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Journal of Virology, October 2009, p. 10085-10095, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.01088-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Chimeric L1-L2 Virus-Like Particles as Potential Broad-Spectrum Human Papillomavirus Vaccines{triangledown}

Christina Schellenbacher,1 Richard Roden,2 and Reinhard Kirnbauer1*

Laboratory of Viral Oncology (LVO), Division of Immunology, Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University Vienna (MUW), Austria,1 Department of Pathology, Johns Hopkins University, Baltimore, Maryland2

Received 28 May 2009/ Accepted 16 July 2009

The amino (N) terminus of the human papillomavirus (HPV) minor capsid protein L2 can induce low-titer, cross-neutralizing antibodies. The aim of this study was to improve immunogenicity of L2 peptides by surface display on highly ordered, self-assembled virus-like particles (VLP) of major capsid protein L1, and to more completely characterize neutralization epitopes of L2. Overlapping peptides comprising amino acids (aa) 2 to 22 (hereafter, chimera or peptide 2-22), 13 to 107, 18 to 31, 17 to 36, 35 to 75, 75 to 112, 115 to 154, 149 to 175, and 172 to 200 of HPV type 16 (HPV16) L2 were genetically engineered into the DE surface loop of bovine papillomavirus type 1 L1 VLP. Except for chimeras 35-75 and 13-107, recombinant fusion proteins assembled into VLP. Vaccination of rabbits with Freund's adjuvanted native VLP induced higher L2-specific antibody titers than vaccination with corresponding sodium dodecyl sulfate-denatured proteins. Immune sera to epitopes within residues 13 to 154 neutralized HPV16 in pseudovirion neutralization assays, whereas chimera 17-36 induced additional cross-neutralization to divergent high-risk HPV18, -31, -45, -52, and -58; low-risk HPV11; and beta-type HPV5 (titers of 50 to 10,000). Aluminum hydroxide-monophosphoryl lipid A (Alum-MPL)-adjuvanted VLP induced similar patterns of neutralization in both rabbits and mice, albeit with 100-fold-lower titers than Freund's adjuvant. Importantly, Alum-MPL-adjuvanted immunization with chimeric HPV16L1-HPV16L2 (peptide 17-36) VLP induced neutralization or cross-neutralization of HPV16, -18, -31, -45, -52, and -58; HPV6 and -11; and HPV5 (titers of 50 to 100,000). Immunization with HPV16 L1-HPV16 L2 (chimera 17-36) VLP in adjuvant applicable for human use induces broad-spectrum neutralizing antibodies against HPV types evolutionarily divergent to HPV16 and thus may protect against infection with mucosal high-risk, low-risk, and beta HPV types and associated disease.

* Corresponding author. Mailing address: Department of Dermatology, DIAID. Medical University Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Phone: 43-1-40400-7768. Fax: 43-1-403 0224. E-mail: reinhard.kirnbauer{at}meduniwien.ac.at

{triangledown} Published ahead of print on 29 July 2009.

Journal of Virology, October 2009, p. 10085-10095, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.01088-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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