{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:10:54Z","timestamp":1760235054565,"version":"build-2065373602"},"reference-count":186,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T00:00:00Z","timestamp":1626134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI096882","R01AI126890","U01AI131313"],"award-info":[{"award-number":["R01AI096882","R01AI126890","U01AI131313"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Thirty years after its discovery, the hepatitis C virus (HCV) remains a leading cause of liver disease worldwide. Given that many countries continue to experience high rates of transmission despite the availability of potent antiviral therapies, an effective vaccine is seen as critical for the elimination of HCV. The recent failure of the first vaccine efficacy trial for the prevention of chronic HCV confirmed suspicions that this virus will be a challenging vaccine target. Here, we examine the published data from this first efficacy trial along with the earlier clinical and pre-clinical studies of the vaccine candidate and then discuss three key research directions expected to be important in ongoing and future HCV vaccine development. These include the following: 1. design of novel immunogens that generate immune responses to genetically diverse HCV genotypes and subtypes, 2. strategies to elicit broadly neutralizing antibodies against envelope glycoproteins in addition to cytotoxic and helper T cell responses, and 3. consideration of the unique immunological status of individuals most at risk for HCV infection, including those who inject drugs, in vaccine platform development and early immunogenicity trials.<\/jats:p>","DOI":"10.3390\/v13071351","type":"journal-article","created":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T22:25:31Z","timestamp":1626215131000},"page":"1351","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Where to Next? Research Directions after the First Hepatitis C Vaccine Efficacy Trial"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4545-5650","authenticated-orcid":false,"given":"Christopher C.","family":"Phelps","sequence":"first","affiliation":[{"name":"Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher M.","family":"Walker","sequence":"additional","affiliation":[{"name":"Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"},{"name":"Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3181-0554","authenticated-orcid":false,"given":"Jonathan R.","family":"Honegger","sequence":"additional","affiliation":[{"name":"Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"},{"name":"Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1126\/science.2523562","article-title":"Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome","volume":"244","author":"Choo","year":"1989","journal-title":"Science"},{"key":"ref_2","unstructured":"Polaris Observatory HCV Collaborators (2017). Global prevalence and genotype distribution of hepatitis C virus infection in 2015: A modelling study. Lancet Gastroenterol. Hepatol., 2, 161\u2013176."},{"key":"ref_3","unstructured":"WHO (2017). Global Hepatitis Report, 2017, World Health Organization."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2599","DOI":"10.1056\/NEJMoa1512610","article-title":"Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection","volume":"373","author":"Feld","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_5","unstructured":"WHO (2016). Global Health Sector Strategy on Viral Hepatitis 2016\u20132021, World Health Organization."},{"key":"ref_6","unstructured":"Centers for Disease Control and Prevention (2021, January 27). Viral Hepatitis Surveillance\u2014United States, Available online: https:\/\/www.cdc.gov\/hepatitis\/statistics\/SurveillanceRpts.htm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/jvh.12253","article-title":"Hepatitis C disease burden and strategies to manage the burden (Guest Editors Mark Thursz, Gregory Dore and John Ward)","volume":"21","author":"Dore","year":"2014","journal-title":"J. Viral. Hepat."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1053\/j.gastro.2018.08.060","article-title":"Approaches, Progress, and Challenges to Hepatitis C Vaccine Development","volume":"156","author":"Bailey","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1093\/cid\/civ197","article-title":"Hepatitis C virus therapeutic development: In pursuit of \u201cperfectovir\u201d","volume":"60","author":"Dore","year":"2015","journal-title":"Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.bpg.2012.09.011","article-title":"The role of resistance in HCV treatment","volume":"26","author":"Vermehren","year":"2012","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_11","first-page":"103","article-title":"Understanding Hepatitis C Virus Drug Resistance: Clinical Implications for Current and Future Regimens","volume":"25","author":"Wyles","year":"2017","journal-title":"Top. Antivir. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.jhep.2019.11.012","article-title":"Hepatitis C reinfection after successful antiviral treatment among people who inject drugs: A meta-analysis","volume":"72","author":"Hajarizadeh","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.epidem.2008.10.002","article-title":"Potential impact of vaccination on the hepatitis C virus epidemic in injection drug users","volume":"1","author":"Hahn","year":"2009","journal-title":"Epidemics"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Scott, N., McBryde, E., Vickerman, P., Martin, N.K., Stone, J., Drummer, H., and Hellard, M. (2015). The role of a hepatitis C virus vaccine: Modelling the benefits alongside direct-acting antiviral treatments. BMC Med., 13.","DOI":"10.1186\/s12916-015-0440-2"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"33","DOI":"10.4103\/0974-777X.52979","article-title":"Association between hepatitis C and hepatocellular carcinoma","volume":"1","author":"Melo","year":"2009","journal-title":"J. Glob. