Developing vaccines against minor capsid antigen L2 to prevent papillomavirus infection

A subset of human papillomavirus (HPV) genotypes is responsible for ∼5% of all cancer deaths globally, and uterine cervical carcinoma accounts for the majority of these cases. The impact of HPV is greatest for women who do not have access to effective secondary preventive measures, and consequently over 80% of cervical cancer deaths worldwide occur in developing nations. The understanding that persistent infection by this ‘oncogenic’ subset of HPV genotypes is necessary for the development of cervical carcinoma has driven the development of preventive vaccines. Two preventive vaccines comprising recombinant HPV L1 virus‐like particles (VLPs) have been licensed. However, the current cost of these vaccines precludes sustained global delivery, and they target only two of the ∼15 known oncogenic HPV types, although ∼70% of cervical cancer cases are attributed to these two types and there is evidence for some degree of cross‐protection against other closely related types. A possible approach to broader immunity at lower cost is to consider vaccination against L2. L2 vaccines can be produced inexpensively and they also have the promise of conferring much broader cross‐type protective immunity than that observed with L1 VLP immunization. However, L2 vaccine development lags behind L1 VLP vaccines and several technical hurdles remain.

[1]  D. Lowy,et al.  Neutralization of Human Papillomavirus with Monoclonal Antibodies Reveals Different Mechanisms of Inhibition , 2007, Journal of Virology.

[2]  P. Lenz,et al.  Papillomavirus-Like Particles Induce Acute Activation of Dendritic Cells1 , 2001, The Journal of Immunology.

[3]  R. Zinkernagel,et al.  Neutralizing antiviral B cell responses. , 1997, Annual review of immunology.

[4]  D. Lowy,et al.  In vitro generation and type-specific neutralization of a human papillomavirus type 16 virion pseudotype , 1996, Journal of virology.

[5]  C. Meijer,et al.  Randomized controlled trial of an adjuvanted human papillomavirus (HPV) type 6 L2E7 vaccine: infection of external anogenital warts with multiple HPV types and failure of therapeutic vaccination. , 2005, The Journal of infectious diseases.

[6]  W. White,et al.  A Phase 1 study of a recombinant viruslike particle vaccine against human papillomavirus type 11 in healthy adult volunteers. , 2001, The Journal of infectious diseases.

[7]  C. Wheeler,et al.  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 , 2006, The Lancet.

[8]  M. Rudolf,et al.  Induction of HPV16 Capsid Protein-Specific Human T Cell Responses by Virus-Like Particles , 1999, Biological chemistry.

[9]  Luise Florin,et al.  Dissection of human papillomavirus type 33 L2 domains involved in nuclear domains (ND) 10 homing and reorganization. , 2003, Virology.

[10]  R. Roden,et al.  Vaccination to prevent and treat cervical cancer. , 2004, Human pathology.

[11]  N. Christensen,et al.  Immunological analyses of human papillomavirus capsids. , 2001, Vaccine.

[12]  V. Moreno,et al.  Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. , 1995, Journal of the National Cancer Institute.

[13]  N. Christensen,et al.  Protective Immunity to Rabbit Oral and Cutaneous Papillomaviruses by Immunization with Short Peptides of L2, the Minor Capsid Protein , 2002, Journal of Virology.

[14]  Darren W. Henderson,et al.  Neutralization of bovine papillomavirus by antibodies to L1 and L2 capsid proteins , 1994, Journal of virology.

[15]  R. Roden,et al.  Protection against heterologous human papillomavirus challenge by a synthetic lipopeptide vaccine containing a broadly cross-neutralizing epitope of L2 , 2008, Proceedings of the National Academy of Sciences.

[16]  I. Frazer,et al.  HPV6b virus like particles are potent immunogens without adjuvant in man. , 2000, Vaccine.

[17]  I. Bossis,et al.  A Protective and Broadly Cross-Neutralizing Epitope of Human Papillomavirus L2 , 2007, Journal of Virology.

