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Journal of Virology, January 2008, p. 435-450, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.01505-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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

Erik Depla,1,{dagger} Annegret Van der Aa,1,{ddagger} Brian D. Livingston,2,§ Claire Crimi,2 Koen Allosery,1 Veronique De Brabandere,1 Jonathan Krakover,3 Sidharta Murthy,3 Manley Huang,4 Scott Power,4 Lilia Babé,4,¶ Carol Dahlberg,2 Denise McKinney,2 Alessandro Sette,2,|| Scott Southwood,2 Ramilla Philip,3 Mark J. Newman,2 and Lydie Meheus1*

GENimmune NV (Innogenetics NV), Ghent, Belgium,1 Pharmexa-Epimmune Inc., San Diego, California,2 Immunotope Inc., Doylestown, Pennsylvania,3 Danisco US Inc. (Genencor International Inc.), Rochester, New York4

Received 10 July 2007/ Accepted 9 October 2007

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.

* Corresponding author. Mailing address: Lydie Meheus, GENimmune NV, Industriepark Zwijnaarde 7 Box 4, 9052 Gent, Belgium. Phone: 32 9 2410711. Fax: 32 9 2410907. E-mail: lydie.meheus{at}genimmune.be

{triangledown} Published ahead of print on 17 October 2007.

{dagger} Present address: Ablynx NV, Ghent, Belgium.

{ddagger} Present address: ActoGeniX NV, Ghent, Belgium.

§ Present address: Dynavax Technologies Corp., San Francisco, CA.

Present address: Cambridge Antibody Technology Inc., Cambridge, United Kingdom.

|| Present address: La Jolla Institute for Allergy and Immunology, La Jolla, CA.

Journal of Virology, January 2008, p. 435-450, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.01505-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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