Safety and Immunogenicity of a Heterologous Prime-Boost Ebola Virus Vaccine Regimen in Healthy Adults in the United Kingdom and Senegal

Abstract

Background The 2014 West African outbreak of Ebola virus disease highlighted the urgent need to develop an effective Ebola vaccine. Methods We undertook 2 phase 1 studies assessing safety and immunogenicity of the viral vector modified vaccinia Ankara virus vectored Ebola Zaire vaccine (MVA-EBO-Z), manufactured rapidly on a new duck cell line either alone or in a heterologous prime-boost regimen with recombinant chimpanzee adenovirus type 3 vectored Ebola Zaire vaccine (ChAd3-EBO-Z) followed by MVA-EBO-Z. Adult volunteers in the United Kingdom (n = 38) and Senegal (n = 40) were vaccinated and an accelerated 1-week prime-boost regimen was assessed in Senegal. Safety was assessed by active and passive collection of local and systemic adverse events. Results The standard and accelerated heterologous prime-boost regimens were well-tolerated and elicited potent cellular and humoral immunogenicity in the United Kingdom and Senegal, but vaccine-induced antibody responses were significantly lower in Senegal. Cellular immune responses measured by flow cytometry were significantly greater in African vaccinees receiving ChAd3 and MVA vaccines in the same rather than the contralateral limb. Conclusions MVA biomanufactured on an immortalized duck cell line shows potential for very large-scale manufacturing with lower cost of goods. This first trial of MVA-EBO-Z in humans encourages further testing in phase 2 studies, with the 1-week prime-boost interval regimen appearing to be particularly suitable for outbreak control. Clinical Trials Registration NCT02451891; NCT02485912.

Reduced Ebola vaccine responses in CMV+ young adults is associated with expansion of CD57+KLRG1+ T cells

“…As reported in the primary clinical trial results (Venkatraman et al, 2018), vaccine-specific antibody responses were significantly lower in the Senegalese cohort than in the UK cohort at peak and late time points ( Fig. 1 B).…”

“…Both vaccinations were delivered intramuscularly into the deltoid region of the arm. Further details of both studies can be found in the clinical trial paper (Venkatraman et al, 2018) and study protocols, which were submitted with the clinical trial manuscript.…”

“…Antibody responses to vaccination were assessed using a standardized ELISA for total IgG against trimeric Zaire Ebola GP as previously described (Venkatraman et al, 2018). A reference pool of positive serum was used to form a standard curve.…”

“…However, direct evidence of an association between pathogen exposure, altered immune phenotypes, and reduced vaccine responses is lacking. During the 2014-2016 Ebola outbreak in West Africa, we conducted two Phase I clinical trials of the Ebola vaccine candidates chimpanzee adenovirus serotype 3 (ChAd3) and modified vaccinia virus Ankara (MVA), both expressing Zaire Ebola glycoprotein (EBO-Z; Venkatraman et al, 2018). The trials were run concurrently in Oxford, UK, and Dakar, Senegal, with healthy UK adults aged 18-50 yr (n = 16; average, 33 yr) and Senegalese adults aged 18-50 yr (n = 40; average, 28 yr) in the matched dose groups receiving the same vaccine regimen: 3.6 × 10 10 viral particles of ChAd3-EBO-Z at day 0, boosted with 1 × 10 8 plaque-forming units of MVA-EBO-Z 1 wk later.…”

Characterisation of antigenic MHC Class I-restricted T cell epitopes in the glycoprotein of Ebolavirus

“…Although EBOV T cell epitopes in the nucleoprotein have been characterised in human studies of Ebola survivors, to date no minimal epitopes have been characterised in the glycoprotein [31]. This is despite the potent immunogenicity of the glycoprotein both in the context of natural infection [8, 9] and in vaccines expressing GP as the target antigen [22, 32–34].…”