Dose-dependent T-cell Dynamics and Cytokine Cascade Following rVSV-ZEBOV Immunization
Christine Dahlke, Rahel Kasonta, Sebastian Lunemann, Verena Krähling, Madeleine E Zinser, Nadine Biedenkopf, Sarah K Fehling, My L Ly, Anne Rechtien, Hans C Stubbe, Flaminia Olearo, Saskia Borregaard, Alen Jambrecina, Felix Stahl, Thomas Strecker, Markus Eickmann, Marc Lütgehetmann, Michael Spohn, Stefan Schmiedel, Ansgar W Lohse, Stephan Becker, Marylyn M Addo, VEBCON Consortium, Marylyn M Addo, Stephan Becker, Verena Krähling, Selidji Todagbe Agnandji, Sanjeev Krishna, Peter G Kremsner, Jessica S Brosnahan, Philip Bejon, Patricia Njuguna, Claire-Anne Siegrist, Angela Huttner, Marie-Paule Kieny, Kayvon Modjarrad, Vasee Moorthy, Patricia Fast, Barbara Savarese, Olivier Lapujade, Christine Dahlke, Rahel Kasonta, Sebastian Lunemann, Verena Krähling, Madeleine E Zinser, Nadine Biedenkopf, Sarah K Fehling, My L Ly, Anne Rechtien, Hans C Stubbe, Flaminia Olearo, Saskia Borregaard, Alen Jambrecina, Felix Stahl, Thomas Strecker, Markus Eickmann, Marc Lütgehetmann, Michael Spohn, Stefan Schmiedel, Ansgar W Lohse, Stephan Becker, Marylyn M Addo, VEBCON Consortium, Marylyn M Addo, Stephan Becker, Verena Krähling, Selidji Todagbe Agnandji, Sanjeev Krishna, Peter G Kremsner, Jessica S Brosnahan, Philip Bejon, Patricia Njuguna, Claire-Anne Siegrist, Angela Huttner, Marie-Paule Kieny, Kayvon Modjarrad, Vasee Moorthy, Patricia Fast, Barbara Savarese, Olivier Lapujade
Abstract
Background: The recent West African Ebola epidemic led to accelerated efforts to test Ebola vaccine candidates. As part of the World Health Organisation-led VSV Ebola Consortium (VEBCON), we performed a phase I clinical trial investigating rVSV-ZEBOV (a recombinant vesicular stomatitis virus-vectored Ebola vaccine), which has recently demonstrated protection from Ebola virus disease (EVD) in phase III clinical trials and is currently in advanced stages of licensing. So far, correlates of immune protection are incompletely understood and the role of cell-mediated immune responses has not been comprehensively investigated to date.
Methods: We recruited 30 healthy subjects aged 18-55 into an open-label, dose-escalation phase I trial testing three doses of rVSV-ZEBOV (3×105 plaque-forming units (PFU), 3×106 PFU, 2×107 PFU) (ClinicalTrials.gov; NCT02283099). Main study objectives were safety and immunogenicity, while exploratory objectives included lymphocyte dynamics, cell-mediated immunity and cytokine networks, which were assessed using flow cytometry, ELISpot and LUMINEX assay.
Findings: Immunization with rVSV-ZEBOV was well tolerated without serious vaccine-related adverse events. Ebola virus-specific neutralizing antibodies were induced in nearly all individuals. Additionally, vaccinees, particularly within the highest dose cohort, generated Ebola glycoprotein (GP)-specific T cells and initiated a cascade of signaling molecules following stimulation of peripheral blood mononuclear cells with Ebola GP peptides.
Interpretation: In addition to a benign safety and robust humoral immunogenicity profile, subjects immunized with 2×107 PFU elicited higher cellular immune responses and stronger interlocked cytokine networks compared to lower dose groups. To our knowledge these data represent the first detailed cell-mediated immuneprofile of a clinical trial testing rVSV-ZEBOV, which is of particular interest in light of its potential upcoming licensure as the first Ebola vaccine. VEBCON trial Hamburg, Germany (NCT02283099).
Keywords: Cytokines; Ebola vaccine; Humoral and cell-mediated immune responses; Phase I study; T-cell responses; rVSV-ZEBOV.
Copyright © 2017. Published by Elsevier B.V.
