{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T23:18:50Z","timestamp":1792624730446,"version":"4.5.0"},"reference-count":55,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,4,24]],"date-time":"2018-04-24T00:00:00Z","timestamp":1524528000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,4,24]],"date-time":"2018-04-24T00:00:00Z","timestamp":1524528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The significant public health problem of Hepatitis C virus (HCV) has been partially addressed with the advent of directly acting antiviral agents (DAAs). However, the development of an effective preventative vaccine would have a significant impact on HCV incidence and would represent a major advance towards controlling and possibly eradicating HCV globally. We previously reported a genotype 1a HCV viral-like particle (VLP) vaccine that produced neutralizing antibodies (NAb) and T cell responses to HCV. To advance this approach, we produced a quadrivalent genotype 1a\/1b\/2a\/3a HCV VLP vaccine to produce broader immune responses. We show that this quadrivalent vaccine produces antibody and NAb responses together with strong T and B cell responses in vaccinated mice. Moreover, selective neutralizing human monoclonal antibodies (HuMAbs) targeting conserved antigenic domain B and D epitopes of the E2 protein bound strongly to the HCV VLPs, suggesting that these critical epitopes are expressed on the surface of the particles. Our findings demonstrate that a quadrivalent HCV VLP based vaccine induces broad humoral and cellular immune responses that will be necessary for protection against HCV. Such a vaccine could provide a substantial addition to highly active antiviral drugs in eliminating HCV.<\/jats:p>","DOI":"10.1038\/s41598-018-24762-9","type":"journal-article","created":{"date-parts":[[2018,4,18]],"date-time":"2018-04-18T11:08:23Z","timestamp":1524049703000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Immunological responses following administration of a genotype 1a\/1b\/2\/3a quadrivalent HCV VLP vaccine"],"prefix":"10.1038","volume":"8","author":[{"given":"D.","family":"Christiansen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Earnest-Silveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Chua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Meuleman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.","family":"Boo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Grubor-Bauk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. C.","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z. Y.","family":"Keck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. K. H.","family":"Foung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. E.","family":"Drummer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. J.","family":"Gowans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Torresi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,4,24]]},"reference":[{"key":"24762_CR1","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1016\/j.jhep.2016.01.001","volume":"64","author":"H Midgard","year":"2016","unstructured":"Midgard, H. et al. Hepatitis C reinfection after sustained virological response. Journal of Hepatology 64, 1020\u20131026, https:\/\/doi.org\/10.1016\/j.jhep.2016.01.001 (2016).","journal-title":"Journal of Hepatology"},{"key":"24762_CR2","doi-asserted-by":"publisher","first-page":"e80216","DOI":"10.1371\/journal.pone.0080216","volume":"8","author":"R Sacks-Davis","year":"2013","unstructured":"Sacks-Davis, R. et al. High rates of hepatitis C virus reinfection and spontaneous clearance of reinfection in people who inject drugs: a prospective cohort study. PLoS One 8, e80216, https:\/\/doi.org\/10.1371\/journal.pone.0080216 (2013).","journal-title":"PLoS One"},{"key":"24762_CR3","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1016\/S1473-3099(12)70010-5","volume":"12","author":"J