Open-label phase I clinical trial of Ad5-EBOV in Africans in China

Abstract

Background: To determine the safety and immunogenicity of a novel recombinant adenovirus type 5 vector based Ebola virus disease vaccine (Ad5-EBOV) in Africans in China.

Methods: A phase 1, dose-escalation, open-label trial was conducted. 61 healthy Africans were sequentially enrolled, with 31 participants receiving one shot intramuscular injection and 30 participants receiving a double-shot regimen. Primary and secondary end points related to safety and immunogenicity were assessed within 28 d after vaccination. This study was registered with ClinicalTrials.gov (NCT02401373).

Results: Ad5-EBOV is well tolerated and no adverse reaction of grade 3 or above was observed. 53 (86.89%) participants reported at least one adverse reaction within 28 d of vaccination. The most common reaction was fever and the mild pain at injection site, and there were no significant difference between these 2 groups. Ebola glycoprotein-specific antibodies appeared in all 61 participants and antibodies titers peaked after 28 d of vaccination. The geometric mean titres (GMTs) were similar between these 2 groups (1919.01 vs 1684.70 P = 0.5562). The glycoprotein-specific T-cell responses rapidly peaked after 14 d of vaccination and then decreased, however, the percentage of subjects with responses were much higher in the high-dose group (60.00% vs 9.68%, P = 0.0014). Pre-existing Ad5 neutralizing antibodies could significantly dampen the specific humoral immune response and cellular response to the vaccine.

Conclusion: The application of Ad5-EBOV demonstrated safe in Africans in China and a specific GP antibody and T-cell response could occur 14 d after the first immunization. This acceptable safety profile provides a reliable basis to proceed with trials in Africa.

Keywords: Ad5-EBOV; GP antibody; T-cell response; immunogenicity; safety.

Figures

Figure 1.

Screening, enrollment, vaccinations, and follow-up in the study. The low dose group and high dose group were enrolled sequentially according to a dose­escalation protocol. All the 61 participants completed the study­injection regimen and 28 d of follow­up. All available study data were used for final analysis.

Figure 2.

Glycoprotein-specific T-cell response measured by Enzyme-Linked ImmunoSpot at different time points pre- and post-vaccination. IFN-γ expressing T-cells per 106 PBMC in the all participants (A, n = 31 in the low dose group and n = 30 in the high dose group), and those with pre-existing adenovirus type-5 neutralising antibody titres ≤ 1:200 (B, n = 13 in the low dose group and n = 9 in the high dose group) or >1:200 (C, n = 18 in the low dose group and n = 21 in the high dose group). Cases with undetected T cell response were not shown. The line at median with 75th percentiles (3rd quatile, Q3) were shown in the figure. IFN = interferon. PBMC = peripheral blood mononuclear cells.

Figure 3.

Glycoprotein-specific T-cell response measured by flow cytometry with intracellular cytokine staining (ICS) at different time points pre- and post-vaccination. CD4 T-cell response in all participants (A, n = 31 in the low dose group and n = 30 in the high dose group) and those with pre-existing adenovirus type-5 neutralising antibody titres ≤1:200 (B, n = 13 in the low dose group and n = 9 in the high dose group) or >1:200 (C, n = 18 in the low dose group and n = 21 in the high dose group), and CD8 T-cell response in all participants (D, n = 31 in the low dose group and n = 30 in the high dose group) and those with pre-existing adenovirus type-5 neutralising antibody titres ≤1:200 (E, n = 13 in the low dose group and n = 9 in the high dose group) or >1:200 (F, n = 18 in the low dose group and n = 21 in the high dose group). Proportions of glycoprotein-specific CD4 (G) and CD8 (H) cells that produce any combination of the three cytokines at day14 and day 28. TNF = tumour necrosis factor. IL = interleukin. IFN = interferon. Cases with undetected T cell response were not shown. The line at median with 75th percentiles (3rd quatile, Q3) were shown in the Figure.