Protection against heterologous human papillomavirus challenge by a synthetic lipopeptide vaccine containing a broadly cross-neutralizing epitope of L2

doi:10.1073/pnas.0800868105

Protection against heterologous human papillomavirus challenge by a synthetic lipopeptide vaccine containing a broadly cross-neutralizing epitope of L2

Departments of *Pathology
^‖Oncology Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, MD 21231;
^‡National Cancer Institute, Bethesda, MD 20892;
^§Department of Microbiology and Immunology, University of Melbourne, Parkville 3010, Victoria, Australia; and
^¶VacTX Pty. Ltd., Level 10 (South), 459 Collins Street, Melbourne 3000, Victoria, Australia

Edited by Peter M. HowleyHarvard Medical SchoolBostonMA approved March 6, 2008 (received for review January 28, 2008)

Abstract

Persistent infection with the high-risk subset of genitotropic human papillomavirus (HPV) genotypes is a necessary cause of cervical cancer. Given the global burden of cervical cancer, a low-cost, broadly protective vaccine is needed. RG-1 is a cross-neutralizing and protective monoclonal antibody that recognizes residues 17–36 of HPV16 minor capsid protein L2. Because this epitope is highly conserved in divergent HPV types, we determined whether vaccination with HPV16 L2 17–36 peptide is broadly protective. The peptide was administered to BALB/c mice three times at monthly intervals, either alone or in the context of a synthetic lipopeptide vaccine candidate (P25-P2C-HPV) produced by linkage of the HPV peptide with a broadly recognized T helper epitope (P25) and the Toll-like receptor-2 (TLR2) ligand dipalmitoyl-S-glyceryl cysteine (P2C). In contrast to vaccination with the L2 17–36 peptide or P25-P2C alone, a potent L2-specific antibody response was generated to the P25-P2C-HPV lipopeptide when delivered either s.c. or intranasally. Sera from mice vaccinated with the P25-P2C-HPV lipopeptide neutralized not only HPV16 pseudovirions but also other evolutionarily divergent oncogenic genital (HPV18, HPV45) and cutaneous (HPV5, BPV1) types. The L2-specific antibody response depended on MHC class II, CD40, and MyD88 signaling. Additionally, vaccination with the P25-P2C-HPV lipopeptide protected mice from homologous challenge with HPV16 pseudovirions at cutaneous and genital sites and heterologous challenge with HPV45 pseudovirions. If provided in the appropriate context, therefore, HPV16 L2 17–36 might be used in a totally synthetic cross-protective HPV vaccine.

Footnotes

**To whom correspondence should be addressed. E-mail: roden{at}jhmi.edu
Author contributions: H.H.A. and R.G. contributed equally to this work; H.H.A., R.G., J.T.S., D.C.J., and R.B.S.R. designed research; H.H.A., R.G., B.K., J.N.R., S.J., and W.Z. performed research; J.N.R., J.T.S., W.Z., and D.C.J. contributed new reagents/analytic tools; H.H.A., R.G., B.K., and J.N.R. analyzed data; and H.H.A., J.T.S., D.C.J., and R.B.S.R. wrote the paper.
↵ ^†Present address: Division of Bacteriology and Parasitology, Tulane National Primate Research Center, 18703 Three Rivers Road, B-209, Covington, LA 70433.
Conflict of interest statement: R.B.S.R. is a paid consultant of Knobbe, Martens, Olson, and Bear LLC. Under a licensing agreement among PaxVax Inc. and Acambis, the National Cancer Institute, and Johns Hopkins University, R.G. and R.B.S.R. are entitled to a share of royalty received on the sales of products described in this article. The terms of this arrangement are being managed by Johns Hopkins University in accordance with its conflict of interest policies.
This article is a PNAS Direct Submission.
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