Grebely","year":"2012","unstructured":"Grebely, J. et al. Hepatitis C virus clearance, reinfection, and persistence, with insights from studies of injecting drug users: towards a vaccine. The Lancet infectious diseases 12, 408\u2013414, https:\/\/doi.org\/10.1016\/S1473-3099(12)70010-5 (2012).","journal-title":"The Lancet infectious diseases"},{"key":"24762_CR4","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1053\/j.gastro.2009.09.017","volume":"138","author":"WO Osburn","year":"2010","unstructured":"Osburn, W. O. et al. Spontaneous control of primary hepatitis C virus infection and immunity against persistent reinfection. Gastroenterology 138, 315\u2013324, https:\/\/doi.org\/10.1053\/j.gastro.2009.09.017 (2010).","journal-title":"Gastroenterology"},{"key":"24762_CR5","doi-asserted-by":"publisher","first-page":"1746","DOI":"10.1002\/hep.22534","volume":"48","author":"CK Aitken","year":"2008","unstructured":"Aitken, C. K. et al. High incidence of hepatitis C virus reinfection in a cohort of injecting drug users. Hepatology 48, 1746\u20131752, https:\/\/doi.org\/10.1002\/hep.22534 (2008).","journal-title":"Hepatology"},{"issue":"Suppl 1","key":"24762_CR6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/jgh.12677","volume":"29","author":"W Sievert","year":"2014","unstructured":"Sievert, W. et al. Enhanced antiviral treatment efficacy and uptake in preventing the rising burden of hepatitis C-related liver disease and costs in Australia. Journal of Gastroenterology and Hepatology 29(Suppl 1), 1\u20139, https:\/\/doi.org\/10.1111\/jgh.12677 (2014).","journal-title":"Journal of Gastroenterology and Hepatology"},{"key":"24762_CR7","doi-asserted-by":"publisher","first-page":"1598","DOI":"10.1002\/hep.26431","volume":"58","author":"NK Martin","year":"2013","unstructured":"Martin, N. K. et al. Hepatitis C virus treatment for prevention among people who inject drugs: Modeling treatment scale-up in the age of direct-acting antivirals. Hepatology 58, 1598\u20131609, https:\/\/doi.org\/10.1002\/hep.26431 (2013).","journal-title":"Hepatology"},{"key":"24762_CR8","doi-asserted-by":"publisher","first-page":"638","DOI":"10.5694\/mja11.10981","volume":"196","author":"ME Hellard","year":"2012","unstructured":"Hellard, M. E. et al. Modelling antiviral treatment to prevent hepatitis C infection among people who inject drugs in Victoria, Australia. The Medical journal of Australia 196, 638\u2013641 (2012).","journal-title":"The Medical journal of Australia"},{"key":"24762_CR9","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.epidem.2008.10.002","volume":"1","author":"JA Hahn","year":"2009","unstructured":"Hahn, J. A. et al. Potential impact of vaccination on the hepatitis C virus epidemic in injection drug users. Epidemics 1, 47\u201357, https:\/\/doi.org\/10.1016\/j.epidem.2008.10.002 (2009).","journal-title":"Epidemics"},{"key":"24762_CR10","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-015-0440-2","volume":"13","author":"N Scott","year":"2015","unstructured":"Scott, N. et al. The role of a hepatitis C virus vaccine: modelling the benefits alongside direct-acting antiviral treatments. BMC Med 13, 198, https:\/\/doi.org\/10.1186\/s12916-015-0440-2 (2015).","journal-title":"BMC Med"},{"key":"24762_CR11","doi-asserted-by":"publisher","first-page":"12473","DOI":"10.1128\/JVI.01138-09","volume":"83","author":"TJ Broering","year":"2009","unstructured":"Broering, T. J. et al. Identification and characterization of broadly neutralizing human monoclonal antibodies directed against the E2 envelope glycoprotein of Hepatitis C virus. J Virology 83, 12473\u201312482 (2009).","journal-title":"J Virology"},{"key":"24762_CR12","doi-asserted-by":"publisher","first-page":"2377","DOI":"10.1053\/j.gastro.2009.02.080","volume":"136","author":"KA