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1053\/j.gastro.2009.09.017","article-title":"Spontaneous control of primary hepatitis C virus infection and immunity against persistent reinfection","volume":"138","author":"Osburn","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1084\/jem.20100388","article-title":"Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence","volume":"209","author":"Ciuffreda","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3603","DOI":"10.4049\/jimmunol.175.6.3603","article-title":"Broad repertoire of the CD4+ Th cell response in spontaneously controlled hepatitis C virus infection includes dominant and highly promiscuous epitopes","volume":"175","author":"Lauer","year":"2005","journal-title":"J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1053\/j.gastro.2004.06.015","article-title":"High resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection","volume":"127","author":"Lauer","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1086\/505714","article-title":"Differential antigenic hierarchy associated with spontaneous recovery from hepatitis C virus infection: Implications for vaccine design","volume":"194","author":"Tester","year":"2006","journal-title":"J. Infect. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"15661","DOI":"10.1073\/pnas.202608299","article-title":"Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease","volume":"99","author":"Thimme","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1084\/jem.194.10.1395","article-title":"Determinants of viral clearance and persistence during acute hepatitis C virus infection","volume":"194","author":"Thimme","year":"2001","journal-title":"J. Exp. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1084\/jem.191.9.1499","article-title":"Analysis of successful immune responses in persons infected with hepatitis C virus","volume":"191","author":"Lechner","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1126\/science.1088774","article-title":"HCV persistence and immune evasion in the absence of memory T cell help","volume":"302","author":"Grakoui","year":"2003","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1084\/jem.20030239","article-title":"Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection","volume":"197","author":"Shoukry","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1172\/JCI126277","article-title":"Hepatitis C virus-specific CD4+ T cell phenotype and function in different infection outcomes","volume":"130","author":"Chen","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5550","DOI":"10.1128\/JVI.75.12.5550-5558.2001","article-title":"Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus","volume":"75","author":"Gruener","year":"2001","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3447","DOI":"10.4049\/jimmunol.169.6.3447","article-title":"Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection","volume":"169","author":"Wedemeyer","year":"2002","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1097\/00006454-199705000-00021","article-title":"Natural recovery from acute hepatitis C virus infection by agammaglobulinemic twin children","volume":"16","author":"Adams","year":"1997","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1846","DOI":"10.1086\/383279","article-title":"Clearance of hepatitis C viremia associated with cellular immunity in the absence of seroconversion in the hepatitis C incidence and transmission in prisons study cohort","volume":"189","author":"Post","year":"2004","journal-title":"J. Infect. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/j.1365-2893.2008.01016.x","article-title":"Hepatitis C virus-specific T-cell immune responses in seronegative injection drug users","volume":"16","author":"Zeremski","year":"2009","journal-title":"J. Viral Hepat."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"14199","DOI":"10.1073\/pnas.2335981100","article-title":"In vitro assay for neutralizing antibody to hepatitis C virus: Evidence for broadly conserved neutralization epitopes","volume":"100","author":"Bartosch","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"10149","DOI":"10.1073\/pnas.0403519101","article-title":"Neutralizing antibody response during acute and chronic hepatitis C virus infection","volume":"101","author":"Logvinoff","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7792","DOI":"10.1073\/pnas.91.16.7792","article-title":"Prevention of hepatitis C virus infection in chimpanzees after antibody-mediated in vitro neutralization","volume":"91","author":"Farci","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/nm1698","article-title":"Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge","volume":"14","author":"Law","year":"2008","journal-title":"Nat. Med."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Morin, T.J., Broering, T.J., Leav, B.A., Blair, B.M., Rowley, K.J., Boucher, E.N., Wang, Y., Cheslock, P.S., Knauber, M., and Olsen, D.B. (2012). Human monoclonal antibody HCV1 effectively prevents and treats HCV infection in chimpanzees. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002895"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1073\/pnas.91.4.1294","article-title":"Vaccination of chimpanzees against infection by the hepatitis C virus","volume":"91","author":"Choo","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1111\/j.1600-065X.2010.00977.x","article-title":"Prospects for prophylactic and therapeutic vaccines against the hepatitis C viruses","volume":"239","author":"Houghton","year":"2011","journal-title":"Immunol. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6025","DOI":"10.1073\/pnas.0607026104","article-title":"Rapid induction of virus-neutralizing antibodies and viral clearance in a single-source outbreak of hepatitis C","volume":"104","author":"Pestka","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2140","DOI":"10.1002\/hep.27013","article-title":"Clearance of hepatitis C infection is associated with the early appearance of broad neutralizing antibody responses","volume":"59","author":"Osburn","year":"2014","journal-title":"Hepatology"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Duncan, J.D., Urbanowicz, R.A., Tarr, A.W., and Ball, J.K. (2020). Hepatitis C Virus Vaccine: Challenges and Prospects. Vaccines, 8.","DOI":"10.3390\/vaccines8010090"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1586\/14760584.8.3.333","article-title":"Development of hepatitis C virus vaccines: Challenges and progress","volume":"8","author":"Barth","year":"2009","journal-title":"Expert Rev. Vaccines"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1038\/nrgastro.2016.37","article-title":"Experimental models of hepatitis B and C\u2014New insights and progress","volume":"13","author":"Thomas","year":"2016","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1002\/hep.29494","article-title":"Viral