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References
- Agnandji S.T., Huttner A., Zinser M.E., Njuguna P., Dahlke C., Fernandes J.F., Yerly S., Dayer J.A., Kraehling V., Kasonta R., Adegnika A.A., Altfeld M., Auderset F., Bache E.B., Biedenkopf N., Borregaard S., Brosnahan J.S., Burrow R., Combescure C., Desmeules J., Eickmann M., Fehling S.K., Finckh A., Goncalves A.R., Grobusch M.P., Hooper J., Jambrecina A., Kabwende A.L., Kaya G., Kimani D., Lell B., Lemaitre B., Lohse A.W., Massinga-Loembe M., Matthey A., Mordmuller B., Nolting A., Ogwang C., Ramharter M., Schmidt-Chanasit J., Schmiedel S., Silvera P., Stahl F.R., Staines H.M., Strecker T., Stubbe H.C., Tsofa B., Zaki S., Fast P., Moorthy V., Kaiser L., Krishna S., Becker S., Kieny M.P., Bejon P., Kremsner P.G., Addo M.M., Siegrist C.A. Phase 1 trials of rVSV Ebola vaccine in Africa and Europe. N. Engl. J. Med. 2016;374:1647–1660.
- Blom K., Braun M., Ivarsson M.A., Gonzalez V.D., Falconer K., Moll M., Ljunggren H.G., Michaelsson J., Sandberg J.K. Temporal dynamics of the primary human T cell response to yellow fever virus 17D as it matures from an effector- to a memory-type response. J. Immunol. 2013;190:2150–2158.
- Dahlke C., Lunemann S., Kasonta R., Kreuels B., Schmiedel S., Ly M.L., Fehling S.K., Strecker T., Becker S., Altfeld M., Sow A., Lohse A.W., Munoz-Fontela C., Addo M.M. Comprehensive characterization of cellular immune responses following Ebola virus infection. J Infect Dis. 2017;215(2):287–292. (PMID: 27799354)
- De Santis O., Audran R., Pothin E., Warpelin-Decrausaz L., Vallotton L., Wuerzner G., Cochet C., Estoppey D., Steiner-Monard V., Lonchampt S., Thierry A.C., Mayor C., Bailer R.T., Mbaya O.T., Zhou Y., Ploquin A., Sullivan N.J., Graham B.S., Roman F., De Ryck I., Ballou W.R., Kieny M.P., Moorthy V., Spertini F., Genton B. 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;16:311–320.
- De Wit E., Marzi A., Bushmaker T., Brining D., Scott D., Richt J.A., Geisbert T.W., Feldmann H. Safety of recombinant VSV-Ebola virus vaccine vector in pigs. Emerg. Infect. Dis. 2015;21:702–704.
- Farooq F., Beck K., Paolino K.M., Phillips R., Waters N.C., Regules J.A., Bergmann-Leitner E.S. Circulating follicular T helper cells and cytokine profile in humans following vaccination with the rVSV-ZEBOV Ebola vaccine. Sci. Rep. 2016;6:27944.
- Feldmann H., Jones S.M., Daddario-Dicaprio K.M., Geisbert J.B., Stroher U., Grolla A., Bray M., Fritz E.A., Fernando L., Feldmann F., Hensley L.E., Geisbert T.W. Effective post-exposure treatment of Ebola infection. PLoS Pathog. 2007;3:e2.
- Geisbert T.W., Daddario-Dicaprio K.M., Geisbert J.B., Reed D.S., Feldmann F., Grolla A., Stroher U., Fritz E.A., Hensley L.E., Jones S.M., Feldmann H. Vesicular stomatitis virus-based vaccines protect nonhuman primates against aerosol challenge with Ebola and Marburg viruses. Vaccine. 2008;26:6894–6900.
- Geisbert T.W., Feldmann H. Recombinant vesicular stomatitis virus-based vaccines against Ebola and Marburg virus infections. J. Infect. Dis. 2011;204(Suppl. 3):S1075–S1081.
- Gupta M., Greer P., Mahanty S., Shieh W.J., Zaki S.R., Ahmed R., Rollin P.E. CD8-mediated protection against Ebola virus infection is perforin dependent. J. Immunol. 2005;174:4198–4202.
- Henao-Restrepo A.M., Camacho A., Longini I.M., Watson C.H., Edmunds W.J., Egger M., Carroll M.W., Dean N.E., Diatta I., Doumbia M., Draguez B., Duraffour S., Enwere G., Grais R., Gunther S., Gsell P.S., Hossmann S., Watle S.V., Konde M.K., Keita S., Kone S., Kuisma E., Levine M.M., Mandal S., Mauget T., Norheim G., Riveros X., Soumah A., Trelle S., Vicari A.S., Rottingen J.A., Kieny M.P. 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 Ca Suffit!) Lancet. 2017;389(10068):505–518. (Epub 2016 Dec 23.PMID:28017403)
- Jones S.M., Feldmann H., Stroher U., Geisbert J.B., Fernando L., Grolla A., Klenk H.D., Sullivan N.J., Volchkov V.E., Fritz E.A., Daddario K.M., Hensley L.E., Jahrling P.B., Geisbert T.W. Live attenuated recombinant vaccine protects nonhuman primates against Ebola and Marburg viruses. Nat. Med. 2005;11:786–790.