Dowd","year":"2009","unstructured":"Dowd, K. A., Netski, D. M., Wang, X. H., Cox, A. L. & Ray, S. C. Selection pressure from neutralizing antibodies drives sequence evolution during acute infection with hepatitis C virus. Gastroenterology 136, 2377\u20132386, https:\/\/doi.org\/10.1053\/j.gastro.2009.02.080 (2009).","journal-title":"Gastroenterology"},{"key":"24762_CR13","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1093\/infdis\/jir835","volume":"205","author":"S Raghuraman","year":"2012","unstructured":"Raghuraman, S. et al. Spontaneous clearance of chronic hepatitis C virus infection is associated with appearance of neutralizing antibodies and reversal of T-cell exhaustion. The Journal of infectious diseases 205, 763\u2013771, https:\/\/doi.org\/10.1093\/infdis\/jir835 (2012).","journal-title":"The Journal of infectious diseases"},{"key":"24762_CR14","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1099\/vir.0.83386-0","volume":"89","author":"AM Owsianka","year":"2008","unstructured":"Owsianka, A. M. et al. Broadly neutralizing human monoclonal antibodies to the hepatitis C virus E2 glycoprotein. The Journal of general virology 89, 653\u2013659, https:\/\/doi.org\/10.1099\/vir.0.83386-0 (2008).","journal-title":"The Journal of general virology"},{"key":"24762_CR15","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1002\/hep.24171","volume":"53","author":"P Meuleman","year":"2011","unstructured":"Meuleman, P. et al. In vivo evaluation of the cross-genotype neutralizing activity of polyclonal antibodies against hepatitis C virus. Hepatology 53, 755\u2013762, https:\/\/doi.org\/10.1002\/hep.24171 (2011).","journal-title":"Hepatology"},{"key":"24762_CR16","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1038\/nature10168","volume":"474","author":"M Dorner","year":"2011","unstructured":"Dorner, M. et al. A genetically humanized mouse model for hepatitis C virus infection. Nature 474, 208\u2013211, https:\/\/doi.org\/10.1038\/nature10168 (2011).","journal-title":"Nature"},{"key":"24762_CR17","doi-asserted-by":"publisher","first-page":"7705","DOI":"10.1073\/pnas.0402458101","volume":"101","author":"M Yu","year":"2004","unstructured":"Yu, M. et al. Neutralizing antibodies to hepatitis C virus (HCV) in immune globulins derived from anti-HCV-positive plasma. Proc. Natl. Acad. Sci. USA 101, 7705\u20137710 (2004).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"24762_CR18","doi-asserted-by":"publisher","first-page":"6025","DOI":"10.1073\/pnas.0607026104","volume":"104","author":"JM Pestka","year":"2007","unstructured":"Pestka, J. M. et al. Rapid induction of virus-neutralizing antibodies and viral clearance in a single-source outbreak of hepatitis C. Proc Natl Acad Sci USA 104, 6025\u20136030 (2007).","journal-title":"Proc Natl Acad Sci USA"},{"key":"24762_CR19","doi-asserted-by":"publisher","first-page":"2140","DOI":"10.1002\/hep.27013","volume":"59","author":"WO Osburn","year":"2014","unstructured":"Osburn, W. O. et al. Clearance of hepatitis C infection is associated with the early appearance of broad neutralizing antibody responses. Hepatology 59, 2140\u20132151, https:\/\/doi.org\/10.1002\/hep.27013 (2014).","journal-title":"Hepatology"},{"key":"24762_CR20","doi-asserted-by":"publisher","first-page":"6367","DOI":"10.1016\/j.vaccine.2010.06.084","volume":"28","author":"SE Frey","year":"2010","unstructured":"Frey, S. E. et al. Safety and immunogenicity of HCV E1E2 vaccine adjuvanted with MF59 administered to healthy adults. Vaccine 28, 6367\u20136373, https:\/\/doi.org\/10.1016\/j.vaccine.2010.06.084 (2010).","journal-title":"Vaccine"},{"key":"24762_CR21","doi-asserted-by":"publisher","first-page":"e59776","DOI":"10.1371\/journal.pone.0059776","volume":"8","author":"JL Law","year":"2013","unstructured":"Law, J. L. et al. A hepatitis C virus (HCV) vaccine comprising envelope glycoproteins gpE1\/gpE2 derived from a single isolate elicits