Journal of the National Cancer Institute Advance Access published online on May 26, 2009
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djp106
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© The Author 2009. Published by Oxford University Press.
ARTICLES |
Concatenated Multitype L2 Fusion Proteins as Candidate Prophylactic Pan-Human Papillomavirus Vaccines
Affiliations of authors: Department of Pathology (SJ, BK, RG, RBSR), Department of Oncology (RBSR), and Department of Obstetrics and Gynecology (RBSR), The Johns Hopkins University, Baltimore, MD; Shantha Biotechnics Ltd, Hyderabad, Andhra Pradesh, India (SVC, RJC); Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, MD (DRL, JTS)
Correspondence to: Richard B. S. Roden, PhD, Department of Pathology, The Johns Hopkins University, Rm 308, Cancer Research Bldg 2, 1550 Orleans St, Baltimore, MD 21231 (e-mail: roden{at}jhmi.edu).
Background: Vaccination with minor capsid protein L2 induces antibodies that cross-neutralize diverse papillomavirus types. However, neutralizing antibody titers against the papillomavirus type from which the L2 vaccine was derived are generally higher than the titers against heterologous types, which could limit effectiveness against heterologous types. We hypothesized that vaccination with concatenated multitype L2 fusion proteins derived from known cross-protective epitopes of several divergent human papillomavirus (HPV) types might enhance immunity across clinically relevant HPV genotypes.
Methods: Antibody responses of mice (n = 120) and rabbits (n = 23) to vaccination with HPV-16 amino-terminal L2 polypeptides or multitype L2 fusion proteins, namely, 11-200 x 3 (HPV types 6, 16, 18), 11-88 x 5 (HPV types 1, 5, 6, 16, 18), or 17-36 x 22 (five cutaneous, two mucosal low-risk, and 15 oncogenic types), that were formulated alone or in GPI-0100, alum, or 1018 ISS adjuvants were compared with vaccination with L1 virus-like particles (VLPs), including Gardasil, a licensed quadrivalent HPV L1 vaccine, and a negative control. Mice were challenged with HPV-16 pseudovirions 4 months after vaccination. Statistical tests were two-sided.
Results: The HPV-16 L2 polypeptides generated robust HPV-16–neutralizing antibody responses, albeit lower than those to HPV-16 L1 VLPs, and lower responses against other HPVs. In contrast, vaccination with the multitype L2 fusion proteins 11-200 x 3 and 11-88 x 5 induced high serum neutralizing antibody titers against all heterologous HPVs tested. 11-200 x 3 formulated in GPI-0100 adjuvant or alum with 1018 ISS protected mice against HPV-16 challenge (reduction in HPV-16 infection vs phosphate-buffered saline control, P < .001) 4 months after vaccination as well as HPV-16 L1 VLPs, but 11-200 x 3 alone or formulated with either alum or 1018 ISS was less effective (reduction in HPV-16 infection, P < .001).
Conclusion: Concatenated multitype L2 proteins in adjuvant have potential as pan-oncogenic HPV vaccines.
| CONTEXT AND CAVEATS Prior knowledge Current human papillomavirus (HPV) vaccines are based on capsid L1 proteins and appear to confer only HPV type–specific immunity. Although vaccination with minor capsid protein L2 induces antibodies that neutralize many types of papillomaviruses, the response to the specific virus type is usually higher than it is to other types. Study design Mice were vaccinated with HPV-16 L2 polypeptides, multitype L2 fusion proteins in different adjuvants, Gardasil, HPV-16 L1 virus-like particles (VLPs), or a negative control, followed by challenge with HPV-16 pseudovirions 4 months later. Contributions Vaccination with the multitype L2 fusion proteins induced antibody responses to all HPV types tested and protected mice against HPV-16 challenge as well as HPV-16 L1 VLPs. Implications Multitype L2 proteins have potential as pan-oncogenic HPV vaccines. Limitations To be effective in humans, the vaccine will need to protect against infection for several years; only short times were tested in this study. From the Editors
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R. B. S. Roden is a paid consultant of Merck & Co, Inc., and Knobbe Martens Olson & Bear LLC. S. Jagu and R. B. S. Roden have received unrestricted educational grant funding from GlaxoSmithKline. R. B. S. Roden, R. Gambhira, D. R. Lowy, and J. T. Schiller are coinventors on L2 patents licensed to Shantha Biotechnics Ltd, PaxVax, Inc., and Acambis, Inc. The terms of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies. D. R. Lowy and J. T. Schiller are inventors on US government–owned HPV VLP patents that are licensed to Merck & Co, Inc., and GlaxoSmithKline. S. V. Chivukula and R. J. Chaganti are employees of Shantha Biotechnics Ltd, which is a collaborator in the CRADA for the development of a pan-HPV vaccine with an interest in commercialization, and they hold stock in the company.
The sponsors had no role in the study design, the collection and analysis of the data, the interpretation of the results, the preparation of the manuscript, or the decision to submit the manuscript for publication. SVC and RJC of Shantha Biotechnics Ltd cloned and expressed the HPV-16 L2 proteins and performed all rabbit immunizations.
Present address: Tulane National Primate Research Center, Covington, LA (R. Gambhira).
The authors gratefully acknowledge Dynavax Technologies Corporation for providing 1018 ISS and Hawaii Biotech, Inc., for providing the GPI-0100. We also thank Martin M
ller (Deutsches Krebsforschungszentrum, Germany) for codon-modified HPV-16 L1 and L2, and Tadahito Kanda (National Institute of Infectious Diseases, Japan) for codon-modified HPV-31 and HPV-58 L1 and L2.
Manuscript received October 27, 2008; revised March 3, 2009; accepted March 31, 2009.
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