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

Navin Venkatraman, Birahim Pierre Ndiaye, Georgina Bowyer, Djibril Wade, Saranya Sridhar, Daniel Wright, Jonathan Powlson, Ibrahima Ndiaye, Siry Dièye, Craig Thompson, Momar Bakhoum, Richard Morter, Stefania Capone, Mariarosaria Del Sorbo, Sophie Jamieson, Tommy Rampling, Mehreen Datoo, Rachel Roberts, Ian Poulton, Oliver Griffiths, W Ripley Ballou, François Roman, David J M Lewis, Alison Lawrie, Egeruan Imoukhuede, Sarah C Gilbert, Tandakha N Dieye, Katie J Ewer, Souleymane Mboup, Adrian V S Hill, Navin Venkatraman, Birahim Pierre Ndiaye, Georgina Bowyer, Djibril Wade, Saranya Sridhar, Daniel Wright, Jonathan Powlson, Ibrahima Ndiaye, Siry Dièye, Craig Thompson, Momar Bakhoum, Richard Morter, Stefania Capone, Mariarosaria Del Sorbo, Sophie Jamieson, Tommy Rampling, Mehreen Datoo, Rachel Roberts, Ian Poulton, Oliver Griffiths, W Ripley Ballou, François Roman, David J M Lewis, Alison Lawrie, Egeruan Imoukhuede, Sarah C Gilbert, Tandakha N Dieye, Katie J Ewer, Souleymane Mboup, Adrian V S Hill

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.

Keywords: ChAd3; Ebola; MVA; EBO-Z; vaccine; viral vectors.

© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Flowchart of study design and volunteer recruitment: Consolidated Standards of Reporting Trials (CONSORT) diagram of screening, enrollment, vaccination, and follow-up. All vaccinations were given intramuscularly. One volunteer in group 3 and 1 volunteer in group 4 withdrew from the UK study and were replaced; hence, n = 9 were allocated, but only 8 completed follow-up. This was unrelated to vaccination. All volunteers completed the study. There were no withdrawals in the Senegalese study and all volunteers completed the study. Abbreviations: ChAd3-EBO-Z, recombinant chimpanzee adenovirus type 3 vectored Ebola Zaire vaccine; MVA-EBO-Z, modified vaccinia Ankara virus vectored Ebola Zaire vaccine; pfu, plaque-forming units; vp, viral particles.
Figure 2.
Figure 2.
Humoral responses. Ebola virus glycoprotein–specific immunoglobulin G responses. A, Median time courses for all groups in the UK cohort. B, Comparison of titers at 28 days after modified vaccinia Ankara (MVA) vaccination in all UK groups. Kruskal–Wallis analysis with Dunn posttest comparing prime-boosted groups to the nonboosted group, P = .0048. No significant difference across the boosted groups, P = .757. C, Median time courses for matched groups in the United Kingdom and Senegal (low-dose MVA, 1 week prime-boost interval). D, Titers at 1 week and 6 months after MVA vaccination in the United Kingdom and Senegal. Kruskal–Wallis analysis with Dunn posttest comparisons across groups, P = .0004 and P = .0001, respectively. Bars represent medians and interquartile ranges in all panels. *P < .05, **P < .01, ***P < .001. UK volunteers who received vaccines in a contralateral regimen are highlighted in red. All other UK volunteers received vaccines in an ipsilateral regimen. Abbreviations: EBOV, Ebola virus; ELISA, enzyme-linked immunosorbent assay; GP, glycoprotein; IgG, immunoglobulin G; M+, number of days postvaccination with modified vaccinia Ankara; MVA, modified vaccinia Ankara; PFU, plaque-forming units; UK, United Kingdom.
Figure 3.
Figure 3.
Enzyme-linked immunospot assay (ELISpot) responses to vaccination. A, Median time courses of T-cell responses to vaccination in all UK volunteers. B, T-cell responses in each UK group at 1 week after modified vaccinia Ankara (MVA) (M+7) (Kruskal–Wallis test, P = .0014). C, Comparison of peak post-MVA responses (M+7) in Senegalese volunteers vaccinated with recombinant chimpanzee adenovirus type 3 vectored Ebola Zaire vaccine and boosted 1 week later with modified vaccinia Ankara virus vectored Ebola Zaire vaccine in either an ipsilateral or contralateral regimen compared with the dose- and interval-matched regimen in the United Kingdom. Kruskal–Wallis analysis with Dunn posttest, P = .237; Mann-Whitney test between ipsilateral and contralateral groups in Senegal, P = .0785. Only 3 volunteers across all UK groups received vaccines in a contralateral regimen (highlighted in red); all others received vaccines in an ipsilateral regimen. D, Association between the ELISpot responses to Sudan Ebola virus glycoprotein (GP) peptides and summed GP pools for Zaire Ebola virus in prime-boosted UK volunteers at M+7. Spearman r = 0.78, P < .0001. Black bars on column graphs indicate median and interquartile range. Abbreviations: ChAd3, chimpanzee adenovirus type 3; EBOV, Zaire Ebola virus; ELISpot, enzyme-linked immunospot assay; GP, glycoprotein; M+7, 7 days post– modified vaccinia Ankara; MVA, modified vaccinia Ankara; PFU, plaque-forming units; PBMC, peripheral blood mononuclear cells; SFC, spot-forming cells; SP, signal peptide; SUDV, Sudan Ebola virus; UK, United Kingdom.
Figure 4.
Figure 4.
Total cytokine responses. A, Total cytokine response measured by flow cytometry with intracellular cytokine staining 7 days postboost according to interval and modified vaccinia Ankara (MVA) dose in the UK cohort (Kruskal–Wallis analysis with Dunn posttest comparisons to the MVA-only group, P = .0529 and P = .0136 in the CD4+ and CD8+ subsets, respectively). Percentages above the x-axis indicate response rates in each. B, Expression of the degranulation marker CD107a in the CD8+ subset 7 days postboost in the UK group; Kruskal–Wallis test, P = .0152. C, Total Ebola glycoprotein–specific cytokine responses in Senegalese groups compared with the matched UK group. Kruskal–Wallis test with Dunn multiple comparisons, P = .0085 and P < .0001 for the CD4+ and CD8+ subsets, respectively. D, Frequency of CD107a+CD8+ T cells in Senegalese groups compared to the matched UK group; Kruskal–Wallis test, P = .0002. Horizontal bars indicate group medians and dashed lines show the lower limit of detection. UK volunteers who received vaccines in a contralateral regimen are highlighted in red. Intracellular cytokine staining (ICS) data are available for 5 of 6 MVA-only volunteers, 13 of 16 in the UK 1-week 1.0 × 108 group, 6 of 8 in the UK 4-week 1.0 × 108 group, 7 of 8 in the UK 4-week 1.5 × 108 group, 10 of 20 in the Senegal ipsilateral group, and 9 of 20 in the Senegal contralateral group. Data are not present if there were too few fresh cells remaining after enzyme-linked immunospot assay to conduct ICS, if too few events were obtained, or the sample failed assay quality control. Asterisks indicate level of significance between groups calculated using Dunn posttest comparison after Kruskal–Wallis analysis. *P < .05, **P < .01, ****P < .0001. Abbreviations: M+7, 7 days post– modified vaccinia Ankara; MVA, modified vaccinia Ankara; PFU, plaque-forming units; UK, United Kingdom.