persistence, liver disease, and host response in a hepatitis C-like virus rat model","volume":"68","author":"Trivedi","year":"2018","journal-title":"Hepatology"},{"key":"ref_45","unstructured":"Thimme, R. (2020). T cell immunity to hepatitis C virus: Lessons for a prophylactic HCV vaccine. J. Hepatol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1053\/j.gastro.2008.11.049","article-title":"Rare birds in North America: Acute hepatitis C cohorts","volume":"136","author":"Cox","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2412","DOI":"10.1053\/j.gastro.2009.04.040","article-title":"More rare birds, and the occasional swan","volume":"136","author":"Edlin","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1056\/NEJMoa2023345","article-title":"Randomized Trial of a Vaccine Regimen to Prevent Chronic HCV Infection","volume":"384","author":"Page","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/nm1353","article-title":"A T-cell HCV vaccine eliciting effective immunity against heterologous virus challenge in chimpanzees","volume":"12","author":"Folgori","year":"2006","journal-title":"Nat. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1128\/JVI.80.4.1688-1699.2006","article-title":"A novel adenovirus type 6 (Ad6)-based hepatitis C virus vector that overcomes preexisting anti-ad5 immunity and induces potent and broad cellular immune responses in rhesus macaques","volume":"80","author":"Capone","year":"2006","journal-title":"J. Virol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"115ra112","DOI":"10.1126\/scitranslmed.3002925","article-title":"Vaccine vectors derived from a large collection of simian adenoviruses induce potent cellular immunity across multiple species","volume":"4","author":"Colloca","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"115ra111","DOI":"10.1126\/scitranslmed.3003155","article-title":"Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man","volume":"4","author":"Barnes","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"261ra153","DOI":"10.1126\/scitranslmed.3009185","article-title":"A human vaccine strategy based on chimpanzee adenoviral and MVA vectors that primes, boosts, and sustains functional HCV-specific T cell memory","volume":"6","author":"Swadling","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1099\/vir.0.017491-0","article-title":"Genotype 1 and global hepatitis C T-cell vaccines designed to optimize coverage of genetic diversity","volume":"91","author":"Yusim","year":"2010","journal-title":"J. Gen. Virol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"102","DOI":"10.20411\/pai.v2i1.201","article-title":"Hurdles to the Development of Effective HBV Immunotherapies and HCV Vaccines","volume":"2","author":"Lauer","year":"2017","journal-title":"Pathog. Immun."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1002\/hep.26744","article-title":"Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: Updated criteria and genotype assignment web resource","volume":"59","author":"Smith","year":"2014","journal-title":"Hepatology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1128\/JVI.78.3.1575-1581.2004","article-title":"Cross-genotype immunity to hepatitis C virus","volume":"78","author":"Lanford","year":"2004","journal-title":"J. Virol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"8183","DOI":"10.1128\/JVI.00142-08","article-title":"Previously infected chimpanzees are not consistently protected against reinfection or persistent infection after reexposure to the identical hepatitis C virus strain","volume":"82","author":"Bukh","year":"2008","journal-title":"J. Virol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1086\/496889","article-title":"Protection against chronic hepatitis C virus infection after rechallenge with homologous, but not heterologous, genotypes in a chimpanzee model","volume":"192","author":"Prince","year":"2005","journal-title":"J. Infect. Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1182\/blood-2007-01-069583","article-title":"Immunologic evidence for lack of heterologous protection following resolution of HCV in patients with non-genotype 1 infection","volume":"110","author":"Lauer","year":"2007","journal-title":"Blood"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1136\/gutjnl-2014-308724","article-title":"The broad assessment of HCV genotypes 1 and 3 antigenic targets reveals limited cross-reactivity with implications for vaccine design","volume":"65","author":"Humphreys","year":"2016","journal-title":"Gut"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Letourneau, S., Im, E.J., Mashishi, T., Brereton, C., Bridgeman, A., Yang, H., Dorrell, L., Dong, T., Korber, B., and McMichael, A.J. (2007). Design and pre-clinical evaluation of a universal HIV-1 vaccine. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0000984"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1973","DOI":"10.1002\/eji.201040344","article-title":"Long peptides induce polyfunctional T cells against conserved regions of HIV-1 with superior breadth to single-gene vaccines in macaques","volume":"40","author":"Rosario","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/mt.2013.248","article-title":"Vaccine-elicited human T cells recognizing conserved protein regions inhibit HIV-1","volume":"22","author":"Borthwick","year":"2014","journal-title":"Mol. Ther."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Moyo, N., Borthwick, N.J., Wee, E.G., Capucci, S., Crook, A., Dorrell, L., and Hanke, T. (2017). Long-term follow up of human T-cell responses to conserved HIV-1 regions elicited by DNA\/simian adenovirus\/MVA vaccine regimens. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0181382"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2841","DOI":"10.1097\/QAD.0000000000000047","article-title":"DNA\/long peptide vaccination against conserved regions of SIV induces partial protection against SIVmac251 challenge","volume":"27","author":"Koopman","year":"2013","journal-title":"AIDS"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.vaccine.2017.10.079","article-title":"The generation of a simian adenoviral vectored HCV vaccine encoding genetically conserved gene segments to target multiple HCV genotypes","volume":"36","author":"Donnison","year":"2018","journal-title":"Vaccine"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"5036","DOI":"10.1016\/j.vaccine.2020.05.042","article-title":"Viral vectored hepatitis C virus vaccines generate pan-genotypic T cell responses to conserved subdominant epitopes","volume":"38","author":"Donnison","year":"2020","journal-title":"Vaccine"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/nm1461","article-title":"Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants","volume":"13","author":"Fischer","year":"2007","journal-title":"Nat. