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The impact of anti HPV vaccination on cervical cancer incidence and HPV induced cervical lesions: Consequences for clinical management

  • J.A. Brinkman1
  • A.S. Caffrey2
  • L.I. Muderspach2
  • L.D. Roman2
  • W.M. Kast1,*,

1Norris Comprehensive Cancer Center, USA

2Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Keck/University of Southern California School of Medicine, Los Angeles , CA, USA

DOI: 10.12892/ejgo200502129 Vol.26,Issue 2,March 2005 pp.129-142

Published: 10 March 2005

*Corresponding Author(s): W.M. Kast E-mail:

Abstract

Cervical cancer is the second most common cause of cancer-related deaths in women worldwide. Screening for cervical cancer is accomplished utilizing a Pap smear and pelvic exam. While this technology is widely available and has reduced cervical cancer incidence in industrialized nations, it is not readily available in third world countries in which cervical cancer incidence and mortality is high. Development of cervical cancer is associated with infection with high risk types of human papillomavirus (HPV) creating a unique opportunity to prevent or treat cervical cancer through anti-viral vaccination strategies. Several strategies have been examined in clinical trials for both the prevention of HPV infection and the treatment of pre-existing HPV-related disease. Clinical trials utilizing prophylactic vaccines containing virus-like particles (VLPs) indicate good vaccine efficacy and it is predicted that a prophylactic vaccine may be available within the next five years. But, preclinical research in this area continues in order to deal with issues such as cost of vaccination in underserved third world populations. A majority of clinical trials using therapeutic agents which aim to prevent the progression of pre-existing HPV associated lesions or cancers have shown limited efficacy in eradicating established tumors in humans possibly due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Future trends in clinical trials with therapeutic agents will examine patients with early stage cancers or pre-invasive lesions in order to prevent invasive cervical cancer. Meanwhile, preclinical studies in this field continue and include the further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. Given that cervical cancers are caused by the human papillomavirus, the prospect of therapeutic vaccination to treat existing lesions and prophylactic vaccination to prevent persistent infection with the virus are high and may be implemented in the near future. The consequences for clinical management may include a significant reduction in the frequency of Pap smear screening in the case of prophylactic vaccines, and the availability of less invasive and disfiguring treatment options for women with pre-existing HPV associated lesions in the case of therapeutic vaccines. Implementation of both prophylactic and therapeutic vaccine regimens could result in a significant reduction of health care costs and reduction of worldwide cervical cancer incidence.

Keywords

Human Papillomavirus; Vaccine; Cervical cancer

Cite and Share

J.A. Brinkman,A.S. Caffrey,L.I. Muderspach,L.D. Roman,W.M. Kast. The impact of anti HPV vaccination on cervical cancer incidence and HPV induced cervical lesions: Consequences for clinical management. European Journal of Gynaecological Oncology. 2005. 26(2);129-142.

References

[1] http://www.who.int/vaccine_research/documents/new vaccines/en/index8.html. World Health Organization: Human Papillomaviruses. 2004.

[2] Kurman R.J., Henson D.E., Herbst A.L., Noller K.L., Schiffman M.H.: "Interim guidelines for management of abnormal cervical cytology The 1992 National Cancer Institute Workshop". JAMA, 1994, 271, 1866.

[3] http://www.cancer.org. American Cancer Society Inc., 2004.

[4] Association of Professors of Gynecology and Obstetrics. APGO Educational Series on Women's Health Issues. Advances in the Screening, Diagnosis, and Treatment of Cervical Disease, 2002.

[5] Walboomers J.M., Jacobs M.V., Manos M.M., Bosch F.X., Kummer J.A., Shah K.V. et al.: "Human papillomavirus is a necessary cause of invasive cervical cancer worldwide". J. Pathol., 1999, 189 (1), 12.

[6] Chan S.Y., Delius H., Halpern A.L., Bernard H.U.: "Analysis of genomic sequences of 95 papillomavirus types: uniting typing, phylogeny, and taxonomy". J. Virol., 1995, 69, 3074.

