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J. Biol. Chem., Vol. 281, Issue 25, 17474-17481, June 23, 2006

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Hepatitis B Virus Capsid-like Particles Can Display the Complete, Dimeric Outer Surface Protein C and Stimulate Production of Protective Antibody Responses against Borrelia burgdorferi Infection^*

Claudia Skamel, Martin Ploss, Bettina Böttcher, Thomas Stehle^¶, Reinhard Wallich^||, Markus M. Simon^¶, and Michael Nassal¹

From the University Hospital Freiburg, Internal Medicine II/Molecular Biology, D-79106 Freiburg, Germany, European Molecular Biology Laboratory, D-69117 Heidelberg, Germany, ^¶Max Planck Institute of Immunobiology, D-79108 Freiburg, Germany, and ^||University Hospital Heidelberg, Institute of Immunology, D-61920 Heidelberg, Germany

Hepatitis B virus capsid-like particles (CLPs), icosahedral assemblies formed by 90 or 120 core protein dimers, hold promise as immune-enhancing vaccine carriers for heterologous antigens. Insertions into the immunodominant c/e1 B cell epitope, a surface-exposed loop, are especially immunogenic. However, display of whole proteins, desirable to induce multispecific and possibly neutralizing antibody responses, can be restrained by an unsuitable structure of the foreign protein and by its propensity to undergo homomeric interactions. Here we analyzed CLP formation by core fusions with two distinct variants of the dimeric outer surface lipoprotein C (OspC) of the Lyme disease agent Borrelia burgdorferi. Although the topology of the termini in the OspC dimer does not match that of the insertion sites in the carrier dimer, both fusions, coreOspC_a and coreOspC_b, efficiently formed stable CLPs. Electron cryomicroscopy clearly revealed the surface disposition of the OspC domains, possibly with OspC dimerization occurring across different core protein dimers. In mice, both CLP preparations induced high-titered antibody responses against the homologous OspC variant, but with substantial cross-reactivity against the other variant. Importantly, both conferred protection to mice challenged with B. burgdorferi. These data show the principal applicability of hepatitis B virus CLPs for the display of dimeric proteins, demonstrate the presence in OspC of hitherto uncharacterized epitopes, and suggest that OspC, despite its genetic variability, may be a valid vaccine candidate.

Received for publication, December 21, 2005 , and in revised form, April 12, 2006.

^* This work was supported by the Deutsche Forschungsgemeinschaft through the Priority Programme 1089, Novel Vaccination Strategies. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental text and supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: University Hospital Freiburg, Internal Medicine II/Molecular Biology, Hugstetter Strasse 55, D-79106 Freiburg, Germany. Tel. and Fax: 49-761-270-3507; E-mail: nassal2{at}ukl.uni-freiburg.de.

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