Semin Liver Dis 2000; 20(2): 211-226
DOI: 10.1055/s-2000-9947
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Vaccine Development for Hepatitis C

Martin Lechmann, T. Jake Liang
  • Liver Diseases Section, NIDDK, National Institutes of Health, Bethesda, Maryland
Further Information

Publication History

Publication Date:
31 December 2000 (online)

ABSTRACT

Given the global disease burden and public health impact of hepatitis C, the development of an effective vaccine is of paramount importance. However, many challenging obstacles loom ahead of this goal. The hepatitis C virus (HCV), being an RNA virus, can mutate rapidly in adaptation to the environment, thus contributing to the high sequence divergence of multiple viral isolates in the world. The highest heterogeneity has been found in the hypervariable region of the envelope glycoprotein 2, which contains a principal neutralization epitope. HCV also causes persistent infection in a high percentage of immunocompetent hosts despite active immune response. The lack of an efficient tissue culture system for propagating HCV and testing neutralizing antibodies adds further complexity to the task of vaccine development. The immunologic correlates associated with disease progression or protection are yet to be defined, but recent studies suggest that a vigorous multispecific cellular immune response is important in the resolution of infection. Induction of high-titer, long-lasting, and cross-reactive antienvelope antibodies and a vigorous multispecific cellular immune response that includes both helper and cytotoxic T lymphocytes may be necessary for an effective vaccine. Several promising approaches have been used to develop an HCV vaccine. Novel vaccine candidates based on molecular technology such as recombinant proteins, peptides, viruslike particles, naked DNA, and recombinant viruses are being explored. The final vaccine product may require multiple components that target various aspects of protective immunity. Finally, sterilizing immunity may not be necessary if a vaccine can be developed to prevent chronic infection, which is the major cause of morbidity and mortality from this disease.

REFERENCES

  • 1 Singh M, O'Hagan D. Advances in vaccine adjuvants.  Nat Biotechnol . 1999;  17 1075-1081
  • 2 Brandriss M W, Schlesinger J J, Walsh E E, Briselli M. Lethal 17D yellow fever encephalitis in mice. I. Passive protection by monoclonal antibodies to the envelope proteins of 17D yellow fever and dengue 2 viruses.  J Gen Virol . 1986;  67 229-234
  • 3 Bray M, Lai C J. Dengue virus premembrane and membrane proteins elicit a protective immune response.  Virology . 1991;  185 505-508
  • 4 Konishi E, Pincus S, Paoletti E, Shope R E, Burrage T, Mason P W. Mice immunized with a subviral particle containing the Japanese encephalitis virus prM/M and E proteins are protected from lethal JEV infection.  Virology . 1992;  188 714-720
  • 5 Kreil T R, Burger I, Attakpah E, Olas K, Eibl M M. Passive immunization reduces immunity that results from simultaneous active immunization against tick-borne encephalitis virus in a mouse model.  Vaccine . 1998;  16 955-959
  • 6 Weiner A J, Geysen H M, Christopherson C. Evidence for immune selection of hepatitis C virus (HCV) putative envelope glycoprotein variants: Potential role in chronic HCV infections.  Proc Natl Acad Sci USA . 1992;  89 3468-3472