broad cross-genotype neutralizing antibodies in humans. PLoS One 8, e59776, https:\/\/doi.org\/10.1371\/journal.pone.0059776 (2013).","journal-title":"PLoS One"},{"key":"24762_CR22","doi-asserted-by":"publisher","first-page":"94ra71","DOI":"10.1126\/scitranslmed.3002330","volume":"3","author":"P Garrone","year":"2011","unstructured":"Garrone, P. et al. A prime-boost strategy using virus-like particles pseudotyped for HCV proteins triggers broadly neutralizing antibodies in macaques. Sci Transl Med 3, 94ra71, https:\/\/doi.org\/10.1126\/scitranslmed.3002330 (2011).","journal-title":"Sci Transl Med"},{"key":"24762_CR23","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1002\/hep.26132","volume":"57","author":"E Beaumont","year":"2013","unstructured":"Beaumont, E., Patient, R., Hourioux, C., Dimier-Poisson, I. & Roingeard, P. Chimeric hepatitis B virus\/hepatitis C virus envelope proteins elicit broadly neutralizing antibodies and constitute a potential bivalent prophylactic vaccine. Hepatology 57, 1303\u20131313, https:\/\/doi.org\/10.1002\/hep.26132 (2013).","journal-title":"Hepatology"},{"issue":"447\u2013455","key":"24762_CR24","doi-asserted-by":"publisher","first-page":"e441","DOI":"10.1053\/j.gastro.2013.05.007","volume":"145","author":"D Akazawa","year":"2013","unstructured":"Akazawa, D. et al. Neutralizing antibodies induced by cell culture-derived hepatitis C virus protect against infection in mice. Gastroenterology 145(447\u2013455), e441\u2013444, https:\/\/doi.org\/10.1053\/j.gastro.2013.05.007 (2013).","journal-title":"Gastroenterology"},{"key":"24762_CR25","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1002\/hep.21319","volume":"44","author":"M Puig","year":"2006","unstructured":"Puig, M. et al. CD4\u2009+\u2009immune escape and subsequent T-cell failure following chimpanzee immunization against hepatitis C virus. Hepatology 44, 736\u2013745 (2006).","journal-title":"Hepatology"},{"key":"24762_CR26","doi-asserted-by":"publisher","first-page":"e47492","DOI":"10.1371\/journal.pone.0047492","volume":"7","author":"BY Chua","year":"2012","unstructured":"Chua, B. Y. et al. Hepatitis C VLPs Delivered to Dendritic Cells by a TLR2 Targeting Lipopeptide Results in Enhanced Antibody and Cell-Mediated Responses. PLoS One 7, e47492, https:\/\/doi.org\/10.1371\/journal.pone.0047492 (2012).","journal-title":"PLoS One"},{"key":"24762_CR27","doi-asserted-by":"publisher","first-page":"1865","DOI":"10.1099\/jgv.0.000493","volume":"97","author":"L Earnest-Silveira","year":"2016","unstructured":"Earnest-Silveira, L. et al. Characterization of a hepatitis C virus-like particle vaccine produced in a human hepatocyte-derived cell line. The Journal of General Virology 97, 1865\u20131876, https:\/\/doi.org\/10.1099\/jgv.0.000493 (2016).","journal-title":"The Journal of General Virology"},{"key":"24762_CR28","doi-asserted-by":"publisher","first-page":"10999","DOI":"10.1128\/JVI.00526-10","volume":"84","author":"P Gastaminza","year":"2010","unstructured":"Gastaminza, P. et al. Ultrastructural and biophysical characterization of hepatitis C virus particles produced in cell culture. Journal of Virology 84, 10999\u201311009, https:\/\/doi.org\/10.1128\/JVI.00526-10 (2010).","journal-title":"Journal of Virology"},{"key":"24762_CR29","doi-asserted-by":"publisher","first-page":"9505","DOI":"10.1073\/pnas.1307527110","volume":"110","author":"MT Catanese","year":"2013","unstructured":"Catanese, M. T. et al. Ultrastructural analysis of hepatitis C virus particles. Proceedings of the National Academy of Sciences of the United States of America 110, 9505\u20139510, https:\/\/doi.org\/10.1073\/pnas.1307527110 (2013).