- Jones S.M., Stroher U., Fernando L., Qiu X., Alimonti J., Melito P., Bray M., Klenk H.D., Feldmann H. Assessment of a vesicular stomatitis virus-based vaccine by use of the mouse model of Ebola virus hemorrhagic fever. J Infect Dis. 2007;196(Suppl. 2):S404–S412.
- Kang T.H., Bae H.C., Kim S.H., Seo S.H., Son S.W., Choi E.Y., Seong S.Y., Kim T.W. Modification of dendritic cells with interferon-gamma-inducible protein-10 gene to enhance vaccine potency. J. Gene Med. 2009;11:889–898.
- Khurana S., Fuentes S., Coyle E.M., Ravichandran S., Davey R.T., Jr. & Beigel, J. H. Human antibody repertoire after VSV-Ebola vaccination identifies novel targets and virus-neutralizing IgM antibodies. Nat. Med. 2016;22:1439–1447.
- Krahling V., Becker D., Rohde C., Eickmann M., Eroglu Y., Herwig A., Kerber R., Kowalski K., Vergara-Alert J., Becker S. Development of an antibody capture ELISA using inactivated Ebola Zaire Makona virus. Med. Microbiol. Immunol. 2016;205:173–183.
- Lai L., Davey R., Beck A., Xu Y., Suffredini A.F., Palmore T., Kabbani S., Rogers S., Kobinger G., Alimonti J., Link C.J., Jr., Rubinson L., Stroher U., Wolcott M., Dorman W., Uyeki T.M., Feldmann H., Lane H.C., Mulligan M.J. Emergency postexposure vaccination with vesicular stomatitis virus-vectored Ebola vaccine after needlestick. JAMA. 2015;313:1249–1255.
- Marzi A., Engelmann F., Feldmann F., Haberthur K., Shupert W.L., Brining D., Scott D.P., Geisbert T.W., Kawaoka Y., Katze M.G., Feldmann H., Messaoudi I. Antibodies are necessary for rVSV/ZEBOV-GP-mediated protection against lethal Ebola virus challenge in nonhuman primates. Proc. Natl. Acad. Sci. U. S. A. 2013;110:1893–1898.
- Marzi A., Hanley P.W., Haddock E., Martellaro C., Kobinger G., Feldmann H. Efficacy of vesicular stomatitis virus-Ebola virus postexposure treatment in rhesus macaques infected with Ebola virus Makona. J. Infect. Dis. 2016;214:S360–s366.
- Marzi A., Robertson S.J., Haddock E., Feldmann F., Hanley P.W., Scott D.P., Strong J.E., Kobinger G., Best S.M., Feldmann H. EBOLA VACCINE. VSV-EBOV rapidly protects macaques against infection with the 2014/15 Ebola virus outbreak strain. Science. 2015;349:739–742.
- Mcelroy A.K., Akondy R.S., Davis C.W., Ellebedy A.H., Mehta A.K., Kraft C.S., Lyon G.M., Ribner B.S., Varkey J., Sidney J., Sette A., Campbell S., Stroher U., Damon I., Nichol S.T., Spiropoulou C.F., Ahmed R. Human Ebola virus infection results in substantial immune activation. Proc. Natl. Acad. Sci. U. S. A. 2015;112:4719–4724.
- Meyer M., Garron T., Lubaki N.M., Mire C.E., Fenton K.A., Klages C., Olinger G.G., Geisbert T.W., Collins P.L., Bukreyev A. Aerosolized Ebola vaccine protects primates and elicits lung-resident T cell responses. J. Clin. Invest. 2015;125:3241–3255.
- Miller J.D., Van Der Most R.G., Akondy R.S., Glidewell J.T., Albott S., Masopust D., Murali-Krishna K., Mahar P.L., Edupuganti S., Lalor S., Germon S., Del Rio C., Mulligan M.J., Staprans S.I., Altman J.D., Feinberg M.B., Ahmed R. Human effector and memory CD8 + T cell responses to smallpox and yellow fever vaccines. Immunity. 2008;28:710–722.