  • 7 Pileri P, Uematsu Y, Campagnoli S. Binding of hepatitis C virus to CD81.  Science . 1998;  282 938-941
  • 8 Habersetzer F, Fournillier A, Dubuisson J. Characterization of human monoclonal antibodies specific to the hepatitis C virus glycoprotein E2 with in vitro binding neutralization properties.  Virology . 1998;  249 32-41
  • 9 Farci P, Shimoda A, Wong D. Prevention of hepatitis C virus infection in chimpanzees by hyperimmune serum against the hypervariable region 1 of the envelope 2 protein.  Proc Natl Acad Sci USA . 1996;  93 15394-15399
  • 10 Shimizu Y K, Hijikata M, Iwamoto A, Alter H J, Purcell R H, Yoshikura H. Neutralizing antibodies against hepatitis C virus and the emergence of neutralization escape mutant viruses.  J Virol . 1994;  68 1494-1500
  • 11 Kato N, Ootsuyama Y, Sekiya H. Genetic drift in hypervariable region 1 of the viral genome in persistent hepatitis C virus infection.  J Virol . 1994;  68 4776-4784
  • 12 Allander T, Beyene A, Jacobson S H, Grillner L, Persson M A. Patients infected with the same hepatitis C virus strain display different kinetics of the isolate-specific antibody response.  J Infect Dis . 1997;  175 26-31
  • 13 Zibert A, Meisel H, Kraas W, Schulz A, Jung G, Roggendorf M. Early antibody response against hypervariable region 1 is associated with acute self-limiting infections of hepatitis C virus.  Hepatology . 1997;  25 1245-1249
  • 14 Yuki N, Hayashi N, Kasahara A. Quantitative analysis of antibody to hepatitis C virus envelope 2 glycoprotein in patients with chronic hepatitis C virus infection.  Hepatology . 1996;  23 947-952
  • 15 Fournillier-Jacob A, Lunel F, Cahour A. Antibody responses to hepatitis C envelope proteins in patients with acute or chronic hepatitis C.  J Med Virol . 1996;  50 159-167
  • 16 Grellier L, Brown D, Power J, Dusheiko G. Absence of anti-envelope antibodies and clearance of hepatitis C virus in a cohort of Irish women infected in 1977.  J Viral Hepat . 1997;  4 379-381
  • 17 Prince A M, Brotman B, Lee D H, Ren L, Moore B S, Scheffel J W. Significance of the anti-E2 response in self-limited and chronic hepatitis C virus infections in chimpanzees and in humans.  J Infect Dis . 1999;  180 987-991
  • 18 Houghton M. Strategies and prospects for vaccination against the hepatitis C viruses.  Curr Top Microbiol Immunol . 2000;  242 327-329
  • 19 Chen M, Sallberg M, Sonnerborg A. Limited humoral immunity in hepatitis C virus infection.  Gastroenterology . 1999;  116 135-143
  • 20 Botarelli P, Brunetto M R, Minutello M A. T-lymphocyte response to hepatitis C virus in different clinical courses of infection.  Gastroenterology . 1993;  104 580-587
  • 21 Ferrari C, Valli A, Galati L. T-cell response to structural and nonstructural hepatitis C virus antigens in persistent and self-limited hepatitis C virus infections.  Hepatology . 1994;  19 286-295
  • 22 Missale G, Bertoni R, Lamonaca V. Different clinical behaviors of acute hepatitis C virus infection are associated with different vigor of the anti-viral cell-mediated immune response.  J Clin Invest . 1996;  98 706-714
  • 23 Lechmann M, Ihlenfeldt H G, Braunschweiger I. T- and B-cell responses to different hepatitis C virus antigens in patients with chronic hepatitis C infection and in healthy anti-hepatitis C virus-positive blood donors without viremia [see comments].  Hepatology . 1996;  24 790-795
  • 24 Cramp M E, Carucci P, Rossol S. Hepatitis C virus (HCV) specific immune responses in anti-HCV positive patients without hepatitis C viraemia.  Gut . 1999;  44 424-429