References

    1. World Health Organization. Blueprint for R&D preparedness and response to public health emergencies due to highly infectious pathogens. Geneva, Switzerland: WHO, 2015:7.
    1. Venkatraman N, Silman D, Folegatti PM, Hill AVS. Vaccines against Ebola virus. Vaccine 2018; 36:5454–9.
    1. Agnandji ST, Huttner A, Zinser ME, et al. . Phase 1 trials of rVSV Ebola vaccine in Africa and Europe. N Engl J Med 2016; 374:1647–60.
    1. Henao-Restrepo AM, Longini IM, Egger M, et al. . Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial. Lancet 2015; 386:857–66.
    1. Kibuuka H, Berkowitz NM, Millard M, et al. . RV 247 Study Team Safety and immunogenicity of Ebola virus and Marburg virus glycoprotein DNA vaccines assessed separately and concomitantly in healthy Ugandan adults: a phase 1b, randomised, double-blind, placebo-controlled clinical trial. Lancet 2015; 385:1545–54.
    1. Ledgerwood JE, DeZure AD, Stanley DA, et al. . VRC 207 Study Team Chimpanzee adenovirus vector Ebola vaccine. N Engl J Med 2017; 376:928–38.
    1. Ewer K, Rampling T, Venkatraman N, et al. . A monovalent chimpanzee adenovirus Ebola vaccine boosted with MVA. N Engl J Med 2016; 374:1635–46.
    1. Regules JA, Beigel JH, Paolino KM, et al. . rVSVΔG-ZEBOV-GP Study Group A recombinant vesicular stomatitis virus Ebola vaccine. N Engl J Med 2017; 376:330–41.
    1. Sarwar UN, Costner P, Enama ME, et al. . VRC 206 Study Team Safety and immunogenicity of DNA vaccines encoding Ebolavirus and Marburgvirus wild-type glycoproteins in a phase I clinical trial. J Infect Dis 2015; 211:549–57.
    1. Tapia MD, Sow SO, Lyke KE, et al. . Use of ChAd3-EBO-Z Ebola virus vaccine in Malian and US adults, and boosting of Malian adults with MVA-BN-Filo: a phase 1, single-blind, randomised trial, a phase 1b, open-label and double-blind, dose-escalation trial, and a nested, randomised, double-blind, placebo-controlled trial. Lancet Infect Dis 2016; 16:31–42.
    1. Zhu FC, Hou LH, Li JX, et al. . Safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in China: preliminary report of a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet 2015; 385:2272–9.
    1. Henao-Restrepo AM, Camacho A, Longini IM, et al. . Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!). Lancet 2017; 389:505–18.
    1. World Health Organization. Report of the SAGE Working Group on Ebola Vaccines and Vaccination with provisional recommendations for vaccination. Geneva, Switzerland: WHO, 2015.
    1. Colloca S, Barnes E, Folgori A, et al. . Vaccine vectors derived from a large collection of simian adenoviruses induce potent cellular immunity across multiple species. Sci Transl Med 2012; 4:115ra2.
    1. Barnes E, Folgori A, Capone S, et al. . Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man. Sci Transl Med 2012; 4:115ra1.
    1. Herath S, Le Heron A, Colloca S, et al. . Analysis of T cell responses to chimpanzee adenovirus vectors encoding HIV gag-pol-nef antigen. Vaccine 2015; 33:7283–9.
    1. De Santis O, Audran R, Pothin E, et al. . Safety and immunogenicity of a chimpanzee adenovirus-vectored Ebola vaccine in healthy adults: a randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a study. Lancet Infect Dis 2016; 16:311–20.
    1. Stanley DA, Honko AN, Asiedu C, et al. . Chimpanzee adenovirus vaccine generates acute and durable protective immunity against ebolavirus challenge. Nat Med 2014; 20:1126–9.
    1. Sullivan NJ, Hensley L, Asiedu C, et al. . CD8+ cellular immunity mediates rAd5 vaccine protection against Ebola virus infection of nonhuman primates. Nat Med 2011; 17:1128–31.
    1. Dahlke C, Kasonta R, Lunemann S, et al. . VEBCON Consortium Dose-dependent T-cell dynamics and cytokine cascade following rVSV-ZEBOV immunization. EBioMedicine 2017; 19:107–18.
    1. Martins KA, Jahrling PB, Bavari S, Kuhn JH. Ebola virus disease candidate vaccines under evaluation in clinical trials. Expert Rev Vaccines 2016; 15:1101–12.
    1. . NCT02344407: Partnership for Research on Ebola Vaccines in Liberia (PREVAIL) Available at: . Accessed 21 October 2018.
    1. Green CA, Scarselli E, Sande CJ, et al. . Chimpanzee adenovirus- and MVA-vectored respiratory syncytial virus vaccine is safe and immunogenic in adults. Sci Transl Med 2015; 7:300ra126.
    1. Sanchez A, Rollin PE. Complete genome sequence of an Ebola virus (Sudan species) responsible for a 2000 outbreak of human disease in Uganda. Virus Res 2005; 113:16–25.
    1. Dahlke C, Lunemann S, Kasonta R, et al. . Comprehensive characterization of cellular immune responses following Ebola virus infection. J Infect Dis 2017; 215:287–92.
    1. Rey-Cuille MA, Seck A, Njouom R, et al. . Low immune response to hepatitis B vaccine among children in Dakar, Senegal. PLoS One 2012; 7:e38153.
    1. Prendergast AJ. Malnutrition and vaccination in developing countries. Philos Trans R Soc Lond B Biol Sci 2015; 370.
    1. O’Connor D, Pollard AJ. Characterizing vaccine responses using host genomic and transcriptomic analysis. Clin Infect Dis 2013; 57:860–9.

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