[7] http://hpv-web.lanl.gov/ Los Alamos National Laboratory. Los Alamos National Laboratory HPV sequence database, 2001.

[8] Favre M., Ramoz N., Orth G.: "Human papillomaviruses: general features". Clin. Dermatol., 1997, 15, 181.

[9] Koutsky L.A.: "Epidemiology of genital human papillomavirus infection". Am. J. Med., 1997, 102 (SA), 3.

[10] zur Hausen H.: "Papillomaviruses and cancer: from basic studies to clinical application". Nat. Rev. Cancer, 2002, 2, 342.

[11] Southern S.A., Herrington C.S.: "Molecular events in uterine cervical cancer". Sex Transm. Infect., 1998, 74, 101.

[12] Popescu N.C., DiPaolo J.A.: "Preferential sites for viral integration on mammalian genome". Cancer Genet. Cytogenet., 1989, 42, 157.

[13] Beutner K.R., Tyring S.: "Human papillomavirus and human disease". Am. J. Med., 1997, 102 (SA), 9.

[14] Shah k V, Howley PM:“Papillomavirus". In: Fields B.N. K.D. (ed.). Fields Virology. New York: Raven Press, 1990, 1651.

[15] Gopalakrishnan V., Khan S.A.: "El protein of human papillomavirus type la is sufficient for initiation of viral DNA replication". Proc. Natl Acad. Sci. USA, 1994, 91, 9597.

[16] Hughes F.J., Romanos M.A.: "El protein of human papillomavirus is a DNA helicase/ATPase". Nucleic. Acids. Res., 1993, 21, 5817.

[17] Baker C.C., Phelps WC., Lindgren V., Braun M.J., Gonda M.A., Howley P.M.: "Structural and transcriptional analysis of human papillomavirus type 16 sequences in cervical carcinoma cell lines". J. Viral., 1987, 61, 962.

[18] Alani R.M., Munger K.: "Human papillomaviruses and associated malignancies". J. Clin. Oneal., 1998, 16, 330.

[19] Baker C.C., Phelps W.C., Lindgren V., Braun M.J., Gonda M.A., Howley P.M.: "Structural and transcriptional analysis of human papillomavirus type 16 sequences in cervical carcinoma cell lines". J. Virol., 1987, 61, 962.

[20] Bedell M.A., Jones K.H., Laimins L.A.: "The E6-E7 region of human papillomavirus type 18 is sufficient for transformation of NIH 3T3 and rat-1 cells". J. Virol., 1987, 61, 3635.

[21] Tyring S.K.: "Human papillomavirus infections: epidemiology, pathogenesis, and host immune response". J. Am. Acad. Dermatol., 2000, 43 (1 Pt 2), S18.

[22] Howley P.M.: "Papillomaviridae: the viruses and their replication". In: Fields B.N. KDHP (ed.). Fields Virology. Philadelphia: Lippincott-Raven, 1996, 2045.

[23] Munger K.: "The molecular biology of cervical cancer". J. Cell. Biochem., 1995, 23 (suppl.), 55.

[24] Farthing A.J.,V ousden K.H.: "Functions of human papillomavirus E6 and E7 oncoproteins". Trends Microbial.,1 994,2 ,1 70

[25] Belnap D.M., Olson N.H., Cladel N.M., Newcomb W.W., Brown J.C., Kreider J.W. et al.: "Conserved features in papillomavirus and polyomavirus capsids". J. Mol. Biol., 1996, 259, 249.

[26] de Villiers E.M.: "Papillomavirus and HPV typing". Clin. Dermatol., 1997, 15, 199.

[27] Frazer I.: "Vaccines for papillomavirus infection". Virus. Res., 2002, 89, 271.

[28] Ressing M.E., van Driel W.J., Celis E., Sette A., Brandt M.P., Hartman M. et al.: "Occasional memory cytotoxic T-cell responses of patients with human pap仆lomavirus type 16-positive cervical lesions against a human leukocyte antigen-A *0201-restricted E7-encoded epitope". Cancer Res., 1996, 56, 582.