  • 25 Diepolder H M, Zachoval R, Hoffmann R M. Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection.  Lancet . 1995;  346 1006-1007
  • 26 Lamonaca V, Missale G, Urbani S. Conserved hepatitis C virus sequences are highly immunogenic for CD4(+) T cells: Implications for vaccine development.  Hepatology . 1999;  30 1088-1098
  • 27 Diepolder H M, Gerlach J T, Zachoval R. Immunodominant CD4+ T-cell epitope within nonstructural protein 3 in acute hepatitis C virus infection.  J Virol . 1997;  71 6011-6019
  • 28 Cramp M E, Rossol S, Chokshi S, Carucci P, Williams R, Naoumov N V. Hepatitis C virus-specific T-cell reactivity during interferon and ribavirin treatment in chronic hepatitis C.  Gastroenterology . 2000;  118 346-355
  • 29 Missale G, Cariani E, Lamonaca V. Effects of interferon treatment on the antiviral T-cell response in hepatitis C virus genotype 1b- and genotype 2c-infected patients.  Hepatology . 1997;  26 792-797
  • 30 Lasarte J J, Garcia-Granero M, Lopez A. Cellular immunity to hepatitis C virus core protein and the response to interferon in patients with chronic hepatitis C [see comments].  Hepatology . 1998;  28 815-822
  • 31 Woitas R P, Lechmann M, Jung G, Kaiser R, Sauerbruch T, Spengler U. CD30 induction and cytokine profiles in hepatitis C virus core-specific peripheral blood T lymphocytes.  J Immunol . 1997;  159 1012-1018
  • 32 Lechmann M, Woitas R P, Langhans B. Decreased frequency of HCV core-specific peripheral blood mononuclear cells with type 1 cytokine secretion in chronic hepatitis C [In Process Citation].  J Hepatol . 1999;  31 971-978
  • 33 Cerny A, McHutchison J G, Pasquinelli C. Cytotoxic T lymphocyte response to hepatitis C virus-derived peptides containing the HLA A2.1 binding motif.  J Clin Invest . 1995;  95 521-530
  • 34 Wong D K, Dudley D D, Afdhal N H. Liver-derived CTL in hepatitis C virus infection: Breadth and specificity of responses in a cohort of persons with chronic infection.  J Immunol . 1998;  160 1479-1488
  • 35 Koziel M J, Dudley D, Wong J T. Intrahepatic cytotoxic T lymphocytes specific for hepatitis C virus in persons with chronic hepatitis.  J Immunol . 1992;  149 3339-3344
  • 36 Chang K M, Gruener N H, Southwood S. Identification of HLA-A3 and -B7-restricted CTL response to hepatitis C virus in patients with acute and chronic hepatitis C.  J Immunol . 1999;  162 1156-1164
  • 37 Koziel M J, Dudley D, Afdhal N. HLA class I-restricted cytotoxic T lymphocytes specific for hepatitis C virus. Identification of multiple epitopes and characterization of patterns of cytokine release.  J Clin Invest . 1995;  96 2311-2321
  • 38 Ibe M, Sakaguchi T, Tanaka K. Identification and characterization of a cytotoxic T cell epitope of hepatitis C virus presented by HLA-B*3501 in acute hepatitis.  J Gen Virol . 1998;  79 1735-1744
  • 39 Battegay M, Fikes J, Di Bisceglie M A. Patients with chronic hepatitis C have circulating cytotoxic T cells which recognize hepatitis C virus-encoded peptides binding to HLA-A2.1 molecules.  J Virol . 1995;  69 2462-2470
  • 40 Kaneko T, Nakamura I, Kita H, Hiroishi K, Moriyama T, Imawari M. Three new cytotoxic T cell epitopes identified within the hepatitis C virus nucleoprotein.  J Gen Virol . 1996;  77 1305-1309
  • 41 Koziel M J, Dudley D, Afdhal N. Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes recognize epitopes in the core and envelope proteins of HCV.  J Virol . 1993;  67 7522-7532