[18]  D. Lowy,et al.  Efficient Intracellular Assembly of Papillomaviral Vectors , 2004, Journal of Virology.

[19]  R. Zinkernagel,et al.  The influence of antigen organization on B cell responsiveness. , 1993, Science.

[20]  R. Roden,et al.  Cell Surface-Binding Motifs of L2 That Facilitate Papillomavirus Infection , 2003, Journal of Virology.

[21]  F. Bray,et al.  Chapter 2: The burden of HPV-related cancers. , 2006, Vaccine.

[22]  G. Grindlay,et al.  A peptide encoding a B-cell epitope from the N-terminus of the capsid protein L2 of bovine papillomavirus-4 prevents disease. , 1997, Virology.

[23]  M. Stanley.  Immunology of Human Papillomaviruses , 2012, Springer US.

[24]  D. Lowy,et al.  Cross-neutralization of cutaneous and mucosal Papillomavirus types with anti-sera to the amino terminus of L2. , 2005, Virology.

[25]  R. Roden,et al.  How will HPV vaccines affect cervical cancer? , 2006, Nature Reviews Cancer.

[26]  R. Roden,et al.  Interaction of L2 with β-Actin Directs Intracellular Transport of Papillomavirus and Infection* , 2003, The Journal of Biological Chemistry.

[27]  Y. Taketani,et al.  Common Neutralization Epitope in Minor Capsid Protein L2 of Human Papillomavirus Types 16 and 6 , 1999, Journal of Virology.

[28]  R. Roden,et al.  A papillomavirus-like particle (VLP) vaccine displaying HPV16 L2 epitopes induces cross-neutralizing antibodies to HPV11. , 2007, Vaccine.

[29]  D. Burton.  Antibodies, viruses and vaccines , 2002, Nature Reviews Immunology.

[30]  D. Lowy,et al.  Interaction of papillomaviruses with the cell surface , 1994, Journal of virology.

[31]  Daron G Ferris,et al.  Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. , 2007, The New England journal of medicine.

[32]  R. Roden,et al.  Immunopathology and Infectious Diseases Expression Pattern and Subcellular Localization of Human Papillomavirus Minor Capsid Protein L 2 , 2008 .

[33]  C. Wheeler,et al.  A controlled trial of a human papillomavirus type 16 vaccine. , 2002, The New England journal of medicine.

[34]  M Aguet,et al.  The role of antibody concentration and avidity in antiviral protection. , 1997, Science.

[35]  V. Laniosz,et al.  Bovine Papillomavirus Type 1 Infection Is Mediated by SNARE Syntaxin 18 , 2007, Journal of Virology.

[36]  G. Grindlay,et al.  Prophylactic and therapeutic vaccination against a mucosal papillomavirus. , 1993, The Journal of general virology.

[37]  P. Lenz,et al.  Interaction of papillomavirus virus-like particles with human myeloid antigen-presenting cells. , 2003, Clinical immunology.

[38]  P. Howley,et al.  Role of the human papillomaviruses in human cancer. , 1991, Cancer research.

[39]  Benes L. Trus,et al.  Novel structural features of bovine papillomavirus capsid revealed by a three-dimensional reconstruction to 9 Å resolution , 1997, Nature Structural Biology.

[40]  W W Newcomb,et al.  Conserved features in papillomavirus and polyomavirus capsids. , 1996, Journal of molecular biology.

[41]  D. Lowy,et al.  Assessment of the serological relatedness of genital human papillomaviruses by hemagglutination inhibition , 1996, Journal of virology.

[42]  M. Schiffman.  Integration of human papillomavirus vaccination, cytology, and human papillomavirus testing , 2007, Cancer.

[43]  D. Lowy,et al.  Concatenated Multitype L2 Fusion Proteins as Candidate Prophylactic Pan-Human Papillomavirus Vaccines , 2009, Journal of the National Cancer Institute.