[29] Evans E.M., Man S., Evans A.S., Borysiewicz L.K.: "Infiltration of cervical cancer tissue with human papillomavirus-specific cytotoxic Tlymphocytes". Cancer Res., 1997, 57, 2943.

[30] Nimako M., Fiander AN., Wilkinson G.W., Borysiewicz L.K., Man S.: "Human papillomavirus-specific cytotoxic T lymphocytes in patients with cervical intraepithelial neoplasia grade III". Cancer Res., 1997, 57, 4855.

[31] de Gruijl T.D., Bontkes H.J., Stukart M.J., Walboomers J.M., Remmink A.J., Verheijen R.H. et al.:''T-cell proliferative responses against human papillomavirus type 16 E7 oncoprotein are most prominent in cervical intraepithelial neoplasia patients with a persistent viral infection". J. Gen. Virol., l 996, 77 (Pt 9), 2183.

[32] Luxton J.C., Rowe A.J., Cridland J.C., Coletart T., Wilson P., Shepherd P.S.: "Proliferative T-cell responses to the human papillomavirus type 16 E7 protein in women with cervical dysplasia and cervical carcinoma and in healthy individuals". J. Gen. Virol., 1996, 77 (Pt 7), 1585.

[33] Kadish A.S.,H o G.Y.,B urk R.D.,W ang Y.,R omney S.L.,L edwidge R. et al.: "Lymphoproliferative responses to human papillomavirus (HPV) type 16 proteins E6 and E7: outcome of HPV infection and associated neoplasia". J. Natl. Cancer Inst., 1997, 89, 1285.

[34] de Gruijl T.D., Bontkes H.J., Walboomers J.M., Stukart M.J., Doekhie F.S., Remmink A.J. et al.: "Differential T-helper cell responses to human papillomavirus type 16 E7 related to viral clearance or persistence in patients with cervical neoplasia: a longitudinal study". Cancer Res., 1998, 58, 1700.

[35] Warrino D.E., Olson W.C., Knapp W.T., Scarrow M.I., D'Ambrosio-Brennan L.J., Guido R.S. et al.: "Disease-stage variance in functional CD4(+) T-cell responses against novel pan-human leukocyte antigen-D region presented human papillomavirus-16 E7 epitopes". Clin. Cancer Res., 2004, 10, 3301.

[36] Ribas A., Butterfield L.H., Glaspy J.A., Economou J.S.: "Current developments in cancer vaccines and cellular immunotherapy". J. Clm Oncol., 2003, 21, 2415.

[37] Salit R.B., Kast W.M., Velders M.P.: "Ins and outs of clinical trials with peptide-based vaccines". Front. Biosci., 2002, 7, 204.

[38] Immunobiology: The Immune System in Health and Disease, 3,d ed., York and London: Garland Publishing Co., 1997.

[39] Banchereau J., Briere F., Caux C., Davoust J., Lebecque S., Liu Y.J. et al.: "Immunobiology of dendritic cells". Anna. Rev. Immunol., 2000, 18, 767.

[40] Fausch S.C., Da Silva D.M., Kast W.M.: "Differential uptake and cross-presentation of human papillomavirus virus-like particles by dendritJc cells and Langerhans cells". Cancer Res., 2003, 63, 3478.

[41] Van der Burg S.H., de Jong A., Welters M.J., Offringa R., Melief C.J.:'The status of HPV 16-specific T-cell reactivity in health and disease as a guide to HPV vaccine development". Virus Res., 2002, 89, 275.

[42] Jakob T., Ring J., Udey M.C.: "Multistep navigation of Langerhans/dendritic cells in and out of the skin". J. Allergy Clin. Immunol., 2001, 108, 688.

[43] Fausch S.C., Da Silva D.M., Rudolf M.P., Kast W.M.: "Human papillomavirus virus-like particles do not activate Langerhans cells: a possible immune escape mechanism used by human papillomaviruses". J.Immunol., 2002, 169, 3242.

[44] Trofatter K.F.: "'Diagnosis of human papillomavirus genital tract infection". Am. J. Med., 1997, 102 (SA), 21.

