{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T07:20:53Z","timestamp":1769152853029,"version":"3.49.0"},"reference-count":39,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T00:00:00Z","timestamp":1653955200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010767","name":"Innovative Medicines Initiative 2 Joint Undertaking","doi-asserted-by":"publisher","award":["115861"],"award-info":[{"award-number":["115861"]}],"id":[{"id":"10.13039\/501100010767","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Natural killer cells play an important role in the control of viral infections both by regulating acquired immune responses and as potent innate or antibody-mediated cytotoxic effector cells. NK cells have been implicated in control of Ebola virus infections and our previous studies in European trial participants have demonstrated durable activation, proliferation and antibody-dependent NK cell activation after heterologous two-dose Ebola vaccination with adenovirus type 26.ZEBOV followed by modified vaccinia Ankara-BN-Filo. Regional variation in immunity and environmental exposure to pathogens, in particular human cytomegalovirus, have profound impacts on NK cell functional capacity. We therefore assessed the NK cell phenotype and function in African trial participants with universal exposure to HCMV. We demonstrate a significant redistribution of NK cell subsets after vaccine dose two, involving the enrichment of less differentiated CD56dimCD57\u2212 and CD56dimFc\u03b5R1\u03b3+ (canonical) cells and the increased proliferation of these subsets. Sera taken after vaccine dose two support robust antibody-dependent NK cell activation in a standard NK cell readout; these responses correlate strongly with the concentration of anti-Ebola glycoprotein specific antibodies. These sera also promote comparable IFN-\u03b3 production in autologous NK cells taken at baseline and post-vaccine dose two. However, degranulation responses of post-vaccination NK cells were reduced compared to baseline NK cells and these effects could not be directly attributed to alterations in NK cell phenotype after vaccination. These studies demonstrate consistent changes in NK cell phenotypic composition and robust antibody-dependent NK cell function and reveal novel characteristics of these responses after heterologous two dose Ebola vaccination in African individuals.<\/jats:p>","DOI":"10.3390\/vaccines10060884","type":"journal-article","created":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T21:43:42Z","timestamp":1654119822000},"page":"884","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["NK Cell Subset Redistribution and Antibody Dependent Activation after Ebola Vaccination in Africans"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4462-7484","authenticated-orcid":false,"given":"Helen R.","family":"Wagstaffe","sequence":"first","affiliation":[{"name":"Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK"},{"name":"Department of Infectious Disease, Imperial College London, London W2 1PG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Omu","family":"Anzala","sequence":"additional","affiliation":[{"name":"KAVI\u2014Institute of Clinical Research University of Nairobi, Nairobi 19676, Kenya"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah","family":"Kibuuka","sequence":"additional","affiliation":[{"name":"Makerere University\u2014Walter Reed Project, Kampala 16524, Uganda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zacchaeus","family":"Anywaine","sequence":"additional","affiliation":[{"name":"Medical Research Council\/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe P.O. Box 49, Uganda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0972-4211","authenticated-orcid":false,"given":"Sodiomon B.","family":"Sirima","sequence":"additional","affiliation":[{"name":"Centre National de Recherche et de Formation sur le Paludisme (CNRFP), Unit\u00e9 de Recherche Clinique de Banfora, 1487 Avenue Kumda Yonr\u00e9, Ouagadougou 01 BP 2208, Burkina Faso"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodolphe","family":"Thi\u00e9baut","sequence":"additional","affiliation":[{"name":"Bordeaux Population Health Research Center, University Bordeaux, Inserm, UMR 1219, 33000 Bordeaux, France"},{"name":"CIC 1401, EUCLID\/F-CRIN Clinical Trials Platform, F-33000 