[44]  Cosette M Wheeler,et al.  Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. , 2005, The Lancet. Oncology.

[45]  D. Lowy,et al.  Immune responses induced by lower airway mucosal immunisation with a human papillomavirus type 16 virus-like particle vaccine. , 2005, Vaccine.

[46]  F. X. Bosch,et al.  Epidemiologic classification of human papillomavirus types associated with cervical cancer. , 2003, The New England journal of medicine.

[47]  W. White,et al.  In Vitro Infection and Type-Restricted Antibody-Mediated Neutralization of Authentic Human Papillomavirus Type 16 , 1998, Journal of Virology.

[48]  B. Trus,et al.  Two antibodies that neutralize papillomavirus by different mechanisms show distinct binding patterns at 13 A resolution. , 1998, Journal of molecular biology.

[49]  Claude Fauquet,et al.  Classification of papillomaviruses. , 2004, Virology.

[50]  M. Hagensee,et al.  Three-dimensional structure of vaccinia virus-produced human papillomavirus type 1 capsids , 1994, Journal of virology.

[51]  S. Franceschi,et al.  Human papillomavirus type distribution in invasive cervical cancer and high‐grade cervical lesions: A meta‐analysis update , 2007, International journal of cancer.

[52]  Rolf M. Zinkernagel,et al.  Antiviral antibody responses: the two extremes of a wide spectrum , 2006, Nature Reviews Immunology.

[53]  H. Hausen.  Papillomaviruses and cancer: from basic studies to clinical application , 2002, Nature Reviews Cancer.

[54]  R. Karron,et al.  Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. , 2001, Journal of the National Cancer Institute.

[55]  G. Grindlay,et al.  Vaccination of Cattle with L2 Protein Prevents BPV-4 Infection , 1994 .

[56]  P. Choyke,et al.  Genital transmission of HPV in a mouse model is potentiated by nonoxynol-9 and inhibited by carrageenan , 2007, Nature Medicine.

[57]  A. Benko,et al.  Protection of rabbits against cutaneous papillomavirus infection using recombinant tobacco mosaic virus containing L2 capsid epitopes. , 2006, Vaccine.

[58]  Y. Taketani,et al.  Safety and immunogenicity of a peptide containing the cross-neutralization epitope of HPV16 L2 administered nasally in healthy volunteers. , 2003, Vaccine.

[59]  D. Lowy,et al.  Papillomaviruses and cervical cancer: pathogenesis and vaccine development. , 1998, Journal of the National Cancer Institute. Monographs.

[60]  G. Grindlay,et al.  Vaccination of cattle with bovine papillomavirus type 4 L2 elicits the production of virus-neutralizing antibodies. , 1996, The Journal of general virology.

[61]  H. Kitchener,et al.  Effect of TA-CIN (HPV 16 L2E6E7) booster immunisation in vulval intraepithelial neoplasia patients previously vaccinated with TA-HPV (vaccinia virus encoding HPV 16/18 E6E7). , 2004, Vaccine.

[62]  W. Bornmann,et al.  A preclinical study comparing approaches for augmenting the immunogenicity of a heptavalent KLH-conjugate vaccine against epithelial cancers , 2003, Cancer Immunology, Immunotherapy.

[63]  C. Croce,et al.  Papillomavirus sequences integrate near cellular oncogenes in some cervical carcinomas. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[64]  N. Christensen,et al.  The open reading frame L2 of cottontail rabbit papillomavirus contains antibody-inducing neutralizing epitopes. , 1991, Virology.

[65]  J. Moroianu,et al.  The L2 Minor Capsid Protein of Human Papillomavirus Type 16 Interacts with a Network of Nuclear Import Receptors , 2004, Journal of Virology.

[66]  P. Stern,et al.  Vaccination of healthy volunteers with human papillomavirus type 16 L2E7E6 fusion protein induces serum antibody that neutralizes across papillomavirus species. , 2006, Cancer research.