[45] Palefsky J.M.,H olly E.A.: "Molecular virology and epidemiology of human papillomavirus and cervical cancer". CancerEpidemiol. Biomark Prev., 1995, 4, 415.

[46] Solomon D., Davey D., Kurman R., Moriarty A., O'Connor D., Prey M. et al.:'The 2001 Bethesda System: terminology for reporting results of cervical cytology". JAMA, 2002, 287 (16), 2114.

[47] Melnikow J., Nuovo J., Willan A.R., Chan B.K., Howell L.P.: "Natural history of cervical squamous intraepithelial lesions: a meta-analysis" Obstet. Gynecol., 1998, 92 (4 Pt 2), 727.

[48] Shennan M.E., Solomon D., Schiffman M.: "Qualification of ASCUS. A comparison of equivocal LSIL and equivocal HSIL cervical cytology in the ASCUS LSIL Triage Study". Am. J. Clin. Pathol., 2001, I16, 386.

[49] Sherman M.E., Tabbara S.O., Scott D.R., Kurman R.J., Glass A.G., Manos M.M. et al.: "ASCUS, rule out HSIL: cytologic features, histologic correlates, and human papillomavirus detection". Mod. Pathol., 1999, 12, 335.

[50] Schoolland M., Sterrett G.F., Knowles S.A., Mitchell K.M., Kurinczuk J.J.: "The 'Inconclusive-possible high grade epithelial abnormality' category in Papanicolaou smear reporting". Cancer, 1998, 84, 208.

[51] Cannistra S.A., Niloff J.M.: "Cancer of the uterine cervix". New Engl. J. Med., 1996, 334, 1030.

[52] Mitchell M.F.,To rtolero-Luna G.,C ook E.,W hittaker L.,R hodes-Morris H.,S ilva E.: "A randomized clinical trial of cryotherapy,l aser vaporization, and loop electrosurgical excision for treatment of squamous intraepithelial lesions of the cervix". Obstet. Gynecol., 1998, 92, 737.

[53] Benedet J.L., Bender H., Jones H. III, Ngan H.Y., Pecorelli S.: "FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology". Int. J. Gynaecol. Obstet., 2000, 70, 209.

[54] Hagensee M.E., Yaegashi N., Galloway D.A.: "Self-assembly of human papillomavirus type I capsids by expression of the LI protein alone or by co-expression of the LI and L2 capsid proteins". J. Virol., 1993, 67, 315.

[55] Kirnbauer R., Booy F., Cheng N., Lowy D.R., Schiller J.T.: "Papillomavirus LI major capsid protein self-assembles into virus-like particles that are highly immunogenic". Proc. Natl. Acad. Sci USA, 1992, 89, 12180.

[56] Hofmann K.J., Cook J.C., Joyce J.G., Brown D.R., Schultz L.D., George H.A. et al.: "Sequence determination of human papillomavirus type 6a and assembly of virus-like particles in Saccharomyces cerevisiae". Virology, 1995, 209, 506.

[57] Harro C.D., Pang Y.Y., Roden R.B., Hildesheim A., Wang Z., Reynolds M.J. et al.: "Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 LI virus-like particle vaccine". J. Natl. Cancer Inst., 2001, 93, 284.

[58] Pinto L.A., Edwards J., Castle P.E., Harro C.D., Lowy D.R., Schiller J.T. et al.: "Cellular immune responses to human papillomavirus (HPY)-16 LI in healthy volunteers immunized with recombinant HPV-16 LI virus-like particles". J. Infect. Dis., 2003, 188, 327.

[59] Koutsky L.A., Ault K.A., Wheeler C.M., Brown D.R., Barr E., Alvarez F.B. et al.: "A controlled trial of a human papillomavirus type 16 vaccine". N. Engl. J. Med., 2002, 347, 1645.

[60] Koutsky L.: "Prophylactic HPV Ll Virus-Like particle (VLP) Vaccines". Abstract# 047. Presented at the 21''International Human Papillomavirus Conference, Mexico City, Mexico. February, 2004.

[61] Harper Diane. HPV 16/18 LI V LP Cervical Cancer Vaccine Pilot Efficacy Results. Symposium on Vaccines IL Presented at the 21" International Papillomavirus Conference, Mexico City, Mexico, February, 2004.