  • 42 Kita H, Hiroishi K, Moriyama T. A minimal and optimal cytotoxic T cell epitope within hepatitis C virus nucleoprotein.  J Gen Virol . 1995;  76 3189-3193
  • 43 Chang K M, Rehermann B, McHutchison J G. Immunological significance of cytotoxic T lymphocyte epitope variants in patients chronically infected by the hepatitis C virus.  J Clin Invest . 1997;  100 2376-2385
  • 44 Weiner A, Erickson A L, Kansopon J. Persistent hepatitis C virus infection in a chimpanzee is associated with emergence of a cytotoxic T lymphocyte escape variant.  Proc Natl Acad Sci USA . 1995;  92 2755-2759
  • 45 Tsai S L, Chen Y M, Chen M H. Hepatitis C virus variants circumventing cytotoxic T lymphocyte activity as a mechanism of chronicity.  Gastroenterology . 1998;  115 954-965
  • 46 Hiroishi K, Kita H, Kojima M. Cytotoxic T lymphocyte response and viral load in hepatitis C virus infection.  Hepatology . 1997;  25 705-712
  • 47 Nelson D R, Marousis C G, Davis G L. The role of hepatitis C virus-specific cytotoxic T lymphocytes in chronic hepatitis C.  J Immunol . 1997;  158 1473-1481
  • 48 Rehermann B, Chang K M, McHutchinson J. Differential cytotoxic T-lymphocyte responsiveness to the hepatitis B and C viruses in chronically infected patients.  J Virol . 1996;  70 7092-7102
  • 49 Cooper S, Erickson A L, Adams E J. Analysis of a successful immune response against hepatitis C virus.  Immunity . 1999;  10 439-449
  • 50 Bjoro K, Froland S S, Yun Z, Samdal H H, Haaland T. Hepatitis C infection in patients with primary hypogammaglobulinemia after treatment with contaminated immune globulin.  N Engl J Med . 1994;  331 1607-1611
  • 51 Christie J M, Healey C J, Watson J. Clinical outcome of hypogammaglobulinaemic patients following outbreak of acute hepatitis C: 2 year follow up.  Clin Exp Immunol . 1997;  110 4-8
  • 52 Adams G, Kuntz S, Rabalais G, Bratcher D, Tamburro C H, Kotwal G J. Natural recovery from acute hepatitis C virus infection by agammaglobulinemic twin children.  Pediatr Infect Dis J . 1997;  16 533-534
  • 53 Rosa D, Campagnoli S, Moretto C. A quantitative test to estimate neutralizing antibodies to the hepatitis C virus: Cytofluorimetric assessment of envelope glycoprotein 2 binding to target cells.  Proc Natl Acad Sci USA . 1996;  93 1759-1763
  • 54 Esumi M, Ahmed M, Zhou Y H, Takahashi H, Shikata T. Murine antibodies against E2 and hypervariable region 1 cross-reactively capture hepatitis C virus.  Virology . 1998;  251 158-164
  • 55 Walter E, Keist R, Niederost B, Pult I, Blum H E. Hepatitis B virus infection of tupaia hepatocytes in vitro and in vivo.  Hepatology . 1996;  24 1-5
  • 56 Xie Z C, Riezu-Boj J I, Lasarte J J. Transmission of hepatitis C virus infection to tree shrews.  Virology . 1998;  244 513-520
  • 57 Ulmer J B, Donnelly J J, Parker S E. Heterologous protection against influenza by injection of DNA encoding a viral protein [see comments].  Science . 1993;  259 1745-1749
  • 58 Hoffman S L. Protection against malaria by immunization with a Plasmodium yoelii circumsporozoite protein nucleic acid vaccine.  Vaccine . 1994;  12 1529-1533
  • 59 Huygen K, Content J, Denis O. Immunogenicity and protective efficacy of a tuberculosis DNA vaccine.  Nat Med . 1996;  2 893-898
  • 60 Boyer J D, Ugen K E, Wang B. Protection of chimpanzees from high-dose heterologous HIV-1 challenge by DNA vaccination.  Nat Med . 1997;  3 526-532
  • 61 Vanderzanden L, Bray M, Fuller D. DNA vaccines expressing either the GP or NP genes of Ebola virus protect mice from lethal challenge.  Virology . 1998;  246 134-144
  • 62 Geissler M, Gesien A, Tokushige K, Wands J R. Enhancement of cellular and humoral immune responses to hepatitis C virus core protein using DNA-based vaccines augmented with cytokine-expressing plasmids.  J Immunol . 1997;  158 1231-1237
  • 63 Tokushige K, Wakita T, Pachuk C. Expression and immune response to hepatitis C virus core DNA-based vaccine constructs.  Hepatology . 1996;  24 14-20
  • 64 Major M E, Vitvitski L, Mink M A. DNA-based immunization with chimeric vectors for the induction of immune responses against the hepatitis C virus nucleocapsid.  J Virol . 1995;  69 5798-5805
  • 65 Hu G J, Wang R Y, Han D S, Alter H J, Shih J W. Characterization of the humoral and cellular immune responses against hepatitis C virus core induced by DNA-based immunization.  Vaccine . 1999;  17 3160-3170
  • 66 Geissler M, Tokushige K, Wakita T, Zurawski Jr R V, Wands J R. Differential cellular and humoral immune responses to HCV core and HBV envelope proteins after genetic immunizations using chimeric constructs.  Vaccine . 1998;  16 857-867
  • 67 Rice C M. Flaviviridae: The viruses and their replication. In: Fields BN, Knipe DM, Howeley PM, eds. Virology Vol. 1. 3rd ed. Philadelphia: Lippincott-Raven, 1996: 931-960
  • 68 Forns X, Emerson S U, Tobin G J, Mushahwar I K, Purcell R H, Bukh J. DNA immunization of mice and macaques with plasmids encoding hepatitis C virus envelope E2 protein expressed intracellularly and on the cell surface.  Vaccine . 1999;  17 1992-2002
  • 69 Forns X, Payette P J, Ma X Y. DNA immunization of macaques and chimpanzees with plasmids encoding hepatitis C virus (HCV) envelope E2 protein.  Hepatology . 1999;  30 769
  • 70 Lee S W, Cho J H, Sung Y C. Optimal induction of hepatitis C virus envelope-specific immunity by bicistronic plasmid DNA inoculation with the granulocyte-macrophage colony-stimulating factor gene.  J Virol . 1998;  72 8430-8436
  • 71 Song M K, Lee S W, Suh Y S, Lee K J, Sung Y C. Enhancement of immunoglobulin G2a and cytotoxic T-lymphocyte responses by a booster immunization with recombinant hepatitis C virus E2 protein in E2 DNA-primed mice.  J Virol . 2000;  74 2920-2925
  • 72 Nakano I, Maertens G, Major M E. Immunization with plasmid DNA encoding hepatitis C virus envelope E2 antigenic domains induces antibodies whose immune reactivity is linked to the injection mode.  J Virol . 1997;  71 7101-7109
  • 73 Fournillier A, Nakano I, Vitvitski L. Modulation of immune responses to hepatitis C virus envelope E2 protein following injection of plasmid DNA using single or combined delivery routes.  Hepatology . 1998;  28 237-244
  • 74 Encke J, zu Putlitz J, Geissler M, Wands J R. Genetic immunization generates cellular and humoral immune responses against the nonstructural proteins of the hepatitis C virus in a murine model.  J Immunol . 1998;  161 4917-4923
  • 75 Cho J H, Lee S W, Sung Y C. Enhanced cellular immunity to hepatitis C virus nonstructural proteins by codelivery of granulocyte macrophage-colony stimulating factor gene in intramuscular DNA immunization.  Vaccine . 1999;  17 1136-1144
  • 76 Lagging L M, Meyer K, Hoft D, Houghton M, Belshe R B, Ray R. Immune responses to plasmid DNA encoding the hepatitis C virus core protein.  J Virol . 1995;  69 5859-5863