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/sim.7203","article-title":"Graph-based optimization of epitope coverage for vaccine antigen design","volume":"37","author":"Theiler","year":"2018","journal-title":"Stat. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"33987","DOI":"10.1038\/srep33987","article-title":"Epigraph: A Vaccine Design Tool Applied to an HIV Therapeutic Vaccine and a Pan-Filovirus Vaccine","volume":"6","author":"Theiler","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1080\/21645515.2019.1666957","article-title":"T cell-based strategies for HIV-1 vaccines","volume":"16","author":"Korber","year":"2020","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/nm.2089","article-title":"Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys","volume":"16","author":"Barouch","year":"2010","journal-title":"Nat. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/nm.2108","article-title":"Mosaic vaccines elicit CD8+ T lymphocyte responses that confer enhanced immune coverage of diverse HIV strains in monkeys","volume":"16","author":"Santra","year":"2010","journal-title":"Nat. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.cell.2013.09.061","article-title":"Protective efficacy of a global HIV-1 mosaic vaccine against heterologous SHIV challenges in rhesus monkeys","volume":"155","author":"Barouch","year":"2013","journal-title":"Cell"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1093\/infdis\/jiy212","article-title":"First-in-Human Randomized, Controlled Trial of Mosaic HIV-1 Immunogens Delivered via a Modified Vaccinia Ankara Vector","volume":"218","author":"Baden","year":"2018","journal-title":"J. Infect. Dis."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/S0140-6736(18)31364-3","article-title":"Evaluation of a mosaic HIV-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1\/2a clinical trial (APPROACH) and in rhesus monkeys (NHP 13-19)","volume":"392","author":"Barouch","year":"2018","journal-title":"Lancet"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1128\/CVI.00605-12","article-title":"Hepatitis C genotype 1 mosaic vaccines are immunogenic in mice and induce stronger T-cell responses than natural strains","volume":"20","author":"Yusim","year":"2013","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1038\/mt.2016.3","article-title":"Novel Conserved-region T-cell Mosaic Vaccine With High Global HIV-1 Coverage Is Recognized by Protective Responses in Untreated Infection","volume":"24","author":"Ondondo","year":"2016","journal-title":"Mol. Ther."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1053\/j.gastro.2009.02.080","article-title":"Selection pressure from neutralizing antibodies drives sequence evolution during acute infection with hepatitis C virus","volume":"136","author":"Dowd","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"13300","DOI":"10.1038\/s41598-019-49454-w","article-title":"Clearance of hepatitis C virus is associated with early and potent but narrowly-directed, Envelope-specific antibodies","volume":"9","author":"Walker","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/j.chom.2018.10.012","article-title":"Broadly Neutralizing Antibody Mediated Clearance of Human Hepatitis C Virus Infection","volume":"24","author":"Kinchen","year":"2018","journal-title":"Cell Host Microbe"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"e140590","DOI":"10.1172\/JCI140590","article-title":"Early T follicular helper cell activity accelerates hepatitis C virus-specific B cell expansion","volume":"131","author":"Salinas","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1053\/j.gastro.2010.05.077","article-title":"Meta-analysis of hepatitis C virus vaccine efficacy in chimpanzees indicates an importance for structural proteins","volume":"139","author":"Dahari","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1093\/infdis\/jir511","article-title":"Vaccine-induced cross-genotype reactive neutralizing antibodies against hepatitis C virus","volume":"204","author":"Meunier","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"6367","DOI":"10.1016\/j.vaccine.2010.06.084","article-title":"Safety and immunogenicity of HCV E1E2 vaccine adjuvanted with MF59 administered to healthy adults","volume":"28","author":"Frey","year":"2010","journal-title":"Vaccine"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1053\/j.gastro.2019.11.282","article-title":"Antibody Responses to Immunization With HCV Envelope Glycoproteins as a Baseline for B-Cell-Based Vaccine Development","volume":"158","author":"Chen","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Law, J.L., Chen, C., Wong, J., Hockman, D., Santer, D.M., Frey, S.E., Belshe, R.B., Wakita, T., Bukh, J., and Jones, C.T. (2013). 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.","DOI":"10.1371\/journal.pone.0059776"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e92872","DOI":"10.1172\/jci.insight.92872","article-title":"Broadly neutralizing antibodies with few somatic mutations and hepatitis C virus clearance","volume":"2","author":"Bailey","year":"2017","journal-title":"JCI Insight"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.jhep.2019.02.013","article-title":"Cross-genotype AR3-specific neutralizing antibodies confer long-term protection in injecting drug users after HCV clearance","volume":"71","author":"Merat","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Merat, S.J., Molenkamp, R., Wagner, K., Koekkoek, S.M., van de Berg, D., Yasuda, E., Bohne, M., Claassen, Y.B., Grady, B.P., and Prins, M. (2016). Hepatitis C virus Broadly Neutralizing Monoclonal Antibodies Isolated 25 Years after Spontaneous Clearance. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0165047"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.immuni.2021.02.013","article-title":"Functional convergence of a germline-encoded neutralizing antibody response in rhesus macaques immunized with HCV envelope glycoproteins","volume":"54","author":"Chen","year":"2021","journal-title":"Immunity"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Yechezkel, I., Law, M., and Tzarum, N. (2021). From Structural Studies to HCV Vaccine Design. Viruses, 13.","DOI":"10.3390\/v13050833"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Schlotthauer, F., McGregor, J., and Drummer, H.E. (2021). To Include or Occlude: Rational Engineering of HCV Vaccines for Humoral Immunity. Viruses, 13.","DOI":"10.3390\/v13050805"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Toth, E.A., Chagas, A., Pierce, B.G., and Fuerst, T.R. (2021). Structural and Biophysical Characterization of the HCV E1E2 Heterodimer for Vaccine Development. Viruses, 13.","DOI":"10.3390\/v13061027"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"5751","DOI":"10.1128\/JVI.02200-09","article-title":"Hepatitis C virus hypervariable region 1 modulates receptor interactions, conceals the CD81 binding site, and protects conserved neutralizing epitopes","volume":"84","author":"Bankwitz","year":"2010","journal-title":"J. Virol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3112","DOI":"10.1128\/JVI.02458-15","article-title":"Antibody Response to Hypervariable Region 1 Interferes with Broadly Neutralizing Antibodies to Hepatitis C Virus","volume":"90","author":"Keck","year":"2016","journal-title":"J. Virol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1002\/hep.28705","article-title":"Hypervariable region 1 shielding of hepatitis C virus is a main contributor to genotypic differences in neutralization sensitivity","volume":"64","author":"Prentoe","year":"2016","journal-title":"Hepatology"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"5067","DOI":"10.1128\/JVI.02265-09","article-title":"Acceleration of hepatitis C virus envelope evolution in humans is consistent with progressive humoral immune selection during the transition from acute to chronic infection","volume":"84","author":"Liu","year":"2010","journal-title":"J. Virol."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Pierce, B.G., Keck, Z.Y., Wang, R., Lau, P., Garagusi, K., Elkholy, K., Toth, E.A., Urbanowicz, R.A., Guest, J.D., and Agnihotri, P. (2020). Structure-Based Design of Hepatitis C Virus E2 Glycoprotein Improves Serum Binding and Cross-Neutralization. J. Virol., 94.","DOI":"10.1128\/JVI.00704-20"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"e02141-17","DOI":"10.1128\/JVI.02141-17","article-title":"Role of the E2 Hypervariable Region (HVR1) in the Immunogenicity of a Recombinant Hepatitis C Virus Vaccine","volume":"92","author":"Law","year":"2018","journal-title":"J. Virol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"e01668-16","DOI":"10.1128\/JVI.01668-16","article-title":"An Optimized Hepatitis C Virus E2 Glycoprotein Core Adopts a Functional Homodimer That Efficiently Blocks Virus Entry","volume":"91","author":"McCaffrey","year":"2017","journal-title":"J. Virol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"9584","DOI":"10.1128\/JVI.02782-06","article-title":"Expression and characterization of a minimal hepatitis C virus glycoprotein E2 core domain that retains CD81 binding","volume":"81","author":"McCaffrey","year":"2007","journal-title":"J. Virol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1002\/hep.28989","article-title":"The core domain of hepatitis C virus glycoprotein E2 generates potent cross-neutralizing antibodies in guinea pigs","volume":"65","author":"Vietheer","year":"2017","journal-title":"Hepatology"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"eaaz6225","DOI":"10.1126\/sciadv.aaz6225","article-title":"Proof of concept for rational design of hepatitis C virus E2 core nanoparticle vaccines","volume":"6","author":"He","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"8072","DOI":"10.1128\/JVI.00459-07","article-title":"Hepatitis C virus envelope glycoprotein E2 glycans modulate entry, CD81 binding, and neutralization","volume":"81","author":"Falkowska","year":"2007","journal-title":"J. Virol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"8101","DOI":"10.1128\/JVI.00127-07","article-title":"The neutralizing activity of anti-hepatitis C virus antibodies is modulated by specific glycans on the E2 envelope protein","volume":"81","author":"Helle","year":"2007","journal-title":"J. Virol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1016\/j.jmb.2013.02.025","article-title":"Glycan shifting on hepatitis C virus (HCV) E2 glycoprotein is a mechanism for escape from broadly neutralizing antibodies","volume":"425","author":"Pantua","year":"2013","journal-title":"J. Mol. Biol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"6572","DOI":"10.1016\/j.vaccine.2007.07.003","article-title":"Deletion of N-glycosylation sites of hepatitis C virus envelope protein E1 enhances specific cellular and humoral immune responses","volume":"25","author":"Liu","year":"2007","journal-title":"Vaccine"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1016\/j.bbagen.2015.08.007","article-title":"N-glycosylation-mutated HCV envelope glycoprotein complex enhances antigen-presenting activity and cellular and neutralizing antibody responses","volume":"1860","author":"Ren","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Urbanowicz, R.A., Wang, R., Schiel, J.E., Keck, Z.Y., Kerzic, M.C., Lau, P., Rangarajan, S., Garagusi, K.J., Tan, L., and Guest, J.D. (2019). Antigenicity and Immunogenicity of Differentially Glycosylated Hepatitis C Virus E2 Envelope Proteins Expressed in Mammalian and Insect Cells. J. Virol., 93.","DOI":"10.1128\/JVI.01403-18"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"552","DOI":"10.3389\/fimmu.2015.00552","article-title":"HLA Preferences for Conserved Epitopes: A Potential Mechanism for Hepatitis C Clearance","volume":"6","author":"Rao","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Andrianov, A.K., and Fuerst, T.R. (2021). Immunopotentiating and Delivery Systems for HCV Vaccines. Viruses, 13.","DOI":"10.3390\/v13060981"},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Sepulveda-Crespo, D., Resino, S., and Martinez, I. (2020). Innate Immune Response against Hepatitis C Virus: Targets for Vaccine Adjuvants. Vaccines, 