Bordeaux, France"},{"name":"Inria SISTM Team, F-33405 Talence, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Richert","sequence":"additional","affiliation":[{"name":"Bordeaux Population Health Research Center, University Bordeaux, Inserm, UMR 1219, 33000 Bordeaux, France"},{"name":"CIC 1401, EUCLID\/F-CRIN Clinical Trials Platform, F-33000 Bordeaux, France"},{"name":"Inria SISTM Team, F-33405 Talence, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yves","family":"Levy","sequence":"additional","affiliation":[{"name":"Inserm U955, Vaccine Research Institute, Universit\u00e9 Paris-Est Cr\u00e9teil, H\u00f4pital Henri Mondor, 94010 Creteil, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6925-0225","authenticated-orcid":false,"given":"Christine","family":"Lacabaratz","sequence":"additional","affiliation":[{"name":"Inserm U955, Vaccine Research Institute, Universit\u00e9 Paris-Est Cr\u00e9teil, H\u00f4pital Henri Mondor, 94010 Creteil, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Viki","family":"Bockstal","sequence":"additional","affiliation":[{"name":"Janssen Vaccines and Prevention, 2333 CP Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kerstin","family":"Luhn","sequence":"additional","affiliation":[{"name":"Janssen Vaccines and Prevention, 2333 CP Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Macaya","family":"Douoguih","sequence":"additional","affiliation":[{"name":"Janssen Vaccines and Prevention, 2333 CP Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8963-4768","authenticated-orcid":false,"given":"Martin R.","family":"Goodier","sequence":"additional","affiliation":[{"name":"Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK"},{"name":"Flow Cytometry and Immunology Platform, MRC Unit the Gambia at London School of Hygiene and Tropical Medicine, Banjul P.O. Box 273, The Gambia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,31]]},"reference":[{"key":"ref_1","unstructured":"(2022, March 30). Centres for disease control and prevetion (CDC), Ebola Virus Disease\u2014Democratic Republic of the Congo. Disease Outbreak News, Available online: https:\/\/www.cdc.gov\/vhf\/ebola\/outbreaks\/drc\/2022-apr.html."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1093\/infdis\/jiz071","article-title":"Randomized clinical trial ex-amining safety and immunogenicity of heterologous prime-boost Ebola vaccines, Ad26.ZEBOV and MVA-BN-Filo: 12-month data from Nairobi, Kenya","volume":"220","author":"Mutua","year":"2019","journal-title":"J. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1093\/infdis\/jiz070","article-title":"Randomized clinical trial examining safety and immunogenicity of heterologous prime-boost Ebola vaccines, Ad26.ZEBOV and MVA-BN-Filo: 12-month data from Uganda and Tanzania","volume":"220","author":"Anywaine","year":"2019","journal-title":"J. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1001\/jama.2016.20644","article-title":"Immune Responses to Novel Adenovirus Type 26 and Modified Vaccinia Virus Ankara\u2013Vectored Ebola Vaccines at 1 Year","volume":"317","author":"Winslow","year":"2017","journal-title":"JAMA J. Am. Med. Assoc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1080\/21645515.2017.1264755","article-title":"A two-dose heterologous prime-boost vaccine regimen eliciting sus-tained immune responses to Ebola Zaire could support a preventive strategy for future outbreaks","volume":"13","author":"Shukarev","year":"2017","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1001\/jama.2016.4218","article-title":"Safety and Immunogenicity of Novel Adenovirus Type 26- and Modified Vaccinia Anka-ra-Vectored Ebola Vaccines: A Randomized Clinical Trial","volume":"315","author":"Milligan","year":"2016","journal-title":"JAMA"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Barry, H., Mutua, G., Kibuuka, H., Anywaine, Z., Sirima, S.B., Meda, N., Anzala, O., Eholie, S., B\u00e9tard, C., and Richert, L. (2021). Safety and immunogenicity of 2-dose heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola vaccination in healthy and HIV-infected adults: A randomised, placebo-controlled Phase II clinical trial in Africa. PLoS Med., 18.","DOI":"10.1371\/journal.pmed.1003813"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/S1473-3099(20)30476-X","article-title":"Safety and immunogenicity of a