[62] Suzich JoAnn. Selection of Vaccine Candidate. Symposium on Vaccines II. Presented at the 21st International Papillomavirus Conference, Mexico City, Mexico, February, 2004.

[63] http://unisci.com/stories/20022/0610024.htm. UniSci Daily University Science News; Scientists Developing an Edible Vaccine against HPV, 2004.

[64] Gerber S., Lane C., Brown D.M., Lord E., D止orenzo M., Clements J.D. et al.: "Human papillomavirus virus-like particles are efficient oral immunogens when co-administered with Escherichia coli heat-labile enterotoxin mutant Rl92G or CpG DNA". J. Viral., 2001, 75, 4752.

[65] Revaz Y., Benyacoub J., Kast W.M., Schiller J.T., De Grandi P., Nardelli-Haefliger D.: "Mucosal vaccination with a recombinant Salmonella typhimurium expressing human papillomavirus type 16 (HPV16) LI virus-like particles (VLPs) or HPV 16 V LPs purified from insect cells inhibits the growth of HPV 16-expressing tumor cells in mice". Virology, 2001, 279, 354.

[66] Da Silva D.M., Pastrana D.V., Schiller J.T., Kast W.M.: "Effect of preexisting neutralizing antibodies on the anti-tumor immune response induced by chimeric human papillomavirus virus-like particle vaccines". Virology, 2001, 290, 350.

[67] Steller M.A., Gurski K.J.. Murakami M., Daniel R.W., Shah K.Y., Celis E. et al.: "Cell-mediated immunological responses in cervical and vaginal cancer patients immunized with a lipidated epitope of human papillomavirus type 16 ET'. Clin. Cancer Res., 1998, 4, 2103.

[68] Kast W.M., Brandt R.M., Drijthout J.W., Melief C.J.: "Human leukocyte antigen-A2. l restricted candidate cytotoxic T lymphocyte epitopes of human papillomavirus type 16 E6 and E7 proteins identified by using the processing-defective human cell line T 2". J. Immunother., 1993, 14, 115.

[69] Ressing M.E., Sette A., Brandt R.M., Ruppert J., Wentworth P.A., Hartman M. et al.: "Human CTL epitopes encoded by human papillomavtrus type 16 E6 and E7 identified through in vivo and in vitro immunogenicity studies of HLA-A *0201-binding peptides". J. Immunol., 1995, 154, 5934.

[70] Alexander M., Salgaller M.L., Celis E., Sette A., Barnes W.A., Rosenberg S.A. et al.: "Generation of tumor-specific cytolytic T lymphocytes from peripheral blood of cervical cancer patients by in vitro stimulation with a synthetic human papillomavirus type 16 E7epitope". Am. J Obstet. Gynecol., 1996, 175, 1586.

[71] van Driel W.J., Ressing M.E., Kenter G.G., Brandt R.M., Krul E.J., van Rossum A.B. et al.: "Vaccination with HPV l6 peptides of patients with advanced cervical carcinoma: clinical evaluation of a phase I-II trial". Eur. J. Cancer, 1999, 35, 946.

[72] Ressing M.E., van Driel W.J., Brandt R.M., Kenter G.G., de Jong J.H., Bauknecht T. et al.: "Detection of T helper responses, but not of human papillomavirus-specific cytotoxic T lymphocyte responses, after peptide vaccination of patients with cervical carcinoma". J. lmmunother., 2000, 23, 255.

[73] Muderspach L., Wilczynski S., Roman L., Bade L., Felix J., Small L.A. et al.: "A phase I trial of a human papillomavirus (HPV) peptide vaccine for women with high-grade cervical and vulvar intraepithelial neoplasia who are HPV 16 positive". Clin. Cancer Res., 2000, 6, 3406.

[74] Hallez S., Simon P., Maudoux F., Doyen J., Noel J.C., Beliard A. et al.: "Phase I/II trial of immunogenicity of a human papillomavirus (HPV) type 16 E7 protein-based vaccine in women with oncogenic HPV-positive cervical intraepithelial neoplasia". Cancer Immunol. Immunother., 2004, 53, 642.