8.","DOI":"10.3390\/vaccines8020313"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1056\/NEJMoa2035389","article-title":"Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine","volume":"384","author":"Baden","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"2603","DOI":"10.1056\/NEJMoa2034577","article-title":"Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine","volume":"383","author":"Polack","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/s41586-021-03275-y","article-title":"BNT162b vaccines protect rhesus macaques from SARS-CoV-2","volume":"592","author":"Vogel","year":"2021","journal-title":"Nature"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1038\/s41586-020-2622-0","article-title":"SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness","volume":"586","author":"Corbett","year":"2020","journal-title":"Nature"},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Sahin, U., Muik, A., Vogler, I., Derhovanessian, E., Kranz, L.M., Vormehr, M., Quandt, J., Bidmon, N., Ulges, A., and Baum, A. (2021). BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans. Nature.","DOI":"10.1038\/s41586-021-03653-6"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1056\/NEJMoa2024671","article-title":"Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates","volume":"383","author":"Corbett","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1056\/NEJMoa2022483","article-title":"An mRNA Vaccine against SARS-CoV-2\u2014Preliminary Report","volume":"383","author":"Jackson","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1093\/cid\/ciu643","article-title":"Emerging epidemic of hepatitis C virus infections among young nonurban persons who inject drugs in the United States, 2006\u20132012","volume":"59","author":"Suryaprasad","year":"2014","journal-title":"Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1007\/s11481-011-9292-5","article-title":"Opioid drug abuse and modulation of immune function: Consequences in the susceptibility to opportunistic infections","volume":"6","author":"Roy","year":"2011","journal-title":"J. Neuroimmune Pharmacol. Off. J. Soc. NeuroImmune Pharmacol."},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Zhang, R., Meng, J., Lian, Q., Chen, X., Bauman, B., Chu, H., Segura, B., and Roy, S. (2018). Prescription opioids are associated with higher mortality in patients diagnosed with sepsis: A retrospective cohort study using electronic health records. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0190362"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1016\/j.vaccine.2014.02.072","article-title":"Immune response to hepatitis B vaccination in drug using populations: A systematic review and meta-regression analysis","volume":"32","author":"Kamath","year":"2014","journal-title":"Vaccine"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/0008-8749(90)90326-M","article-title":"Morphine-induced immune alterations in vivo","volume":"126","author":"Arora","year":"1990","journal-title":"Cell. Immunol."},{"key":"ref_127","first-page":"9","article-title":"Immune alterations in morphine-treated rhesus monkeys","volume":"267","author":"Carr","year":"1993","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.jneuroim.2013.09.013","article-title":"Effect of chronic morphine administration on circulating T cell population dynamics in rhesus macaques","volume":"265","author":"Cornwell","year":"2013","journal-title":"J. Neuroimmunol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1007\/s10753-016-0310-x","article-title":"Morphine Suppresses T helper Lymphocyte Differentiation to Th1 Type Through PI3K\/AKT Pathway","volume":"39","author":"Mao","year":"2016","journal-title":"Inflammation"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1067\/msy.2001.116033","article-title":"Morphine directs T cells toward T(H2) differentiation","volume":"130","author":"Roy","year":"2001","journal-title":"Surgery"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.jneuroim.2003.10.016","article-title":"Chronic morphine treatment differentiates T helper cells to Th2 effector cells by modulating transcription factors GATA 3 and T-bet","volume":"147","author":"Roy","year":"2004","journal-title":"J. Neuroimmunol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1111\/j.1476-5381.2011.01475.x","article-title":"Depletion and recovery of lymphoid subsets following morphine administration","volume":"164","author":"Zhang","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.virol.2006.06.020","article-title":"Chronic morphine exposure causes pronounced virus replication in cerebral compartment and accelerated onset of AIDS in SIV\/SHIV-infected Indian rhesus macaques","volume":"354","author":"Kumar","year":"2006","journal-title":"Virology"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"2904","DOI":"10.3389\/fimmu.2019.02904","article-title":"The Role of Opioid Receptors in Immune System Function","volume":"10","author":"Eisenstein","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_135","doi-asserted-by":"crossref","unstructured":"Brejchova, J., Holan, V., and Svoboda, P. (2020). Expression of Opioid Receptors in Cells of the Immune System. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010315"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"2611","DOI":"10.1038\/s41467-020-16159-y","article-title":"Single cell transcriptomics reveals opioid usage evokes widespread suppression of antiviral gene program","volume":"11","author":"Karagiannis","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1007\/s11481-011-9296-1","article-title":"Opioids and HIV\/HCV infection","volume":"6","author":"Wang","year":"2011","journal-title":"J. Neuroimmune Pharmacol. Off. J. Soc. NeuroImmune Pharmacol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"e8","DOI":"10.1097\/QAI.0000000000001270","article-title":"Brief Report: The Relationship Between Injection Drug Use Risk Behaviors and Markers of Immune Activation","volume":"75","author":"Deren","year":"2017","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_139","doi-asserted-by":"crossref","unstructured":"Tomescu, C., Colon, K., Smith, P., Taylor, M., Azzoni, L., Metzger, D.S., and Montaner, L.J. (2020). Persons who inject drugs (PWID) retain functional NK cells, dendritic cell stimulation, and adaptive immune recall responses despite prolonged opioid use. J. Leukoc. Biol.","DOI":"10.1002\/JLB.5A0920-604R"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/S1473-3099(07)70237-2","article-title":"Vaccine immunogenicity in injecting drug users: A systematic review","volume":"7","author":"Baral","year":"2007","journal-title":"Lancet Infect. Dis."