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"24762_CR30","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1016\/j.vaccine.2015.11.061","volume":"34","author":"A Kumar","year":"2016","unstructured":"Kumar, A. et al. Immune responses against hepatitis C virus genotype 3a virus-like particles in mice: A novel VLP prime-adenovirus boost strategy. Vaccine 34, 1115\u20131125, https:\/\/doi.org\/10.1016\/j.vaccine.2015.11.061 (2016).","journal-title":"Vaccine"},{"key":"24762_CR31","doi-asserted-by":"publisher","first-page":"1459","DOI":"10.1038\/sj.bjc.6603469","volume":"95","author":"L Villa","year":"2006","unstructured":"Villa, L. et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6\/11\/16\/18 L1 virus-like particle vaccine through 5 years of follow-up. British Journal of Cancer 95, 1459\u20131466 (2006).","journal-title":"British Journal of Cancer"},{"key":"24762_CR32","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.jviromet.2016.06.012","volume":"236","author":"L Earnest-Silveira","year":"2016","unstructured":"Earnest-Silveira, L. et al. Large scale production of a mammalian cell derived quadrivalent hepatitis C virus like particle vaccine. Journal of virological methods 236, 87\u201392, https:\/\/doi.org\/10.1016\/j.jviromet.2016.06.012 (2016).","journal-title":"Journal of virological methods"},{"key":"24762_CR33","doi-asserted-by":"publisher","first-page":"9224","DOI":"10.1128\/JVI.78.17.9224-9232.2004","volume":"78","author":"Z Keck","year":"2004","unstructured":"Keck, Z. et al. Hepatitis C virus E2 has three immunogenic domains containing conformational epitopes with distinct propertires and biological functions. J. Virol. 78, 9224\u20139232 (2004).","journal-title":"J. Virol."},{"key":"24762_CR34","doi-asserted-by":"publisher","first-page":"6061","DOI":"10.1128\/JVI.02475-07","volume":"82","author":"ZY Keck","year":"2008","unstructured":"Keck, Z. Y. et al. Definition of a conserved immunodominant domain on hepatitis C virus E2 glycoprotein by neutralizing human monoclonal antibodies. Journal of Virology 82, 6061\u20136066, https:\/\/doi.org\/10.1128\/JVI.02475-07 (2008).","journal-title":"Journal of Virology"},{"key":"24762_CR35","doi-asserted-by":"publisher","first-page":"10451","DOI":"10.1128\/JVI.05259-11","volume":"85","author":"ZY Keck","year":"2011","unstructured":"Keck, Z. Y. et al. Mapping a region of hepatitis C virus E2 that is responsible for escape from neutralizing antibodies and a core CD81-binding region that does not tolerate neutralization escape mutations. Journal of Virology 85, 10451\u201310463, https:\/\/doi.org\/10.1128\/JVI.05259-11 (2011).","journal-title":"Journal of Virology"},{"key":"24762_CR36","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1080\/14760584.2016.1194759","volume":"15","author":"C Fauvelle","year":"2016","unstructured":"Fauvelle, C. et al. Hepatitis C virus vaccine candidates inducing protective neutralizing antibodies. Expert Rev Vaccines 15, 1535\u20131544, https:\/\/doi.org\/10.1080\/14760584.2016.1194759 (2016).","journal-title":"Expert Rev Vaccines"},{"key":"24762_CR37","doi-asserted-by":"publisher","first-page":"1922","DOI":"10.1002\/hep.28850","volume":"64","author":"ZY Keck","year":"2016","unstructured":"Keck, Z. Y. et al. Affinity maturation of a broadly neutralizing human monoclonal antibody that prevents acute hepatitis C virus infection in mice. Hepatology 64, 1922\u20131933, https:\/\/doi.org\/10.1002\/hep.28850 (2016).","journal-title":"Hepatology"},{"key":"24762_CR38","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.1002\/hep.28989","volume":"65","author":"PT Vietheer","year":"2017","unstructured":"Vietheer, P. T. et al. The core domain of hepatitis C virus glycoprotein E2 generates potent cross-neutralizing antibodies in guinea pigs. Hepatology 65, 1117\u20131131, https:\/\/doi.org\/10.1002\/hep.28989 (2017).","journal-title":"Hepatology"},{"key":"24762_CR39","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1016\/j.jim.2005.10.009","volume":"308","author":"CL