Rational Design of a Multiepitope Vaccine Encoding T-Lymphocyte Epitopes for Treatment of Chronic Hepatitis B Virus Infections

@article{citeulike:2134453, abstract = {Protein sequences from multiple hepatitis B virus (HBV) isolates were analyzed for the presence of amino acid motifs characteristic of cytotoxic T-lymphocyte (CTL) and helper T-lymphocyte (HTL) epitopes with the goal of identifying conserved epitopes suitable for use in a therapeutic vaccine. Specifically, sequences bearing HLA-A1, -A2, -A3, -A24, -B7, and -DR supertype binding motifs were identified, synthesized as peptides, and tested for binding to soluble HLA. The immunogenicity of peptides that bound with moderate to high affinity subsequently was assessed using HLA transgenic mice (CTL) and HLA cross-reacting H-2bxd (BALB/c x C57BL/6J) mice (HTL). Through this process, 30 CTL and 16 HTL epitopes were selected as a set that would be the most useful for vaccine design, based on epitope conservation among HBV sequences and HLA-based predicted population coverage in diverse ethnic groups. A plasmid DNA-based vaccine encoding the epitopes as a single gene product, with each epitope separated by spacer residues to enhance appropriate epitope processing, was designed. Immunogenicity testing in mice demonstrated the induction of multiple CTL and HTL responses. Furthermore, as a complementary approach, mass spectrometry allowed the identification of correctly processed and major histocompatibility complex-presented epitopes from human cells transfected with the DNA plasmid. A heterologous prime-boost immunization with the plasmid DNA and a recombinant MVA gave further enhancement of the immune responses. Thus, a multiepitope therapeutic vaccine candidate capable of stimulating those cellular immune responses thought to be essential for controlling and clearing HBV infection was successfully designed and evaluated in vitro and in HLA transgenic mice. 10.1128/JVI.01505-07}, author = {Depla, Erik and Van der Aa, Annegret and Livingston, Brian D. and Crimi, Claire and Allosery, Koen and De Brabandere, Veronique and Krakover, Jonathan and Murthy, Sidharta and Huang, Manley and Power, Scott and Babe, Lilia and Dahlberg, Carol and Mckinney, Denise and Sette, Alessandro and Southwood, Scott and Philip, Ramilla and Newman, Mark J. and Meheus, Lydie }, citeulike-article-id = {2134453}, doi = {10.1128/JVI.01505-07}, journal = {J. Virol.}, keywords = {b, epitope, hepatitis, t-lymphocyte, vaccine, virus}, month = {January}, number = {1}, pages = {435--450}, posted-at = {2007-12-17 02:01:04}, priority = {5}, title = {Rational Design of a Multiepitope Vaccine Encoding T-Lymphocyte Epitopes for Treatment of Chronic Hepatitis B Virus Infections}, url = {http://dx.doi.org/10.1128/JVI.01505-07}, volume = {82}, year = {2008} }

TY - JOUR ID - citeulike:2134453 L3 - citeulike-article-id:2134453 TI - Rational Design of a Multiepitope Vaccine Encoding T-Lymphocyte Epitopes for Treatment of Chronic Hepatitis B Virus Infections JF - J. Virol. VL - 82 IS - 1 SP - 435 EP - 450 N2 - Protein sequences from multiple hepatitis B virus (HBV) isolates were analyzed for the presence of amino acid motifs characteristic of cytotoxic T-lymphocyte (CTL) and helper T-lymphocyte (HTL) epitopes with the goal of identifying conserved epitopes suitable for use in a therapeutic vaccine. Specifically, sequences bearing HLA-A1, -A2, -A3, -A24, -B7, and -DR supertype binding motifs were identified, synthesized as peptides, and tested for binding to soluble HLA. The immunogenicity of peptides that bound with moderate to high affinity subsequently was assessed using HLA transgenic mice (CTL) and HLA cross-reacting H-2bxd (BALB/c x C57BL/6J) mice (HTL). Through this process, 30 CTL and 16 HTL epitopes were selected as a set that would be the most useful for vaccine design, based on epitope conservation among HBV sequences and HLA-based predicted population coverage in diverse ethnic groups. A plasmid DNA-based vaccine encoding the epitopes as a single gene product, with each epitope separated by spacer residues to enhance appropriate epitope processing, was designed. Immunogenicity testing in mice demonstrated the induction of multiple CTL and HTL responses. Furthermore, as a complementary approach, mass spectrometry allowed the identification of correctly processed and major histocompatibility complex-presented epitopes from human cells transfected with the DNA plasmid. A heterologous prime-boost immunization with the plasmid DNA and a recombinant MVA gave further enhancement of the immune responses. Thus, a multiepitope therapeutic vaccine candidate capable of stimulating those cellular immune responses thought to be essential for controlling and clearing HBV infection was successfully designed and evaluated in vitro and in HLA transgenic mice. 10.1128/JVI.01505-07 KW - b KW - epitope KW - hepatitis KW - t-lymphocyte KW - vaccine KW - virus AU - Depla, Erik AU - Van der Aa, Annegret AU - Livingston, Brian AU - Crimi, Claire AU - Allosery, Koen AU - De Brabandere, Veronique AU - Krakover, Jonathan AU - Murthy, Sidharta AU - Huang, Manley AU - Power, Scott AU - Babe, Lilia AU - Dahlberg, Carol AU - Mckinney, Denise AU - Sette, Alessandro AU - Southwood, Scott AU - Philip, Ramilla AU - Newman, Mark AU - Meheus, Lydie PY - 2008/01/01/ UR - http://dx.doi.org/10.1128/JVI.01505-07 ER -