  • 77 Lee S W, Cho J H, Lee K J, Sung Y C. Hepatitis C virus envelope DNA-based immunization elicits humoral and cellular immune responses.  Mol Cells . 1998;  8 444-451
  • 78 Inchauspe G, Vitvitski L, Major M E. Plasmid DNA expressing a secreted or a nonsecreted form of hepatitis C virus nucleocapsid: Comparative studies of antibody and T-helper responses following genetic immunization.  DNA Cell Biol . 1997;  16 185-195
  • 79 Tokushige K, Moradpour D, Wakita T, Geissler M, Hayashi N, Wands J R. Comparison between cytomegalovirus promoter and elongation factor-1 alpha promoter-driven constructs in the establishment of cell lines expressing hepatitis C virus core protein.  J Virol Methods . 1997;  64 73-80
  • 80 Arichi T, Saito T, Major M E. Prophylactic DNA vaccine for hepatitis C virus (HCV) infection: HCV-specific cytotoxic T lymphocyte induction and protection from HCV-recombinant vaccinia infection in an HLA-A2.1 transgenic mouse model.  Proc Natl Acad Sci USA . 2000;  97 297-302
  • 81 Saito T, Sherman G J, Kurokohchi K. Plasmid DNA-based immunization for hepatitis C virus structural proteins: Immune responses in mice.  Gastroenterology . 1997;  112 1321-1330
  • 82 Nishimura Y, Kamei A, Uno-Furuta S. A single immunization with a plasmid encoding hepatitis C virus (HCV) structural proteins under the elongation factor 1-alpha promoter elicits HCV-specific cytotoxic T-lymphocytes (CTL).  Vaccine . 1999;  18 675-680
  • 83 Gordon E J, Bhat R, Liu Q, Wang Y F, Tackney C, Prince A M. Immune responses to hepatitis C virus structural and nonstructural proteins induced by plasmid DNA immunizations [In Process Citation].  J Infect Dis . 2000;  181 42-50
  • 84 Kim J J, Bagarazzi M L, Trivedi N. Engineering of in vivo immune responses to DNA immunization via codelivery of costimulatory molecule genes.  Nat Biotechnol . 1997;  15 641-646
  • 85 Mendoza R B, Cantwell M J, Kipps T J. Immunostimulatory effects of a plasmid expressing CD40 ligand (CD154) on gene immunization.  J Immunol . 1997;  159 5777-5781
  • 86 Ihata A, Watabe S, Sasaki S. Immunomodulatory effect of a plasmid expressing CD40 ligand on DNA vaccination against human immunodeficiency virus type-1.  Immunology . 1999;  98 436-442
  • 87 Boyle J S, Brady J L, Lew A M. Enhanced responses to a DNA vaccine encoding a fusion antigen that is directed to sites of immune induction.  Nature . 1998;  392 408-411
  • 88 Jacobs S C, Stephenson J R, Wilkinson G W. High-level expression of the tick-borne encephalitis virus NS1 protein by using an adenovirus-based vector: Protection elicited in a murine model.  J Virol . 1992;  66 2086-2095
  • 89 Gallichan W S, Johnson D C, Graham F L, Rosenthal K L. Mucosal immunity and protection after intranasal immunization with recombinant adenovirus expressing herpes simplex virus glycoprotein B.  J Infect Dis . 1993;  168 622-629
  • 90 Fooks A R, Schadeck E, Liebert U G. High-level expression of the measles virus nucleocapsid protein by using a replication-deficient adenovirus vector: Induction of an MHC-1-restricted CTL response and protection in a murine model.  Virology . 1995;  210 456-465
  • 91 Makimura M, Miyake S, Akino N. Induction of antibodies against structural proteins of hepatitis C virus in mice using recombinant adenovirus.  Vaccine . 1996;  14 28-36
  • 92 Bruna-Romero O, Lasarte J J, Wilkinson G. Induction of cytotoxic T-cell response against hepatitis C virus structural antigens using a defective recombinant adenovirus.  Hepatology . 1997;  25 479-477
