Abstract
Natural killer (NK) cells are implicated among immune effectors after vaccination against viral pathogens, including Ebola virus. The two-dose heterologous Ebola virus vaccine regimen, adenovirus type 26.ZEBOV followed by modified vaccinia Ankara-BN-Filo (EBOVAC2 consortium, EU Innovative Medicines Initiative), induces NK cell activation and anti-Ebola glycoprotein (GP) antibody-dependent NK cell activation post-dose 1, which is further elevated post-dose 2. Here, in a multicentre, phase 2 clinical trial (EBL2001), we demonstrate durable ex vivo NK cell activation 180 days after dose 2, with responses enriched in CD56bright NK cells. In vitro antibody-dependent responses to immobilised Ebola GP increased after dose 1, and remained elevated compared to pre-vaccination levels in serum collected 180 days later. Peak NK cell responses were observed post-dose 2 and NK cell IFN-γ responses remained significantly elevated at 180 days post-dose 2. Individual variation in NK cell responses were influenced by both anti-Ebola GP antibody concentrations and intrinsic interindividual differences in NK cell functional capacity. In summary, this study demonstrates durable NK cell responses after Ad26.ZEBOV, MVA-BN-Filo Ebola virus vaccination and could inform the immunological evaluation of future iterations of the vaccine regimen and vaccination schedules.
Highlights
Adenovirus type 26 (Ad26).ZEBOV, modified vaccinia Ankara (MVA)-BN-Filo is a safe and immunogenic, two dose anti-Ebola vaccine regimen that recently received marketing authorisation approval under exceptional circumstances by the European Medicines Agency (EMA)[1,2,3,4,5]
Natural killer (NK) cell phenotypic changes after Ad26.ZEBOV, MVA-BN-Filo vaccination are sustained at day 180 post-dose 2 Previously, we demonstrated NK cell activation (CD25/IL-2Ra expression) accompanied by proliferation (Ki67 expression) of less differentiated (CD56bright and CD56dimCD57−) NK cell subsets up to 21 days after dose 2 of Ad26.ZEBOV, MVA-BN-Filo vaccination[13]
Other than a significant difference in the frequencies of CD56bright NK cells comparing baseline to 180 days post-dose 2, there was no significant difference in the frequencies of CD56dim, CD25+, or Ki67+ NK cells between vaccination visits (Supplementary Fig. 2a–d)
Summary
Adenovirus type 26 (Ad26).ZEBOV, modified vaccinia Ankara (MVA)-BN-Filo is a safe and immunogenic, two dose anti-Ebola vaccine regimen that recently received marketing authorisation approval under exceptional circumstances by the European Medicines Agency (EMA)[1,2,3,4,5]. Stimulation of human PBMC with Ebola GP (EBOV GP) in vitro induces the secretion of high levels of pro and anti-inflammatory cytokines including IL-10, GM-CSF, IL-1β, and TNFα and lower levels of IL-12, IL-18, and type I IFN7–13. Ad26.ZEBOV, MVA-BN-Filo vaccination induces a proliferative increase in less differentiated NK cells up to 21 days post-dose 2, accompanied by an increased frequency of CD25+ NK cells, suggesting an increased responsiveness to CD4+ T cell derived IL-213
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