Ewen","year":"2006","unstructured":"Ewen, C. L., Rong, J., Kokaji, A. I., Bleackley, R. C. & Kane, K. P. Evaluating antigen-specific cytotoxic T lymphocyte responses by a novel mouse granzyme B ELISPOT assay. J Immunol Methods 308, 156\u2013166, https:\/\/doi.org\/10.1016\/j.jim.2005.10.009 (2006).","journal-title":"J Immunol Methods"},{"key":"24762_CR40","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-10190-8","volume":"7","author":"N Islam","year":"2017","unstructured":"Islam, N. et al. Hepatitis C cross-genotype immunity and implications for vaccine development. Sci Rep 7, 12326, https:\/\/doi.org\/10.1038\/s41598-017-10190-8 (2017).","journal-title":"Sci Rep"},{"key":"24762_CR41","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1002\/hep.26733","volume":"59","author":"F Douam","year":"2014","unstructured":"Douam, F. et al. Critical interaction between E1 and E2 glycoproteins determines binding and fusion properties of hepatitis C virus during cell entry. Hepatology 59, 776\u2013788, https:\/\/doi.org\/10.1002\/hep.26733 (2014).","journal-title":"Hepatology"},{"key":"24762_CR42","doi-asserted-by":"publisher","first-page":"6205","DOI":"10.1073\/pnas.1114927109","volume":"109","author":"E Giang","year":"2012","unstructured":"Giang, E. et al. Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus. Proceedings of the National Academy of Sciences of the United States of America 109, 6205\u20136210, https:\/\/doi.org\/10.1073\/pnas.1114927109 (2012).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"24762_CR43","doi-asserted-by":"publisher","first-page":"e8254","DOI":"10.1371\/journal.pone.0008254","volume":"4","author":"N Mancini","year":"2009","unstructured":"Mancini, N. et al. Hepatitis C virus (HCV) infection may elicit neutralizing antibodies targeting epitopes conserved in all viral genotypes. PLoS One 4, e8254, https:\/\/doi.org\/10.1371\/journal.pone.0008254 (2009).","journal-title":"PLoS One"},{"key":"24762_CR44","doi-asserted-by":"publisher","first-page":"1090","DOI":"10.1126\/science.1243876","volume":"342","author":"L Kong","year":"2013","unstructured":"Kong, L. et al. Hepatitis C virus E2 envelope glycoprotein core structure. Science 342, 1090\u20131094, https:\/\/doi.org\/10.1126\/science.1243876 (2013).","journal-title":"Science"},{"key":"24762_CR45","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/nature13117","volume":"509","author":"AG Khan","year":"2014","unstructured":"Khan, A. G. et al. Structure of the core ectodomain of the hepatitis C virus envelope glycoprotein 2. Nature 509, 381\u2013384, https:\/\/doi.org\/10.1038\/nature13117 (2014).","journal-title":"Nature"},{"key":"24762_CR46","doi-asserted-by":"publisher","first-page":"6753","DOI":"10.1073\/pnas.1131929100","volume":"100","author":"K Murata","year":"2003","unstructured":"Murata, K. et al. Immunization with hepatitis C virus-like particles protects mice from recombinant hepatitis C virus-vaccinia infection. Proc. Natl. Acad. Sci. USA 100, 6753\u20136758 (2003).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"24762_CR47","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1086\/505714","volume":"194","author":"S Smyk-Pearson","year":"2006","unstructured":"Smyk-Pearson, S. et al. Differential antigenic hierarchy associated with spontaneous Recovery from hepatitis C virus infection: implications for vaccine design. J Infectious Diseases 194, 454\u2013463 (2006).","journal-title":"J Infectious Diseases"},{"key":"24762_CR48","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/j.jhep.2014.09.024","volume":"62","author":"M Spaan","year":"2015","unstructured":"Spaan, M. et al. CD4(+)CXCR5(+) T cells in chronic HCV infection produce less IL-21, yet are efficient at supporting B cell responses. Journal of Hepatology 62, 303\u2013310, https:\/\/doi.org\/10.1016\/j.jhep.2014.09.024 (2015).","journal-title":"Journal of