  • 93 Lasarte J J, Corrales F J, Casares N. Different doses of adenoviral vector expressing IL-12 enhance or depress the immune response to a coadministered antigen: The role of nitric oxide.  J Immunol . 1999;  162 5270-5277
  • 94 Shirai M, Okada H, Nishioka M. An epitope in hepatitis C virus core region recognized by cytotoxic T cells in mice and humans.  J Virol . 1994;  68 3334-3342
  • 95 Large M K, Kittlesen D J, Hahn Y S. Suppression of host immune responses by the core protein of hepatitis C virus: Possible implications for hepatitis C virus persistence.  J Immunol . 1999;  162 931-938
  • 96 Paoletti E, Taylor J, Meignier B, Meric C, Tartaglia J. Highly attenuated poxvirus vectors: NYVAC, ALVAC and TROVAC.  Dev Biol Stand . 1995;  84 159-163
  • 97 Moss B, Carroll M W, Wyatt L S. Host range restricted, non-replicating vaccinia virus vectors as vaccine candidates.  Adv Exp Med Biol . 1996;  397 7-13
  • 98 Davis N L, Brown K W, Johnston R E. A viral vaccine vector that expresses foreign genes in lymph nodes and protects against mucosal challenge.  J Virol . 1996;  70 3781-3787
  • 99 Frolov I, Hoffman T A, Pragai B M. Alphavirus-based expression vectors: Strategies and applications.  Proc Natl Acad Sci USA . 1996;  93 11371-11377
  • 100 Smerdou C, Liljestrom P. Two-helper RNA system for production of recombinant Semliki forest virus particles.  J Virol . 1999;  73 1092-1098
  • 101 Shata M T, Stevceva L, Agwale S, Lewis G K, Hone D M. Recent advances with recombinant bacterial vaccine vectors.  Mol Med Today . 2000;  6 66-71
  • 102 Shirai M, Chen M, Arichi T. Use of intrinsic and extrinsic helper epitopes for in vivo induction of anti-hepatitis C virus cytotoxic T lymphocytes (CTL) with CTL epitope peptide vaccines.  J Infect Dis . 1996;  173 24-31
  • 103 Hiranuma K, Tamaki S, Nishimura Y. Helper T cell determinant peptide contributes to induction of cellular immune responses by peptide vaccines against hepatitis C virus.  J Gen Virol . 1999;  80 187-193
  • 104 Oseroff C, Sette A, Wentworth P. Pools of lipidated HTL-CTL constructs prime for multiple HBV and HCV CTL epitope responses.  Vaccine . 1998;  16 823-833
  • 105 Sarobe P, Pendleton C D, Akatsuka T. Enhanced in vitro potency and in vivo immunogenicity of a CTL epitope from hepatitis C virus core protein following amino acid replacement at secondary HLA-A2.1 binding positions.  J Clin Invest . 1998;  102 1239-1248
  • 106 Esumi M, Rikihisa T, Nishimura S. Experimental vaccine activities of recombinant E1 and E2 glycoproteins and hypervariable region 1 peptides of hepatitis C virus in chimpanzees.  Arch Virol . 1999;  144 973-980
  • 107 Shang D, Zhai W, Allain J P. Broadly cross-reactive, high-affinity antibody to hypervariable region 1 of the hepatitis C virus in rabbits.  Virology . 1999;  258 396-405
  • 108 Puntoriero G, Meola A, Lahm A. Towards a solution for hepatitis C virus hypervariability: Mimotopes of the hypervariable region 1 can induce antibodies cross-reacting with a large number of viral variants.  EMBO J . 1998;  17 3521-3533
  • 109 Watanabe K, Yoshioka K, Ito H. The hypervariable region 1 protein of hepatitis C virus broadly reactive with sera of patients with chronic hepatitis C has a similar amino acid sequence with the consensus sequence [In Process Citation].  Virology . 1999;  264 153-158