[75] http://www.stressgen.com. StressGen Reports HSPE7 Results From Two clinical Trials, 2004.

[76] de Jong A., O'Neill T., Khan A.Y., Kwappenberg K.M., Chisholm S.E., Whittle N.R. et al.: "Enhancement of human papillomavirus (HPY) type 16 E6 and E7-specific T-cell immunity in healthy volunteers through vaccination with TA-CIN, an HPY16 L2E7E6 fusion protein vaccine". Vaccine, 2002, 20, 3456.

[77] Bamden M., Papalia L., Davis R., Millar C., Nikolic N., O'Brien K., Wang L., McKenzie A., White 0., Frazer I.: "Antigen-Specific CD4+ and CDS+ T Cell Responses to HPV I 6 E6E7 ISCOMATRIX® Vaccine in Healthy Volunteers". Abstract #629. Presented at the 21" International Papillomavirus Conference, Mexico City, Mexico, February 2004.

[78] Chen Y.F., Lin C.W., Tsao Y.P., Chen S.L.: "Cytotoxic-T-lymphocyte human papillomavirus type 16 ES peptide with CpG-oligodeoxynucleotide can eliminate tumor growth in C57BL/6 mice". J. Virol., 2004, 78, 1333.

[79] Zwaveling S., Ferreira Mota S.C., Nouta J., Johnson M., Lipford G.B., Offringa R. et al.: "Established human papillomavirus type 16-expressing tumors are effectively eradicated following vaccination with long peptides". J. lmmunol., 2002, 169, 350.

[80] Eiben G.L., Da Silva D.M., Fausch S.C., Le Poole J.C., Nishimura M.l., Kast W.M.: "Cervical cancer vaccines: recent advances in HPV research". Viral. lmmunol., 2003, 16, 111.

[81] Klencke B., Matijevic M., Urban R.G., Lathey J.L., Hedley M.L., BetTy M. et al.: "Encapsulated plasmid DNA treatment forhuman papillomavirus 16-associated anal dysplasia: a Phase I study of ZYC lOl". Clin. Cancer Res., 2002, 8, 1028.

[82] Sheets E.E., Urban R.G., Crum C.P., Hedley M.L., Politch J.A., Gold M.A. et al.: "Immunotherapy of human cervical high-grade cervical intraepithelial neoplasia with microparticle-delivered human papillomavirus 16 E7 plasmid DNA". Am. J. Obstet. Gynecol., 2003, 188, 916.

[83] Garcia F., Petry K.U., Muderspach L., Gold M.A., Braly P., Crum C.P., Magill M., Silverman M., Urban R.G., Hedley M.L., Beach K.J.: "A multicenter randomized placebo controlled trial of ZYC lOla in high grade CIN". Abstract #571. Presented at the 21" International Papillomavirus Conference Mexico City, Mexico, February 2004.

[84] Velders M.P., Weijzen S., Eiben G.L., Elmishad A.G., Kloetzel P.M., Higgins T. et al.: "Defined flanking spacers and enhanced proteolysis is essential for eradication of established tumors by an epitope string DNA vaccine". J. lmmunol., 2001, 166, 5366.

[85] Liu W.J., Zhao K.N., Gao F.G., Leggatt G.R., Fernando G.J., Frazer I.H.: "Polynucleotide viral vaccines: codon optimization and ubiguitin conjugation enhances prophylactic and therapeutic efficacy". Vaccine, 2001, 20, 862.

[86] Hung C.F., Cheng W.F., He L., Ling M., Juang J., Lin C.T. et al.: "Enhancing major histocompatibility complex class I antigen presentation by targeting antigen to centrosomes". Cancer Res., 2003, 63, 2393.

[87] Peng S., Hung C.-F., Trimble C., He L., Yeatermeyer J., Wu T.-C.: "Development of a DNA Vaccine targeting HPV-16 Oncoprotein E6" Abstract #563. Presented at the 21" International Papillomavirus Conference Mexico City, Mexico, February 2004.