[67]  Wolfgang Mayer,et al.  Structure and transcription of human papillomavirus sequences in cervical carcinoma cells , 1985, Nature.

[68]  A. Hildesheim,et al.  Evaluation of systemic and mucosal anti-HPV16 and anti-HPV18 antibody responses from vaccinated women. , 2008, Vaccine.

[69]  M. Lehtinen,et al.  Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus-like particle (VLP) vaccine. , 2007, Vaccine.

[70]  W. Liu,et al.  Sequence close to the N-terminus of L2 protein is displayed on the surface of bovine papillomavirus type 1 virions. , 1997, Virology.

[71]  E. Rybicki,et al.  Therapeutic immunisation of rabbits with cottontail rabbit papillomavirus (CRPV) virus-like particles (VLP) induces regression of established papillomas , 2008, Virology Journal.

[72]  N. Dimmock.  Neutralization of Animal Viruses , 1993, Current Topics in Microbiology and Immunology.

[73]  C. Wheeler,et al.  Effi cacy of a prophylactic adjuvanted bivalent L 1 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 , 2007 .

[74]  I. Bossis,et al.  Interaction of tSNARE Syntaxin 18 with the Papillomavirus Minor Capsid Protein Mediates Infection , 2005, Journal of Virology.

[75]  D. Hall,et al.  Electron microscopy and three-dimensional image reconstruction. , 1995, Methods in cell biology.

[76]  D. Lowy,et al.  Characterization of a human papillomavirus type 16 variant-dependent neutralizing epitope , 1997, Journal of virology.

[77]  R. Roden,et al.  Expression pattern and subcellular localization of human papillomavirus minor capsid protein L2. , 2009, The American journal of pathology.

[78]  A. Purcell,et al.  The central role played by peptides in the immune response and the design of peptide-based vaccines against infectious diseases and cancer. , 2002, Current drug targets.

[79]  R. Schlegel,et al.  Systemic immunization with papillomavirus L1 protein completely prevents the development of viral mucosal papillomas. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[80]  D. Lowy,et al.  Virus-like particles of bovine papillomavirus type 4 in prophylactic and therapeutic immunization. , 1996, Virology.

[81]  D. Lowy,et al.  HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes. , 1989, The EMBO journal.

[82]  D. Lowy,et al.  Cleavage of the papillomavirus minor capsid protein, L2, at a furin consensus site is necessary for infection , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[83]  G. Grindlay,et al.  Studies on vaccination against papillomaviruses: prophylactic and therapeutic vaccination with recombinant structural proteins. , 1991, Virology.

[84]  D. Lowy,et al.  Mechanisms of Human Papillomavirus Type 16 Neutralization by L2 Cross-Neutralizing and L1 Type-Specific Antibodies , 2008, Journal of Virology.

[85]  H. Kitchener,et al.  Prime‐boost vaccination strategy in women with high‐grade, noncervical anogenital intraepithelial neoplasia: clinical results from a multicenter phase II trial , 2006, International journal of gynecological cancer : official journal of the International Gynecological Cancer Society.

[86]  Luise Florin,et al.  Identification of a Dynein Interacting Domain in the Papillomavirus Minor Capsid Protein L2 , 2006, Journal of Virology.

[87]  S. Szu,et al.  Perspective: hypothesis: serum IgG antibody is sufficient to confer protection against infectious diseases by inactivating the inoculum. , 1995, The Journal of infectious diseases.

[88]  D. Lowy,et al.  Positively Charged Termini of the L2 Minor Capsid Protein Are Necessary for Papillomavirus Infection , 2001, Journal of Virology.

[89]  S. H. van der Burg,et al.  Immunological Responses in Women with Human Papillomavirus Type 16 (HPV-16)-Associated Anogenital Intraepithelial Neoplasia Induced by Heterologous Prime-Boost HPV-16 Oncogene Vaccination , 2004, Clinical Cancer Research.

[90]  I. Frazer,et al.  Interaction of human papillomavirus (HPV) type 16 capsid proteins with HPV DNA requires an intact L2 N-terminal sequence , 1994, Journal of virology.

