebola. 52,53 The malaria vaccine candidate ME-TRAP, based on a heterologous prime-boost schema with MVA and FP9, was shown to be safe and relatively immunogenic, 54,55 but not efficacious. 50 Against tuberculosis, the MVA-Ag85A vaccine was safe in children (n = 24, 1-7 y/o) and adolescents (N = 12, 13-15 y/o), initiating CD4 + T-cell responses that were moderately sustained at 6 months in adolescents.…”

“…In children, vector‐based vaccines have been tested against malaria, 49,50 tuberculosis, 51 and Ebola 52,53 . The malaria vaccine candidate ME‐TRAP, based on a heterologous prime‐boost schema with MVA and FP9, was shown to be safe and relatively immunogenic, 54,55 but not efficacious 50 .…”

“…The vaccine was generally safe, although local symptoms such as pain were reported in around 42% and more frequently in the youngest (55% aged 1‐5 years vs 31% aged 13‐17 years). Systemic symptoms were described by half of the subjects, being mainly fever (1‐5 years old) and headache (13‐17 years old); however, severe events were recorded in only 1% of participants 53,56 …”