[88] Cid-Arregui A., Juarez V., zur Hausen H.: "A synthetic E7 gene of human papillomavirus type 16 that yields enhanced expression of the protein in mammalian cells and is useful for DNA immunization studies". J. Virol., 2003, 77, 4928.

[89] Liu W.J., Gao F., Zhao K.N., Zhao W., Fernando G.J., Thomas R. et al.: "Codon modified human papillomavirus type 16 E7 DNA vaccine enhances cytotoxic T-lymphocyte induction and anti-tumour activity". Virology, 2002, 301, 43.

[90] Liu W.J., Zhao K.N., Gao F.G., Leggatt G.R., Fernando G.J., Frazer I.H.: "Polynucleotide viral vaccines: codon optimization and ubiquitin conjugation enhances prophylactic and therapeutic efficacy". Vaccine, 2001, 20, 862.

[91] Osen W., Peiler T., Ohlschlager P., Caldeira S., Faath S., Michel N. et al.: "A DNA vaccine based on a shuffled E7 oncogene of the human papillomavirus type 16 (HPV 16) induces E7-specific cytotoxic T-cells but lacks transforming activity". Vaccine, 2001, 19, 4276.

[92] Brinkman J., Xue X., Garcia M., de La L., Kast W.M.:'The efficacy of an insertion duplication DNA vaccine for eradicating established tumors in mice". Abstract #562. Presented at the 21" International Papillomavirus Conference Mexico City, Mexico, February 2004.

[93] Doan T., Herd K., Ramshaw I., Thomson S., Tindle R.: "A polytope DNA vaccine elicits multiple CTL responses and protects against HPV16 E7-expressing? tumors". Abstract #566. Presented at the 2l st Internation Papillomavirus Conference Mexico City, Mexico. February 2004.

[94] Hung C.F., He L., Juang J., Lin T.J., Ling M., Wu T.C.: "Improving DNA vaccine potency by linking Marek's disease virus type I VP22 to an antigen". J. Virol., 2002, 76, 2676.

[95] Cheng W.F., Hung C.F., Hsu K.F., Chai C.Y., He L., Polo J.M. et al.: "Cancer immunotherapy using Sindbis virus replicon particles encoding a YP22-antigen fusion". Hum. Gene Ther., 2002, 13, 553.

[96] Kaufmann A.M., Stern P.L., Rankin E.M., Sommer H., Nuessler Y ., Schneider A. et al.: "Safety and immunogenicity of TA-HPV, a recombinant vaccinia virus expressing modified human papillomavirus (HPV)-16 and HPV-18 E6 and E7 genes, in women with progressive cervical cancer". Clin. Cancer Res., 2002, 8, 3676.

[97] Baldwin P.J., Yan der Burg S.H., Boswell C.M., Offringa R., Hickling J.K., Dobson J. et al.: "Vaccinia-expressed human papillomavirus 16 and 18 e6 and e7 as a therapeutic vaccination for vulvar and vaginal intraepithelial neoplasia". Clin. Cancer Res., 2003, 9, 5205.

[98] Davidson E.J., Boswell C.M., Sehr P., Pawlita M., Tomlinson A.E., Mc Vey R.J. et al.: "Immunological and clinical responses in women with vulvar intraepithelial neoplasia vaccinated with a vaccinia virus encoding human papillomavirus 16/18 oncoproteins". Cancer Res., 2003, 63, 6032.

[99] http://www.transgene.fr/us/page.php?fam= 1 &rub=2&iframe=pro-duct_pipeline/iframe_mva_hpv il2.htm MVA-HPV-IL2. CLINICAL UPDATE. Results of Phase II trials. 2004.

[100] Da Silva D.M., Schiller J.T., Kast W.M.: "Heterologous boosting increases immunogenicity of chimeric papillomavirus virus-like particle vaccines". Vaccine, 2003, 21, 3219.

[101] Van der Burg S.H., Kwappenberg K.M., O'Neill T., Brandt R.M., Melief C.J., Hickling J.K. et al.: "Pre-clinical safety and efficacy of TACIN, a recombinant HPV16 L2E6E7 fusion protein vaccine, in homologous and heterologous prime-boost regimens". Vaccine, 2001, 19, 3652.