two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in adults in Europe (EBOVAC2): A randomised, observer-blind, participant-blind, placebo-controlled, phase 2 trial","volume":"21","author":"Pollard","year":"2020","journal-title":"Lancet Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.chom.2018.07.009","article-title":"A Role for Fc Function in Therapeutic Monoclonal Antibody-Mediated Protection against Ebola Virus","volume":"24","author":"Gunn","year":"2018","journal-title":"Cell Host Microbe"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"45552","DOI":"10.1038\/srep45552","article-title":"Anti-body-dependent-cellular-cytotoxicity-inducing antibodies significantly affect the post-exposure treatment of Ebola virus infection","volume":"7","author":"Liu","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.chom.2018.12.005","article-title":"A Two-Antibody Pan-Ebolavirus Cocktail Confers Broad Ther-apeutic Protection in Ferrets and Nonhuman Primates","volume":"25","author":"Bornholdt","year":"2019","journal-title":"Cell Host Microbe"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.chom.2018.12.004","article-title":"Development of a Human Antibody Cocktail that Deploys Multiple Functions to Confer Pan-Ebolavirus Protection","volume":"25","author":"Wec","year":"2019","journal-title":"Cell Host Microbe"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1093\/infdis\/jiz657","article-title":"Antibody-Dependent Natural Killer Cell Activation After Ebola Vaccination","volume":"223","author":"Wagstaffe","year":"2019","journal-title":"J. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3936","DOI":"10.1172\/JCI132438","article-title":"Ebola virus glycoprotein stimulates IL-18\u2013dependent natural killer cell responses","volume":"130","author":"Wagstaffe","year":"2020","journal-title":"J. Clin. Invest."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/s41541-021-00280-0","article-title":"Durable natural killer cell responses after heterologous two-dose Ebola vaccination","volume":"6","author":"Wagstaffe","year":"2021","journal-title":"NPJ Vaccines"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"eaaw9522","DOI":"10.1126\/scitranslmed.aaw9522","article-title":"Immune system development varies ac-cording to age, location, and anemia in African children","volume":"12","author":"Hill","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.1182\/blood-2014-05-576124","article-title":"Rapid NK cell differentiation in a population with near-universal human cytomegalovirus infection is attenuated by NKG2C deletions","volume":"124","author":"Goodier","year":"2014","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5766","DOI":"10.1128\/JVI.00052-07","article-title":"Cytomegalovirus Infection in Gambian Infants Leads to Profound CD8 T-Cell Differentiation","volume":"81","author":"Miles","year":"2007","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.immuni.2015.02.013","article-title":"Epigenetic Modification and Antibody-Dependent Expansion of Memory-like NK Cells in Human Cytomegalovirus-Infected Individuals","volume":"42","author":"Lee","year":"2015","journal-title":"Immunity"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.immuni.2015.02.008","article-title":"Cytomegalovirus Infection Drives Adaptive Epigenetic Diversification of NK Cells with Altered Signaling and Effector Function","volume":"42","author":"Schlums","year":"2015","journal-title":"Immunity"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1111\/tmi.13188","article-title":"HIV, HCMV and mycobacterial antibody levels: A cross-sectional study in a rural Ugandan cohort","volume":"24","author":"Stockdale","year":"2018","journal-title":"Trop. Med. Int. Health"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/S2055-6640(20)30456-8","article-title":"Human cytomegalovirus (CMV) in Africa: A neglected but important pathogen","volume":"2","author":"Bates","year":"2016","journal-title":"J. Virus Erad."