- Nakaya H.I., Wrammert J., Lee E.K., Racioppi L., Marie-Kunze S., Haining W.N., Means A.R., Kasturi S.P., Khan N., Li, G. M., Mccausland, M., Kanchan, V., Kokko, K. E., Li, S., Elbein, R., Mehta, A. K., Aderem, A., Subbarao, K., Ahmed, R. & Pulendran, B. Systems biology of vaccination for seasonal influenza in humans. Nat. Immunol. 2011;12:786–795.
- Pavot V. Ebola virus vaccines: where do we stand? Clin. Immunol. 2016;173:44–49.
- Qiu X., Fernando L., Alimonti J.B., Melito P.L., Feldmann F., Dick D., Stroher U., Feldmann H., Jones S.M. Mucosal immunization of cynomolgus macaques with the VSVDeltaG/ZEBOVGP vaccine stimulates strong ebola GP-specific immune responses. PLoS One. 2009;4:e5547.
- Regules J.A., Beigel J.H., Paolino K.M., Voell J., Castellano A.R., Hu Z., Munoz P., Moon J.E., Ruck R.C., Bennett J.W., Twomey P.S., Gutierrez R.L., Remich S.A., Hack H.R., Wisniewski M.L., Josleyn M.D., Kwilas S.A., Van Deusen N., Mbaya O.T., Zhou Y., Stanley D.A., Jing W., Smith K.S., Shi M., Ledgerwood J.E., Graham B.S., Sullivan N.J., Jagodzinski L.L., Peel S.A., Alimonti J.B., Hooper J.W., Silvera P.M., Martin B.K., Monath T.P., Ramsey W.J., Link C.J., Lane H.C., Michael N.L., Davey R.T., Jr., Thomas S.J. A recombinant vesicular stomatitis virus Ebola vaccine. N. Engl. J. Med. 2017;376:330–341.
- Ruibal P., Oestereich L., Ludtke A., Becker-Ziaja B., Wozniak D.M., Kerber R., Korva M., Cabeza-Cabrerizo M., Bore J.A., Koundouno F.R., Duraffour S., Weller R., Thorenz A., Cimini E., Viola D., Agrati C., Repits J., Afrough B., Cowley L.A., Ngabo D., Hinzmann J., Mertens M., Vitoriano I., Logue C.H., Boettcher J.P., Pallasch E., Sachse A., Bah A., Nitzsche K., Kuisma E., Michel J., Holm T., Zekeng E.G., Garcia-Dorival I., Wolfel R., Stoecker K., Fleischmann E., Strecker T., Di Caro A., Avsic-Zupanc T., Kurth A., Meschi S., Mely S., Newman E., Bocquin A., Kis Z., Kelterbaum A., Molkenthin P., Carletti F., Portmann J., Wolff S., Castilletti C., Schudt G., Fizet A., Ottowell L.J., Herker E., Jacobs T., Kretschmer B., Severi E., Ouedraogo N., Lago M., Negredo A., Franco L., Anda P., Schmiedel S., Kreuels B., Wichmann D., Addo M.M., Lohse A.W., De Clerck H., Nanclares C., Jonckheere S., Van Herp M., Sprecher A., Xiaojiang G., Carrington M., Miranda O., Castro C.M., Gabriel M., Drury P., Formenty P., Diallo B., Koivogui L., Magassouba N., Carroll M.W., Gunther S., Munoz-Fontela C. Unique human immune signature of Ebola virus disease in Guinea. Nature. 2016;533:100–104.
- Sullivan N.J., Geisbert T.W., Geisbert J.B., Xu, L., Yang, Z. Y., Roederer, M., Koup, R. A., Jahrling, P. B. & Nabel, G. J. Accelerated vaccination for Ebola virus haemorrhagic fever in non-human primates. Nature. 2003;424:681–684.
- Sullivan N.J., Martin J.E., Graham B.S., Nabel G.J. Correlates of protective immunity for Ebola vaccines: implications for regulatory approval by the animal rule. Nat. Rev. Microbiol. 2009;7:393–400.
- Wilson J.A., Hart M.K. Protection from Ebola virus mediated by cytotoxic T lymphocytes specific for the viral nucleoprotein. J. Virol. 2001;75:2660–2664.
- Wong G., Audet J., Fernando L., Fausther-Bovendo H., Alimonti J.B., Kobinger G.P., Qiu X. Immunization with vesicular stomatitis virus vaccine expressing the Ebola glycoprotein provides sustained long-term protection in rodents. Vaccine. 2014;32:5722–5729.
- Wong G., Richardson J.S., Pillet S., Patel A., Qiu X., Alimonti J., Hogan J., Zhang Y., Takada A., Feldmann H., Kobinger G.P. Immune parameters correlate with protection against ebola virus infection in rodents and nonhuman primates. Sci. Transl. Med. 2012;4 (158ra146)
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