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      Concatenated Multitype L2 Fusion Proteins as Candidate Prophylactic Pan-Human Papillomavirus Vaccines

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          Abstract

          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 × 3 (HPV types 6, 16, 18), 11-88 × 5 (HPV types 1, 5, 6, 16, 18), or 17-36 × 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 × 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 × 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.

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          Most cited references52

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          Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial

          The Lancet, 369(9580), 2161-2170
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            Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial.

            Effective vaccination against HPV 16 and HPV 18 to prevent cervical cancer will require a high level of sustained protection against infection and precancerous lesions. Our aim was to assess the long-term efficacy, immunogenicity, and safety of a bivalent HPV-16/18 L1 virus-like particle AS04 vaccine against incident and persistent infection with HPV 16 and HPV 18 and their associated cytological and histological outcomes. We did a follow-up study of our multicentre, double-blind, randomised, placebo-controlled trial reported in 2004. We included women who originally received all three doses of bivalent HPV-16/18 virus-like particle AS04 vaccine (0.5 mL; n=393) or placebo (n=383). We assessed HPV DNA, using cervical samples, and did yearly cervical cytology assessments. We also studied the long-term immunogenicity and safety of the vaccine. More than 98% seropositivity was maintained for HPV-16/18 antibodies during the extended follow-up phase. We noted significant vaccine efficacy against HPV-16 and HPV-18 endpoints: incident infection, 96.9% (95% CI 81.3-99.9); persistent infection: 6 month definition, 94.3 (63.2-99.9); 12 month definition, 100% (33.6-100). In a combined analysis of the initial efficacy and extended follow-up studies, vaccine efficacy of 100% (42.4-100) against cervical intraepithelial neoplasia (CIN) lesions associated with vaccine types. We noted broad protection against cytohistological outcomes beyond that anticipated for HPV 16/18 and protection against incident infection with HPV 45 and HPV 31. The vaccine has a good long-term safety profile. Up to 4.5 years, the HPV-16/18 L1 virus-like particle AS04 vaccine is highly immunogenic and safe, and induces a high degree of protection against HPV-16/18 infection and associated cervical lesions. There is also evidence of cross protection.
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              Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial

              Vaccination against the most common oncogenic human papillomavirus (HPV) types, HPV-16 and HPV-18, could prevent development of up to 70% of cervical cancers worldwide. We did a randomised, double-blind, controlled trial to assess the efficacy, safety, and immunogenicity of a bivalent HPV-16/18 L1 virus-like particle vaccine for the prevention of incident and persistent infection with these two virus types, associated cervical cytological abnormalities, and precancerous lesions. We randomised 1113 women between 15-25 years of age to receive three doses of either the vaccine formulated with AS04 adjuvant or placebo on a 0 month, 1 month, and 6 month schedule in North America and Brazil. Women were assessed for HPV infection by cervical cytology and self-obtained cervicovaginal samples for up to 27 months, and for vaccine safety and immunogenicity. In the according-to-protocol analyses, vaccine efficacy was 91.6% (95% CI 64.5-98.0) against incident infection and 100% against persistent infection (47.0-100) with HPV-16/18. In the intention-to-treat analyses, vaccine efficacy was 95.1% (63.5-99.3) against persistent cervical infection with HPV-16/18 and 92.9% (70.0-98.3) against cytological abnormalities associated with HPV-16/18 infection. The vaccine was generally safe, well tolerated, and highly immunogenic. The bivalent HPV vaccine was efficacious in prevention of incident and persistent cervical infections with HPV-16 and HPV-18, and associated cytological abnormalities and lesions. Vaccination against such infections could substantially reduce incidence of cervical cancer.
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                Author and article information

                Journal
                J Natl Cancer Inst
                jnci
                jnci
                JNCI Journal of the National Cancer Institute
                Oxford University Press
                0027-8874
                1460-2105
                2 June 2009
                2 June 2009
                2 June 2009
                2 June 2009
                : 101
                : 11
                : 782-792
                Affiliations
                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)
                Author notes
                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@ 123456jhmi.edu ).

                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 Műller (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.

                Article
                10.1093/jnci/djp106
                2689872
                19470949
                54e1a4a5-bc94-4170-a586-aa69641d6866
                © 2009 The Author(s).

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.0/uk/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 October 2008
                : 3 March 2009
                : 31 March 2009
                Categories
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                Oncology & Radiotherapy
                Oncology & Radiotherapy

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