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/21645515.2017.1283082","article-title":"Immunogenicity and safety of high-dose hepatitis B vaccine among drug users: A randomized, open-labeled, blank-controlled trial","volume":"13","author":"Feng","year":"2017","journal-title":"Hum. Vaccine Immunother."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1016\/j.vaccine.2016.01.051","article-title":"Active opioid use does not attenuate the humoral responses to inactivated influenza vaccine","volume":"34","author":"Moroz","year":"2016","journal-title":"Vaccine"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1086\/422605","article-title":"Prevalence of production of virus-specific interferon-gamma among seronegative hepatitis C-resistant subjects reporting injection drug use","volume":"190","author":"Freeman","year":"2004","journal-title":"J. Infect. Dis."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1086\/589510","article-title":"Hepatitis C virus (HCV)-specific immune responses of long-term injection drug users frequently exposed to HCV","volume":"198","author":"Mizukoshi","year":"2008","journal-title":"J. Infect. Dis."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1086\/593337","article-title":"Hepatitis C virus (HCV)--specific T cell responses in injection drug users with apparent resistance to HCV infection","volume":"198","author":"Thurairajah","year":"2008","journal-title":"J. Infect. Dis."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1128\/CVI.00050-12","article-title":"Hepatitis C virus-multispecific T-cell responses without viremia or seroconversion among Egyptian health care workers at high risk of infection","volume":"19","author":"Abdelwahab","year":"2012","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1093\/infdis\/jit270","article-title":"Occupational exposure to hepatitis C virus: Early T-cell responses in the absence of seroconversion in a longitudinal cohort study","volume":"208","author":"Heller","year":"2013","journal-title":"J. Infect. Dis."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1111\/j.1365-2362.2007.01753.x","article-title":"Induction of hepatitis C virus (HCV)-specific T cells by needle stick injury in the absence of HCV-viraemia","volume":"37","author":"Kubitschke","year":"2007","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.ajic.2008.08.003","article-title":"Evidence of hepatitis C virus-specific interferon gamma-positive T cells in health care workers in an infectious disease department","volume":"37","author":"Perrella","year":"2009","journal-title":"Am. J. Infect. Control"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"44","DOI":"10.4269\/ajtmh.2005.73.1.0730044","article-title":"Exposure to hepatitis C virus induces cellular immune responses without detectable viremia or seroconversion","volume":"73","author":"Osman","year":"2005","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1093\/infdis\/jiq123","article-title":"Strong hepatitis C virus (HCV)-specific cell-mediated immune responses in the absence of viremia or antibodies among uninfected siblings of HCV chronically infected children","volume":"203","author":"Hashem","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"6681","DOI":"10.4049\/jimmunol.162.11.6681","article-title":"Presence of effector CD8+ T cells in hepatitis C virus-exposed healthy seronegative donors","volume":"162","author":"Scognamiglio","year":"1999","journal-title":"J. Immunol."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"12252","DOI":"10.1128\/JVI.78.22.12252-12258.2004","article-title":"Cellular immune responses in seronegative sexual contacts of acute hepatitis C patients","volume":"78","author":"Kamal","year":"2004","journal-title":"J. Virol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/75063","article-title":"Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C","volume":"6","author":"Takaki","year":"2000","journal-title":"Nat. Med."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1038\/nm.3408","article-title":"Subinfectious hepatitis C virus exposures suppress T cell responses against subsequent acute infection","volume":"19","author":"Park","year":"2013","journal-title":"Nat. Med."},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"Esposito, I., Cicconi, P., D\u2019Alise, A.M., Brown, A., Esposito, M., Swadling, L., Holst, P.J., Bassi, M.R., Stornaiuolo, M., and Mori, F. (2020). MHC class II invariant chain-adjuvanted viral vectored vaccines enhances T cell responses in humans. Sci. Transl. Med., 12.","DOI":"10.1126\/scitranslmed.aaz7715"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1016\/j.jhep.2016.01.001","article-title":"Hepatitis C reinfection after sustained virological response","volume":"64","author":"Midgard","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1016\/j.jhep.2018.07.025","article-title":"Hepatitis C virus reinfection after successful treatment with direct-acting antiviral therapy in a large population-based cohort","volume":"69","author":"Rossi","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"2695","DOI":"10.1093\/cid\/ciz693","article-title":"Low Hepatitis C Reinfection Following Direct-acting Antiviral Therapy Among People Who Inject Drugs on Opioid Agonist Therapy","volume":"70","author":"Akiyama","year":"2020","journal-title":"Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1053\/jhep.2001.21162","article-title":"Differential CD4(+) and CD8(+) T-cell responsiveness in hepatitis C virus infection","volume":"33","author":"Chang","year":"2001","journal-title":"Hepatology"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"12584","DOI":"10.1128\/JVI.76.24.12584-12595.2002","article-title":"Broad specificity of virus-specific CD4+ T-helper-cell responses in resolved hepatitis C virus infection","volume":"76","author":"Day","year":"2002","journal-title":"J. Virol."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1016\/S0016-5085(99)70353-7","article-title":"Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C","volume":"117","author":"Gerlach","year":"1999","journal-title":"Gastroenterology"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1128\/JVI.02021-06","article-title":"Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression","volume":"81","author":"Radziewicz","year":"2007","journal-title":"J. Virol."