[91]  D. Lowy,et al.  Papillomavirus L1 capsids agglutinate mouse erythrocytes through a proteinaceous receptor , 1995, Journal of virology.

[92]  A. Lorincz,et al.  Human papillomavirus type 16 immortalized cervical keratinocytes contain transcripts encoding E6, E7, and E2 initiated at the P97 promoter and express high levels of E7. , 1991, Virology.

[93]  Xavier Castellsagué,et al.  Against which human papillomavirus types shall we vaccinate and screen? the international perspective , 2004, International journal of cancer.

[94]  F. Holding,et al.  Phase IIa safety and immunogenicity of a therapeutic vaccine, TA-GW, in persons with genital warts. , 1999, The Journal of infectious diseases.

[95]  N. Christensen,et al.  Chimeric Human Papillomavirus Type 16 (HPV-16) L1 Particles Presenting the Common Neutralizing Epitope for the L2 Minor Capsid Protein of HPV-6 and HPV-16 , 2003, Journal of Virology.

[96]  Corey Smith,et al.  A totally synthetic vaccine of generic structure that targets Toll-like receptor 2 on dendritic cells and promotes antibody or cytotoxic T cell responses. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[97]  Y. Taketani,et al.  A surface immunodeterminant of human papillomavirus type 16 minor capsid protein L2. , 1998, Virology.

[98]  M. Campo.  Vaccination against papillomavirus. , 1991, Cancer cells.

[99]  D. Lowy,et al.  Concatenated Multitype L2 Fusion Proteins as Candidate Prophylactic Pan-Human Papillomavirus Vaccines , 2009, Journal of the National Cancer Institute.

[100]  H. Hausen,et al.  A new type of papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer. , 1984, The EMBO journal.

[101]  D. Lowy,et al.  NHPV16 VLP vaccine induces human antibodies that neutralize divergent variants of HPV16. , 2001, Virology.

[102]  D. Lowy,et al.  Maturation of Papillomavirus Capsids , 2005, Journal of Virology.

[103]  B. Trus,et al.  Arrangement of L2 within the Papillomavirus Capsid , 2008, Journal of Virology.

[104]  Daron G Ferris,et al.  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 , 2004, The Lancet.

[105]  M. Pawlita,et al.  Human Papillomavirus Type 16 L1 Capsomeres Induce L1-Specific Cytotoxic T Lymphocytes and Tumor Regression in C57BL/6 Mice , 2003, Journal of Virology.

[106]  J. Schiller,et al.  A Membrane-Destabilizing Peptide in Capsid Protein L2 Is Required for Egress of Papillomavirus Genomes from Endosomes , 2006, Journal of Virology.

[107]  R. Roden,et al.  Protection of Rabbits against Challenge with Rabbit Papillomaviruses by Immunization with the N Terminus of Human Papillomavirus Type 16 Minor Capsid Antigen L2 , 2007, Journal of Virology.

[108]  G. Grindlay,et al.  Linear B-cell epitopes in the N-terminus of L2 of bovine papillomavirus type 4. , 1997, Research in veterinary science.

[109]  N. Christensen,et al.  Immunization with viruslike particles induces long-term protection of rabbits against challenge with cottontail rabbit papillomavirus , 1996, Journal of virology.

[110]  C. Wheeler,et al.  HPV antibody levels and clinical efficacy following administration of a prophylactic quadrivalent HPV vaccine. , 2008, Vaccine.

[111]  F. Holding,et al.  Phase I safety and antigenicity of TA-GW: a recombinant HPV6 L2E7 vaccine for the treatment of genital warts. , 1999, Vaccine.

[112]  D. Segre,et al.  Immunity to bovine cutaneous papillomatosis produced by vaccine homologous to the challenge agent. , 1959, Journal of the American Veterinary Medical Association.