  • 110 Choo Q L, Kuo G, Ralston R. Vaccination of chimpanzees against infection by the hepatitis C virus.  Proc Natl Acad Sci USA . 1994;  91 1294-1298
  • 111 Delpha E, Priem S, Verschoor E. 1332therapeutic vaccination of chronically infected chimpanzees with the HCV E1 protein.  Hepatology . 1999;  30 408A
  • 112 Christensen N D, Reed C A, Cladel N M, Han R, Kreider J W. Immunization with viruslike particles induces long-term protection of rabbits against challenge with cottontail rabbit papillomavirus.  J Virol . 1996;  70 960-965
  • 113 Roy P, Bishop D H, LeBlois H, Erasmus B J. Long-lasting protection of sheep against bluetongue challenge after vaccination with virus-like particles: Evidence for homologous and partial heterologous protection.  Vaccine . 1994;  12 805-811
  • 114 Laurent S, Vautherot J F, Madelaine M F, Le Gall G, Rasschaert D. Recombinant rabbit hemorrhagic disease virus capsid protein expressed in baculovirus self-assembles into viruslike particles and induces protection.  J Virol . 1994;  68 6794-6798
  • 115 Wagner R, Teeuwsen V J, Deml L. Cytotoxic T cells and neutralizing antibodies induced in rhesus monkeys by virus-like particle HIV vaccines in the absence of protection from SHIV infection.  Virology . 1998;  245 65-74
  • 116 Liu X S, Abdul-Jabbar I, Qi Y M, Frazer I H, Zhou J. Mucosal immunisation with papillomavirus virus-like particles elicits systemic and mucosal immunity in mice.  Virology . 1998;  252 39-45
  • 117 Rudolf M P, Nieland J D, DaSilva D M. Induction of HPV16 capsid protein-specific human T cell responses by virus-like particles.  Biol Chem . 1999;  380 335-340
  • 118 Wagner R, Deml L, Schirmbeck R, Reimann J, Wolf H. Induction of a MHC class I-restricted, CD8 positive cytolytic T-cell response by chimeric HIV-1 virus-like particles in vivo: Implications on HIV vaccine development.  Behring Inst Mitt . 1994;  95 23-34
  • 119 Baumert T F, Ito S, Wong D T, Liang T J. Hepatitis C virus structural proteins assemble into viruslike particles in insect cells.  J Virol . 1998;  72 3827-3836
  • 120 Baumert T F, Vergalla J, Satoi J. Hepatitis C Virus-like Particles Synthesized in Insect Cells as a Potential Vaccine Candidate.  Gastroenterology . 1999;  117 1397-1407
  • 121 Lechmann M, Vergalla J, Satoi J, Baumert T F, Vergalla J, Satoi J, Baumert T F, Liang T J. Induction of humoral and cellular immune responses in mice by immunization with insect-cell derived HCV-like particles.  Hepatology . 1999;  30 453A
  • 122 Krawczynski K, Alter M J, Tankersley D L. Effect of immune globulin on the prevention of experimental hepatitis C virus infection.  J Infect Dis . 1996;  173 822-828
  • 123 Krawczynski K, Fattom A, Culver D. Passive transfer of anti-HCV in chronic and acute HCV infection in chimpanzees-trials of experimental immune treatment.  Hepatology . 1999;  30 423A
  • 124 Kent S J, Zhao A, Best S J, Chandler J D, Boyle D B, Ramshaw I A. Enhanced T-cell immunogenicity and protective efficacy of a human immunodeficiency virus type 1 vaccine regimen consisting of consecutive priming with DNA and boosting with recombinant fowlpox virus.  J Virol . 1998;  72 10180-10188
  • 125 Robinson H L, Montefiori D C, Johnson R P. Neutralizing antibody-independent containment of immunodeficiency virus challenges by DNA priming and recombinant pox virus booster immunizations.  Nat Med . 1999;  5 526-534
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