[102] Smyth L.J.C., van Poelgeest M.I.E., Davidson E.J., Kwappenberg K.M.C., Burt D., Pawlita M. et al. "Immunological responses in women with HPV 16 associated vulvar intraepithelial neoplasia (VIN) induced by heterologous prime-boost vaccinations in a phase IIA clinical trial". Abstract #408. Presented at 21" International Papillomavirus Conference Mexico City, Mexico, February 2004.

[103] Li J., Sun Y., Garen A.: "Immunization and immunotherapy for cancers involving infection by a human papillomavirus in a mouse model" Proc. Natl. Acad Sci. USA, 2002, 99, 16232.

[104] Daemen T., Riezebos-Brilman A., Bungener L., Regts J., Dontje B., Wilschut J.: "Eradication of established HPV 16-transformed tumours after immunisation with recombinant Semliki Forest virus expressing a fusion,rotein of E6 and ET'. Vaccine, 2003, 21, 1082.

[105] Garoff H., Li K.J.:''Recent advances in gene expression using alphavirus vectors". Curr. Opin. Biotechnol., 1998, 9, 464.

[l06] Hsu K.F., Hung C.F., Cheng W.F., He L., Slater L.A., Ling M. et al.: "Enhancement of suicidal DNA vaccine potency by linking Mycobacterium tuberculosis heat shock protein 70 to an antigen". Gene Ther., 2001, 8, 376.

[107] Cassetti M.C., McElhiney S.P., Shahabi V., Pullen J.K., Le Poole I.C., Eiben G.L. et al.: "Antitumor efficacy of Venezuelan equine encephahtis virus replicon particles encoding mutated HPV16 E6 and E7 genes". Vaccine, 2004, 22, 520.

[108] Herd K.A., Harvey T.Khromykh A.A., Tindle R.W.: "Recombinant Kunjin virus replicon vaccines induce protective T-cell immunity against human papillomavirus 16 E7-expressing tumour". Virology, 2004, 319, 237.

[109] Insinga R.P., Glass A.G., Rush B.B.: "The healthcare costs of cervical human Papillomavirus-related disease". Abstract #543. Presented at the 21" International Papillomavirus Conference Mexico City, Mexico, February 2004.

[110] Canfell K., Barnabas R., Beral V.: "HPV vaccination and cancer incidence in screened populations. Abstract #411. presented at the 21st International Papillomavirus Conference Mexico City, Mexico, February 2004.

[111] Goldie SJ., Kohli M., Grima D., Weinstein M.C., Wright T.C., Bosch F.X. et al.: "Projected clinical benefits and cost-effectiveness of a human papillomavirus 16/18 vaccine". J. Natl. Cancer Inst., 2004, 96, 604.

[112] Nardclli-Haefliger D., Wirthner D., Schiller J.T., Lowy D.R., Hildesheim A., Ponci F. et al.: "Specific antibody levels at the cervix duringthe menstrual cycle of women vaccinated with human papillomavirus 16 virus-like particles". J. Natl. Cancer Inst., 2003, 95 (15), 1128.

[113] Kahn J.A., Bernstein D.I.: "Human papillomavirus vaccines". Pediatr. Infect. Dis. J., 2003, 22, 443.

[114] McCree D.H., Mcfarlane M., Leichliter J., St.Lawrence J.S., Sharpe P., Daley E. et al.: "Formative research to access the impact of diagnosis and educational needs of high-risk Human Papillomavirus (HR-HPV) positive patients". Abstract #556. Presented at the 21st International Papillomavirus Conference Mexico City, Mexico, February 2004.

[115] Holcomb B., Baily J.M., Crawford K., Ruffin M.T.: "Adults'Knowledge and behaviors related to Human Papillomavirus infection". Abstract #557. Presented at the 21st International Papillomavirus Conference Mexico City, Mexico, February 2004.

[116] Crum C.P.:'"The beginning of the end for cervical cancer?". N. Engl..I. Med., 2002, 347, 1703.

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