[113]  S. H. van der Burg,et al.  Enhancement of human papillomavirus (HPV) type 16 E6 and E7-specific T-cell immunity in healthy volunteers through vaccination with TA-CIN, an HPV16 L2E7E6 fusion protein vaccine. , 2002, Vaccine.

[114]  D. Lowy,et al.  Reactivity of human sera in a sensitive, high-throughput pseudovirus-based papillomavirus neutralization assay for HPV16 and HPV18. , 2004, Virology.

[115]  Daron G Ferris,et al.  Efficacy of a bivalent L 1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women : a randomised controlled trial , 2005 .

[116]  Y. L. Lin,et al.  Effective vaccination against papilloma development by immunization with L1 or L2 structural protein of cottontail rabbit papillomavirus. , 1992, Virology.

[117]  D. Brobst,et al.  Induced immunity of skin, vagina, and urinary bladder to bovine papillomatosis. , 1962, Cancer research.

[118]  J. Peto,et al.  Human papillomavirus is a necessary cause of invasive cervical cancer worldwide , 1999, The Journal of pathology.

[119]  M. Campo.  Vaccination against papillomavirus in cattle. , 1997, Current topics in microbiology and immunology.

[120]  Y. Taketani,et al.  Nasal immunization of mice with peptide having a cross-neutralization epitope on minor capsid protein L2 of human papillomavirus type 16 elicit systemic and mucosal antibodies. , 2001, Vaccine.

[121]  J. M. van der Hulst,et al.  Association of cervical cancer with the presence of CD4+ regulatory T cells specific for human papillomavirus antigens , 2007, Proceedings of the National Academy of Sciences.

[122]  Julian Peto,et al.  Prevalence of Human Papillomavirus in Cervical Cancer: a Worldwide Perspective , 1995 .

[123]  H. Kitchener,et al.  Immunological and clinical responses in women with vulval intraepithelial neoplasia vaccinated with a vaccinia virus encoding human papillomavirus 16/18 oncoproteins. , 2003, Cancer research.

[124]  D. Sidransky,et al.  Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. , 2000, Journal of the National Cancer Institute.

[125]  Petra Lenz,et al.  Determinants of Autoantibody Induction by Conjugated Papillomavirus Virus-Like Particles , 2002, The Journal of Immunology.

[126]  M. Sapp,et al.  Structure, attachment and entry of polyoma- and papillomaviruses. , 2009, Virology.

[127]  P. Livingston,et al.  Antibody inducing polyvalent cancer vaccines. , 2005, Cancer treatment and research.

[128]  R. Schlegel,et al.  A formalin-inactivated vaccine protects against mucosal papillomavirus infection: a canine model. , 1994, Pathobiology : journal of immunopathology, molecular and cellular biology.

[129]  D. Lowy,et al.  Minor capsid protein of human genital papillomaviruses contains subdominant, cross-neutralizing epitopes. , 2000, Virology.

[130]  P. Stern,et al.  Vaccination with HPV16 L2E6E7 fusion protein in GPI-0100 adjuvant elicits protective humoral and cell-mediated immunity. , 2009, Vaccine.

[131]  G. Grindlay,et al.  Vaccination of cattle with the N-terminus of L2 is necessary and sufficient for preventing infection by bovine papillomavirus-4. , 1995, Virology.

[132]  D. Lowy,et al.  Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[133]  J. Berzofsky,et al.  Cellular immune responses to HPV-18, -31, and -53 in healthy volunteers immunized with recombinant HPV-16 L1 virus-like particles. , 2006, Virology.

[134]  T. Baker,et al.  Structures of bovine and human papillomaviruses. Analysis by cryoelectron microscopy and three-dimensional image reconstruction. , 1991, Biophysical journal.

[135]  D. Lowy,et al.  Immunization with viruslike particles from cottontail rabbit papillomavirus (CRPV) can protect against experimental CRPV infection , 1995, Journal of virology.

[136]  D. Lowy,et al.  Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. , 2007, JAMA.