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1128\/JVI.02242-14","article-title":"Tetramer enrichment reveals the presence of phenotypically diverse hepatitis C virus-specific CD8+ T cells in chronic infection","volume":"89","author":"Nitschke","year":"2015","journal-title":"J. Virol."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"11398","DOI":"10.1128\/JVI.01177-06","article-title":"PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion","volume":"80","author":"Urbani","year":"2006","journal-title":"J. Virol."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1002\/hep.20749","article-title":"Comprehensive analyses of CD8+ T cell responses during longitudinal study of acute human hepatitis C","volume":"42","author":"Cox","year":"2005","journal-title":"Hepatology"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1084\/jem.20050121","article-title":"Cellular immune selection with hepatitis C virus persistence in humans","volume":"201","author":"Cox","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/S1074-7613(01)00245-X","article-title":"The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes","volume":"15","author":"Erickson","year":"2001","journal-title":"Immunity"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1002\/hep.22242","article-title":"Virological and immunological determinants of intrahepatic virus-specific CD8+ T-cell failure in chronic hepatitis C virus infection","volume":"47","author":"Timm","year":"2008","journal-title":"Hepatology"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.jhep.2014.05.043","article-title":"Restoration of HCV-specific CD8+ T cell function by interferon-free therapy","volume":"61","author":"Martin","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1093\/infdis\/jiz291","article-title":"Dynamic Changes in Ex Vivo T-Cell Function After Viral Clearance in Chronic HCV Infection","volume":"220","author":"Han","year":"2019","journal-title":"J. Infect. Dis."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1002\/hep.27278","article-title":"T-cell immunity and hepatitis C virus reinfection after cure of chronic hepatitis C with an interferon-free antiviral regimen in a chimpanzee","volume":"60","author":"Callendret","year":"2014","journal-title":"Hepatology"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"15050","DOI":"10.1038\/ncomms15050","article-title":"TCF1(+) hepatitis C virus-specific CD8(+) T cells are maintained after cessation of chronic antigen stimulation","volume":"8","author":"Wieland","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/s41590-020-00817-w","article-title":"Memory-like HCV-specific CD8(+) T cells retain a molecular scar after cure of chronic HCV infection","volume":"22","author":"Hensel","year":"2021","journal-title":"Nat. Immunol."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/j.jhep.2019.06.025","article-title":"Elimination of hepatitis C virus has limited impact on the functional and mitochondrial impairment of HCV-specific CD8+ T cell responses","volume":"71","author":"Aregay","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1038\/s41467-019-14137-7","article-title":"Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection","volume":"11","author":"Barili","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/j.immuni.2017.09.006","article-title":"Early Transcriptional Divergence Marks Virus-Specific Primary Human CD8(+) T Cells in Chronic versus Acute Infection","volume":"47","author":"Wolski","year":"2017","journal-title":"Immunity"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41586-019-1326-9","article-title":"TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection","volume":"571","author":"Alfei","year":"2019","journal-title":"Nature"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1172\/JCI129642","article-title":"Follicular T helper cells shape the HCV-specific CD4+ T cell repertoire after virus elimination","volume":"130","author":"Smits","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"19924","DOI":"10.1038\/s41598-020-77020-2","article-title":"Reconstitution of T follicular helper-humoral immune axis with elimination of hepatitis C virus","volume":"10","author":"Khanam","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_181","doi-asserted-by":"crossref","unstructured":"Hartnell, F., Esposito, I., Swadling, L., Brown, A., Phetsouphanh, C., de Lara, C., Gentile, C., Turner, B., Kopycinski, J., and Dorrell, L. (2020). Characterising HCV specific CD4+ T-cells following viral-vectored vaccination, directly acting anti-virals and spontaneous viral cure. Hepatology.","DOI":"10.1002\/hep.31160"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"2564","DOI":"10.3748\/wjg.v20.i10.2564","article-title":"Immune dysfunction in cirrhosis","volume":"20","author":"Sipeki","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.jhep.2020.03.031","article-title":"DAA therapy and long-term hepatic function in advanced\/decompensated cirrhosis: Real-world experience from HCV-TARGET cohort","volume":"73","author":"Verna","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.3389\/fimmu.2019.01926","article-title":"Direct-Acting Antiviral Treatment of HCV Infection Does Not Resolve the Dysfunction of Circulating CD8(+) T-Cells in Advanced Liver Disease","volume":"10","author":"Vranjkovic","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.1016\/j.vaccine.2005.11.064","article-title":"Humoral and cellular immune responses to influenza vaccine in patients with advanced cirrhosis","volume":"24","author":"Cheong","year":"2006","journal-title":"Vaccine"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/nm.4036","article-title":"Targeting EZH2 in cancer","volume":"22","author":"Kim","year":"2016","journal-title":"Nat. Med."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/7\/1351\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:29:46Z","timestamp":1760164186000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/7\/1351"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,13]]},"references-count":186,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["v13071351"],"URL":"https:\/\/doi.org\/10.3390\/v13071351","relation":{},"ISSN":["1999-4915"],"issn-type":[{"type":"electronic","value":"1999-4915"}],"subject":[],"published":{"date-parts":[[2021,7,13]]}}}