Hepatology"},{"key":"24762_CR49","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2015.11.005","author":"B Raziorrouh","year":"2015","unstructured":"Raziorrouh, B. et al. Virus-specific CD4+ T Cells Have Functional and Phenotypic Characteristics of Follicular T-helper Cells in Patients With Acute and Chronic HCV Infections. Gastroenterology. https:\/\/doi.org\/10.1053\/j.gastro.2015.11.005 (2015).","journal-title":"Gastroenterology"},{"key":"24762_CR50","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1084\/jem.20100388","volume":"209","author":"J Schulze Zur Wiesch","year":"2012","unstructured":"Schulze Zur Wiesch, J. et al. Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence. The Journal of experimental medicine 209, 61\u201375, https:\/\/doi.org\/10.1084\/jem.20100388 (2012).","journal-title":"The Journal of experimental medicine"},{"key":"24762_CR51","doi-asserted-by":"publisher","first-page":"12245","DOI":"10.1128\/JVI.02070-15","volume":"89","author":"Y Alhammad","year":"2015","unstructured":"Alhammad, Y. et al. Monoclonal Antibodies Directed toward the Hepatitis C Virus Glycoprotein E2 Detect Antigenic Differences Modulated by the N-Terminal Hypervariable Region 1 (HVR1), HVR2, and Intergenotypic Variable Region. J Virol 89, 12245\u201312261, https:\/\/doi.org\/10.1128\/JVI.02070-15 (2015).","journal-title":"J Virol"},{"key":"24762_CR52","doi-asserted-by":"publisher","first-page":"1895","DOI":"10.4049\/jimmunol.1100664","volume":"187","author":"AC Tan","year":"2011","unstructured":"Tan, A. C., La Gruta, N. L., Zeng, W. & Jackson, D. C. Precursor frequency and competition dictate the HLA-A2-restricted CD8+ T cell responses to influenza A infection and vaccination in HLA-A2.1 transgenic mice. J Immunol 187, 1895\u20131902, https:\/\/doi.org\/10.4049\/jimmunol.1100664 (2011).","journal-title":"J Immunol"},{"key":"24762_CR53","doi-asserted-by":"publisher","first-page":"8913","DOI":"10.1128\/JVI.00049-11","volume":"85","author":"JM Gottwein","year":"2011","unstructured":"Gottwein, J. M. et al. Development and application of hepatitis C reporter viruses with genotype 1 to 7 core-nonstructural protein 2 (NS2) expressing fluorescent proteins or luciferase in modified JFH1 NS5A. J Virol 85, 8913\u20138928, https:\/\/doi.org\/10.1128\/JVI.00049-11 (2011).","journal-title":"J Virol"},{"key":"24762_CR54","doi-asserted-by":"crossref","unstructured":"Chin, R. et al. Impaired dendritic cell maturation in response to pandemic H1N109 influenza virus. Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology, 10.1016\/j.jcv.2012.11.009 (2012).","DOI":"10.1016\/j.jcv.2012.11.009"},{"key":"24762_CR55","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.jim.2013.02.009","volume":"391","author":"M Jahnmatz","year":"2013","unstructured":"Jahnmatz, M. et al. Optimization of a human IgG B-cell ELISpot assay for the analysis of vaccine-induced B-cell responses. J Immunol Methods 391, 50\u201359, https:\/\/doi.org\/10.1016\/j.jim.2013.02.009 (2013).","journal-title":"J Immunol Methods"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-24762-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-24762-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-24762-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T23:34:45Z","timestamp":1671579285000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-24762-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,24]]},"references-count":55,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["24762"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-24762-9","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.733101096.793545438","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,24]]},"assertion":[{"value":"7 November 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 March 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 April 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"6483"}}