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.jviromet.2018.02.018","article-title":"Use of the Filovirus Animal Non-Clinical Group (FANG) Ebola virus immuno-assay requires fewer study participants to power a study than the Alpha Diagnostic International assay","volume":"255","author":"Logue","year":"2018","journal-title":"J. Virol. Methods"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/s41541-020-0179-4","article-title":"Rapid dose-dependent Natural Killer (NK) cell modulation and cytokine responses following human rVSV-ZEBOV Ebo-lavirus vaccination","volume":"5","author":"Pejoski","year":"2020","journal-title":"NPJ Vaccines"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3853","DOI":"10.1182\/blood-2010-04-281675","article-title":"Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK-cell differentiation uncoupled from NK-cell education","volume":"116","author":"Riese","year":"2010","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8349","DOI":"10.1128\/JVI.00924-14","article-title":"CD4 + T-Cell Help Enhances NK Cell Function following Therapeutic HIV-1 Vaccination","volume":"88","author":"Jost","year":"2014","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4657","DOI":"10.4049\/jimmunol.1403080","article-title":"Impaired NK Cell Responses to Pertussis and H1N1 Influenza Vaccine Antigens in Human Cytomegalovirus-Infected Individuals","volume":"194","author":"Nielsen","year":"2015","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1111\/imm.12239","article-title":"Differential activation of CD 57-defined natural killer cell subsets during recall responses to vaccine antigens","volume":"142","author":"White","year":"2014","journal-title":"Immunology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1002\/eji.201746974","article-title":"Enhancement of cytokine-driven NK cell IFN-gamma production after vaccination of HCMV infected Africans","volume":"47","author":"Darboe","year":"2017","journal-title":"Eur. J. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"313","DOI":"10.4049\/jimmunol.1502049","article-title":"Influenza Vaccination Generates Cytokine-Induced Memory-like NK Cells: Impact of Human Cytomegalovirus In-fection","volume":"197","author":"Goodier","year":"2016","journal-title":"J. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1182\/blood-2011-08-372003","article-title":"Phenotypic and functional het-erogeneity of human NK cells developing after umbilical cord blood transplantation: A role for human cytomegalovirus?","volume":"119","author":"Falco","year":"2012","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1002\/jmv.23642","article-title":"Impact of human cytomegalovirus (CMV) infection on immune response to pandemic 2009 H1N1 influenza vaccine in healthy adults","volume":"85","author":"Wald","year":"2013","journal-title":"J. Med. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"281ra43","DOI":"10.1126\/scitranslmed.aaa2293","article-title":"Cytomegalovirus infection enhances the immune response to influenza","volume":"7","author":"Furman","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.3389\/fimmu.2020.01083","article-title":"Limited Impact of Human Cytomegalovirus Infection in African Infants on Vaccine-Specific Responses Following Diphtheria-Tetanus-Pertussis and Measles Vaccination","volume":"11","author":"Cox","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e154187","DOI":"10.1172\/jci.insight.154187","article-title":"CMV-associated T cell and NK cell terminal differentiation does not affect immunogenicity of ChAdOx1 vaccination","volume":"7","author":"Sharpe","year":"2022","journal-title":"JCI Insight"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3389\/fimmu.2016.00101","article-title":"Synergy between Common \u03b3 Chain Family Cytokines and IL-18 Potentiates Innate and Adaptive Pathways of NK Cell Activation","volume":"7","author":"Nielsen","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"533","DOI":"10.3389\/fimmu.2020.00533","article-title":"Differential IL-18 Dependence of Canonical and Adaptive NK Cells for Antibody Dependent Responses to P. falciparum","volume":"11","author":"Sherratt","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e125106","DOI":"10.1172\/jci.insight.125106","article-title":"Immune parameters and outcomes during Ebola virus disease","volume":"4","author":"Reynard","year":"2019","journal-title":"JCI Insight"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"eabg6128","DOI":"10.1126\/scitranslmed.abg6128","article-title":"Ebola vaccine\u2013induced protection in nonhuman primates correlates with antibody specificity and Fc-mediated effects","volume":"13","author":"Meyer","year":"2021","journal-title":"Sci. Transl. 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