Characterization of sequence variations in immunodominant regions of the HBV-nucleocapsid protein as a prerequisite for the development of an epitope-based vaccine.
OBJECTIVE
In hepatitis B virus infection, viral elimination is dependent on an efficient antiviral T cell response which is not detectable in chronic hepatitis B. Therefore, new therapeutic concepts focus on T cell activation, such as epitope-based T cell-targeted vaccines. However, with the development of peptide-based vaccines in mind, viral mutations frequently described in hepatitis B within known immunodominant helper epitopes may have an influence on peptide selection.


METHODS
Mutant peptides within immunodominant epitopes (aa 1-20, aa 91-105, and aa 143-157) at position 12, 14, 93, 97, 147, 151, 153, and 155 were tested with peripheral blood mononuclear and specific clone cells for their ability to induce proliferation, produce cytokines, induce T cell receptor down-regulation or antagonize wild-type activity of the hepatitis B core antigen-specific CD4+ T cell clones.


RESULTS
Five variants could not induce T cell proliferation or cytokine production when the variants were presented alone. Coincubation with wild-type epitopes leads to T cell activation showing that the variants do not act as T cell receptor antagonists for hepatitis B virus-specific CD4+ T cells. In contrast, five other variants and wild-type peptides stimulated CD4+ T cell proliferation and production of Th1 cytokines.


CONCLUSIONS
Our data demonstrate that frequently occurring mutations within immunodominant epitopes have rather a nonstimulatory than a strengthening effect and thus should not included in a vaccine.
Gruener
Norbert H
NH
Department of Internal Medicine II, Klinikum Grosshadern, University of Munich, Marchioninistrasse 15, 81377 Munich, Germany.
Gerlach
Tilman J
TJ
Ulsenheimer
Axel
A
Diepolder
Helmut M
HM
Wierenga
Eddy
E
Zachoval
Reinhart
R
Heeg
Malte
M
Pape
Gerd Rudolf
GR
Jung
Maria-Christina
MC
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002999:Clone Cells; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D000939:Epitopes / Q000276:immunology*; D005434:Flow Cytometry; D006509:Hepatitis B / Q000473:pathology; D006514:Hepatitis B Surface Antigens / Q000235:genetics; D017325:Hepatitis B Vaccines / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009154:Mutation / Q000235:genetics / Q000502:physiology; D019590:Nucleocapsid Proteins / Q000235:genetics* / Q000276:immunology* / Q000494:pharmacology; D010455:Peptides / Q000235:genetics / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000235:genetics
D016207:Cytokines; D000939:Epitopes; D006514:Hepatitis B Surface Antigens; D017325:Hepatitis B Vaccines; D019590:Nucleocapsid Proteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell