Preventive and Therapeutic Vaccines against Human Papillomaviruses Associated Cervical Cancers

Document Type: Review Article

Authors

1 Women’s Health Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran

2 Microbiology and Virology Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Cervical cancer is, globally known to be, one of the most common cancers among women especially in
developing countries. More than 90% of cervical cancers are associated with high-risk human
papillomaviruses (HPVs) particularly HPV types 16 and 18. Two major strategies have been developed for
prevention and treatment of cervical cancer and other HPV-associated malignancies; the first one is based on
HPV virus-like particles (VLPs) containing HPV structural proteins. VLP based vaccines can induce
genotype specific virus neutralizing antibodies for preventing HPV infections. The other strategy is based on
HPV early genes especially E6 and E7 for eliminating the established HPV infections; therefore they are
classified as HPV therapeutic vaccines. This article reviews the preventive and therapeutic vaccines against
HPV infections and cervical cancer.

Keywords


1.Hung CF, Monie A, Alvarez RD, Wu TC. DNA vaccines for cervical cancer: From bench to bedside. Exp Mol Med 2007; 39:679-689.

2. Castellsague X, Schneider A, Kaufmann AM, Bosch FX. HPV vaccination against cervical cancer in women above 25 years of age: Key considerations and current perspectives. Gynecol Oncol 2009; 115:S15-S23.

3.Yousuf S, Syed S. Prophylactic and therapeutic human papillomavirus vaccine: A breakthrough for women health. J Pak Med Assoc 2009; 59:310-314.

4. Frazer IH. Prevention of cervical cancer through papillomavirus vaccination. Nat Rev Immunol 2004; 4:46-54.

5. Streeck RE. A short introduction to papillomavirus biology. Intervirol ?2002; 45:287-289.

6.Moscicki A-B. HPV vaccines: Today and in the future. J Adolesc Health 2008; 43:S26-S40.

7.Adams M, Jasani B, Fiander A. Human papilloma virus (HPV) prophylactic vaccination: Challenges for public health and implications for screening. Vaccine 2007; 25:3007-3013.

8. Brinkman JA, Caffrey AS, Muderspach LI, Roman LD, Kast WM. The impact of anti HPV vaccination on cervical cancer incidence and HPV induced cervical lesions: consequences for clinical management. Eur J Gynaecol Oncol 2005; 26:129-142.

9. Thompson HSG, Davies ML, Holding FP, Fallon RE, Mann AE, Oneill T, et al. Phase I safety and antigenicity of TA-GW: A recombinant HPV6 L2E7 vaccine for the treatment of genital warts. Vaccine 1999; 17:40-49.

10. Park JS, Oh YK, Kang MJ, Kim JA. Enhanced mucosal and systemic immune responses following intravaginal immunization with human papillomavirus 16 L1 virus-like particle vaccinein thermosensitive mucoadhesive delivery systems. J Med Virol 2003; 70:633-641.

11. Giannoudis A, Herrington CS. Human papillomavirus variants and squamous neoplasia of the cervix. J Pathol 2001; 193:295-302.

12. Mirshahabi H, Soleimanjahi H, Meshkat Z, Bamdad T, Hassan ZM. Isolation of Iranian human papillomavirus type 16 E6 gene and construction of its cloning vector. Pak J Biol Sci 2006; 9:2652-2656.

13. Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. J Natl Cancer Inst 1995; 87:796-802.

14. Hausen HZ. Human papillomaviruses in the pathogenesis of anogenital cancer. Virol ?1991; 184:9-13.

15. Meshkat Z, Soleimanjahi H, Mahmoudi M, Mirshahabi H, Meshkat M, Kheirandish M, et al. CTL responses to a DNA vaccine encoding E7 gene of human papillomavirus type 16 from an Iranian isolate. Iran J Immunol 2008; 5:82-91.

16. Meshkat Z, Soleimanjahi H, Mahmoudi M, Mirshahabi H, Hassan ZM, Ghaffari SR, et al. Determination of human papillomavirus type 16 genotype and construction of cloning vector pTZ57R encoding HPV16 E7 gene. Saudi Med J 2007; 28:1511-1515.

17. Ljubojevic S, Lipozencic J, Grgec DL, Prstacic R, Skerlev M. Mokos1 ZB. Human papilloma virus associated with genital infection. Coll Antropol 2008; 32:989-997.

18. Pagliusi SR, Aguado MT. Efficacy and other milestones for human papillomavirus vaccine introduction.Vaccine 2004; 23:569-578.

19. de Villiers E-M, Fauquet C, Broker TR, Bernard H-U, zur Hausen H. Classification of papillomaviruses. Virol 2004; 324:17-27.

20. Meshkat Z, Hassan ZM, Soleimanjahi H, Mahmoodi M, Mirshahabi H, Farhadi Langeroudi M . Detection of human papillomaviruses type 16 and 18 by polymerase chain reaction (PCR) and restriction fragment length polymorphisms (RFLP) in paraffin-embedded cervical cancer tissue specimens. Arch Razi Inst 2007; 61:159-165.

21. Mirshahabi H, Meshkat Z, Soleimanjahi H, Hassan ZM. Construction a DNA Vaccine Containing Human Papillomavirus Type 16 Early Genes as a Potential Vaccine for Cervical Cancer Prevention and Therapy. Iran J Pathol 2009; 4:65 -70.

22. Jenkins D. A review of cross-protection against oncogenic HPV by an HPV-16/18 AS04-adjuvanted cervical cancer vaccine: Importance of virological and clinical endpoints and implications for mass vaccination in cervical cancer prevention. Gynecol Oncol 2008; 110:S18-S25.

23. Rapp L, Chen JJ. The papillomavirus E6 proteins. Biochim Biophys Acta 1998; 1378:F1-F19.

24. Scheffner M, Huibregtse JM, Vierstra RD, Howley PM. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 1993; 75:495-505.

25. Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 1990; 63:1129-1136.

26. Massimi P, Pim D, Banks L. Human papillomavirus type 16 E7 binds to the conserved carboxy-terminal region of the TATA box binding protein and this contributes to E7 transforming activity. J Gen Virol 1997;78:2607-2613.

27. Comerford SA, McCance DJ, Dougan G, Tite JP. Identification of T- and B-cell epitopes of the E7 protein of human papillomavirus type 16. J Virol 1991; 65:4681-4690.

28. Mahdavi A, Monk BJ. Vaccines against human papillomavirus and cervical cancer: Promises and challenges. E Oncologist 2005; 10:528-538.

29. Ault KA. Epidemiology and natural history of human papillomavirus infections in the female genital tract. Infect Dis Obstet Gynecol 2006; 2006:1-5.

30. Gissmann L, Osen W, Muller M, Jochmus I. Therapeutic Vvaccines for human papillomaviruses. Intervirol 2001; 44:167-175.

31. Lowey DR, Howley PM. Papillomaviruses. In: Knipe DM, Howley PM, editors. Fields Virology. 5th ed. Philadelphia: Lippincott Williams &Wilkins; 2007. p. 2299-2354.

32. Syrjanen KJ, Syrjanen SM. Papillomavirus infections in human pathology. West Sussex: John Wiley & Sons Ltd; 2000.

33. McIntosh J, Sturpe DA, Khanna N. Human papillomavirus vaccine and cervical cancer prevention: Practice and policy implications for pharmacists. J Am Pharm Assoc 2008; 48:e1-e17.

34. Centers for Disease Control and Prevention:Quadrivalent human papillomavirus vaccine. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5602a1.htm. Accessed August 16, 2010.

35. Chakrabarti O, Krishna S. Molecular interactions of ‘high risk’ human papillomaviruses E6 and E7 oncoproteins: implications for tumor progression. J Biosci 2003; 28:337-348.

36. Huh K-W, DeMasi J, Ogawa H, Nakatani Y, Howley PM, Munger K. Association of the human papillomavirus type 16 E7 oncoprotein with the 600-KDa retinoblastoma protein-associated factor p600. Proc Natl Acad Sci 2004; 102:11492-11497.

37. Sathish N, Abrahama P, Peedicayil A, Sridharan G, John S, Shaji RV, et al. HPV DNA in plasma of patients with cervical carcinoma. J Clin Virol 2004; 31:204-209.

38. Munoz N, Kjaer SK, Sigurdsson K, Iversen O-E, Hernandez-Avila M, Wheeler CM, et al. Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated genital diseases in young women. J Natl Cancer Inst 2010; 102:325-339.

39. Abbaszadegan MR, Omidi A, Niyazi A, Gholamin M, Jami-Ahmadi K, Ghafarzadegan K, et al. Prevalence of human papillomavirus type 16 and 18 and p53 mutant protein expression in esophageal squamous cell carcinomas. Iran J Basic Med Sci 2003; 6:38-342.

40. Seyedi Alavi Gh, Sharifi N, Sadeghian A, Jabari H, Bahreyni M, Bagheri H. Presence of human papilloma virus sequences in breast cancer tissue and association with histopathological features. Iran J Obstet Gynecol Infertil ? 2009; 12:1-4.

41. Armstrong EP. Prophylaxis of cervical cancer and related cervical disease: a review of the cost-effectiveness of vaccination against oncogenic HPV types. J Manag Care Pharm 2010; 16:217-230.

42. Bosch FX, Lorincz A, Muñoz N, Meijer CJ, Shah KV. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 2002; 55:241-242.

43. Yosefi Z, Msinaie M. Cervical intra-epithelial neoplasia, analysis of incidence, risk factors and management of these patients. Iran J Obstet Gynecol Infertil ? 2004; 7:32-37.

44. Arbyn M, Dillner J. Review of current knowledge on HPV vaccination: an appendix to the European guidelines for quality assurance in cervical cancer screening. J Clin Virol 2007; 38:189-197.

45. Griffith WF. Preinvasive Lesions of the Lower Genital Tract. In: Schorge JO, Schaffer JI, Halvorson LM, Hoffman BL, Bradshaw KD, Cunnigham FG. Williams Gynecology. New York: McGraw Hill; 2008.

46. Kanodia S, Fahey LM, Kast WM. Mechanisms used by human papillomaviruses to escape the host immune response. Curr Cancer Drug Targets 2007; 7:79-89.

47. Downs Jr LS, Scarinci I, Einstein MH, Collins Y, Flowers L. Overcoming the barriers to HPV vaccination in high-risk populations in the US. Gynecol Oncol 2010; 117:486-490.

48. Devaraj K, Gillison ML,Wu T-C. Development of HPV vaccines for HPV-associated head and neck squamous cell carcinoma. Crit Rev Oral Biol Med 2003; 14:345-362.

49. The GlaxoSmithKline Vaccine HPV-007 Study Group. Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years. Lancet 2009; 374:1975-1985.

50. Harper DM, Franco EL, Wheeler CM, Moscicki A-B, Romanowski B, Roteli-Martins CM, 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. Lancet 2006; 367:1247-1255.

51. Frazer IH. Measuring serum antibody to human papillomavirus following infection or vaccination. Gynecol Oncol 2010; 118:S8-S11.

52. Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002; 347:1645-1651.

53. Tovar JM, Bazaldua OV, Vargas L, Reile E. Human papillomavirus, cervical cancer, and the vaccines. Postgrad Med 2008; 120:79-84.

54. Broomal EM, Reynolds SM, Jacobson RM. Epidemiology, clinical manifestations, and recent advances in vaccination against human papillomavirus. Postgrad Med 2010; 122:121-129.

55. Paavonen J, Lehtinen M. Introducing human papillomavirus vaccines - questions remain. Ann Med 2008; 40:162-166.

56. Kim JJ, Goldie SJ. Health and economic implications of HPV vaccination in the United States. N Engl J Med 2008; 359:821-832.

57. Begue P, Henrion R, Blanc B, Girard M, Sancho-Garnier H. Vaccination against human papillomavirus. Implementation and efficacy against cervical cancer control. Bull Acad Natl Med 2007; 191:1805-1816.

58. Stanley M. Human papillomavirus vaccines versus cervical cancer screening. Clin Oncol 2008; 20:388-394.

59. Bryan JT. Developing an HPV vaccine to prevent cervical cancer and genital warts. Vaccine 2007; 25:3001- 3006.

60. Teimoori A, Soleimanjahi H, Fotouhi F, Meshkat Z. Isolation and cloning of human papillomavirus 16 L1 gene from Iranian isolate. Saudi Med J 2008; 29:1105-1108.

61. Rapose A. Human papillomavirus and genital cancer. Indian J Dermatol Venereol Leprol 2009; 75:236-244.

62. Huang CM. Human papillomavirus and vaccination. Mayo Clin Proc 2008; 83:701-707.

63. Schiller JT, Castellsague X, Villa LL, Hildesheim A. An update of prophylactic human papillomavirus L1 virus-like particle vaccine clinical trial results. Vaccine 2008; 26:K53-K61.

64. Govan VA. A novel vaccine for cervical cancer: quadrivalent human papillomavirus (types 6, 11, 16 and 18) recombinant vaccine (Gardasil®). Ther Clin Risk Manag 2008; 4:65-70.

65. Paavonen J, Jenkins D, Bosch FX, Naud P, Salmeron J, Wheeler CM, et al. 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, randomized controlled trial. Lancet 2007;369:2161–2170.

66. Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003; 348:518-527.

67. Rambout L, Hopkins L, Hutton B, Fergusson D. Prophylactic vaccination against human papillomavirus infection and disease in women: a systematic review of randomized controlled trials. CMAJ 2007; 177:469-479.

68. Monsonego J. prevention of cervical cancer (II): prophylactic HPV vaccination, current knowledge, practical procedures and new issues. Presse Med 2007; 36:640-666.

69. Roden RBS, Ling M, Wu T-C. Vaccination to prevent and treat cervical cancer. J Hum Path 2004; 35:971- 982.

70. Gao L, Chain B, Sinclair C, Crawford L, Zhou J, Morris J, et al. Immune response to human papillomavirus type 16 E6 gene in a live vaccinia vector. J Gen Virol 1994; 75:157-64.

71. Meneguzzi G, Cerni C, Kieny MP, Lathe R. Immunization against human papillomavirus type 16 tumor cells with recombinant vaccinia viruses expressing E6 and E7. Virol 1991; 181:62-629.

72. Boursnell ME, Rutherford E, Hickling JK, Rollinson EA, Munro AJ, Rolley N, et al. Construction and characterization of a recombinant vaccinia virus expressing human papillomavirus proteins for immunotherapy of cervical cancer. Vaccine 1996; 14:1485-1494.

73. Garcia-Hernandez E, Gonzalez-Sanchez JL, Andrade-Manzano A, Contreras ML, Padilla S, Guzman CC, et al. Regression of papilloma high-grade lesions (CIN 2 and CIN 3) is stimulated by therapeutic vaccination with MVA E2 recombinant vaccine. Cancer Gene Ther 2006; 13:592-597.

74. Davidson EJ, Boswell CM, Sehr P, Pawlita M, Tomlinson AE, McVey RJ, et al. Immunological and clinical responses in women with vulval intraepithelial neoplasia vaccinated with a vaccinia virus encoding human papillomavirus 16/18 oncoproteins. Cancer Res 2003; 63:6032–6041.

75. van der Burg SH, Kwappenberg KM, O’Neill T, Brandt RMP, Melief CJM, Hickling JK, et al. Preclinical safety and efficacy of TA-CIN, a recombinant HPV16 L2E6E7 fusion protein vaccine, in homologous and heterologous prime-boost regimens. Vaccine 2001; 19:3652-660.

76. 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 2002; 99:16232-1626.

77. He Z, Wlazlo AP, Kowalczyk DW, Cheng J, Xiang ZQ, Giles-Davis W, et al. Viral recombinant vaccines to the E6 and E7 antigens of HPV-16. Virology 2000; 270:146-161.

78. Baez-Astua A, Herraez-Hernandez E, Garbi N, Pasolli HA, Juarez V, zur Hausen H, et al. Low-dose adenovirus vaccine encoding chimeric hepatitis B virus surface antigen-human papillomavirus type 16 E7 proteins induces enhanced E7-specific antibody and cytotoxic T-cell responses. J Virol 2005; 79:12807–12817.

79. Liu DW, Tsao YP, Kung JT, Ding YA, Sytwu HK, Xiao X, et al. Recombinant adeno-associated virus expressing human papillomavirus type 16 E7 peptide DNA fused with heat shock protein DNA as a potential vaccine for cervical cancer. J Virol 2000; 74:2888-2894.

80. Brandsma JL, Shylankevich M, Su Y, Roberts A, Rose JK, Zelterman D, et al. Vesicular stomatitis virus-based therapeutic vaccination targeted to the e1, e2, e6, and e7 proteins of cottontail rabbit papillomavirus. J Virol 2007; 81:5749–5758.

81. Velders MP, McElhiney S, Cassetti MC, Eiben GL, Higgins T, Kovacs GR, et al. Eradication of established tumors by vaccination with Venezuelan equine encephalitis virus replicon particles delivering human papillomavirus 16 E7 RNA. Cancer Res 2001; 61:7861-7867.

82. Cheng W-F, Hung C-F, Hsu K-F, Chia C-Y, He L, Polo JM, et al. Cancer immunotherapy using Sindbis virus replicon particles encoding a VP22–antigen fusion. Hum Gene Ther 2002; 13:553-568.

83. Shi W, Liu J, Huang Y, Qiao L. Papillomavirus pseudovirus: A novel vaccine to induce mucosal and systemic cytotoxic T-lymphocyte responses. J Virol 2001; 75:10139-10148.

84. Gunn GR, Zubair A, Peters C, Pan Z-K, Wu T-C, Paterson Y. Two Listeria monocytogenes vaccine vectors that express different molecular forms of human papilloma virus-16 (HPV-16) E7 induce qualitatively different T cell immunity that correlates with their ability to induce regression of established tumors immortalized by HPV-16. J Immunol 2001; 167:6471-6479.

85. Lin C-W, Lee J-Y, Tsao Y-P, Shen C-P, Lai H-C, Chen S-L. Oral vaccination with recombinant Listeria monocytogenes expressing human papillomavirus type 16 E7 can cause tumor growth in mice to regress. Int J Cancer 2002; 102:629-637.

86. Jabbar IA, Fernando GJ, Saunders N, Aldovini A, Young R, Karen M, et al. Immune responses induced by BCG recombinant for human papillomavirus L1 and E7 proteins. Vaccine 2000; 18:2444-2453.

87. Muderspach L, Wilczynski S, Roman L, Bade L, Felix J, Small LA, 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; 6:3406-3416.

88. Steller MA, Gurski KJ, Murakami M, Daniel RW, Shah KV, Celis E, et al. Cell-mediated immunological responses in cervical and vaginal cancer patients immunized with a lipidated epitope of human papillomavirus type 16 E7. Clin Cancer Res 1998; 4:2103-2109.

89. Lacey CJ, Thompson HS, Monteiro EF, O’Neill T, Davies ML, Holding FP, et al. Phase IIa safety and immunogenicity of a therapeutic vaccine, TA-GW, in persons with genital warts. J Infect Dis 1999; 179:612-618.

90. de Jong A, O’Neill T, Khan AY, Kwappenberg KMC, Chisholm SE, Whittle NR, 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. Vaccine 2002; 20:3456-464.

91. Chu NR, Wu HB, Wu T-C, Boux LJ, Mizzen LA, Siegel MI. Immunotherapy of a human papillomavirus (HPV) type 16 E7–expressing tumour by administration of fusion protein comprising Mycobacterium bovis bacilli Calmette-Guerin (BCG) hsp65 and HPV16 E7. Clin Exp Immunol 2000; 121:216-225.

92. 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; 53:642-650.

93. Robinson HL. Nucleic acid vaccines: an overview. Vaccine 1997; 15:785-787.

94. Meshkat Z. Construction of an expression vector containing immunogenic region of human papillomavirus type 16 E7 and HSP70 genes and evaluate the CMI responses in BALB/c mice. Tehran: Tarbiat Modares University; 2007.

95. Peng S, Trimble C, Ji H, He L, Tsai Y-C, Macaes B, et al. Characterization of HPV-16 E6 DNA vaccines employing intracellular targeting and intracellular spreading strategies. J Biomed Sci 2005; 12:689-700.

96. Elliott G, O’Hare P. Intercellular trafficking and protein delivery by a herpesvirus structural protein. Cell 1997; 88:223-33.

97. 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; 63:2393-2398.

98. Hung C-F, Cheng W-F, Hsu K-F, Chai C-Y, He L, Ling M, et al. Cancer immunotherapy using a DNA vaccine encoding the translocation domain of a bacterial toxin linked to a tumor antigen. Cancer Res 2001; 61:3698-36703.

99. Cheng W-F, Hung C-F, Chai C-Y, Hsu K-F, He L, Ling M, et al. Tumor-specific immunity and antiangiogenesis generated by a DNA vaccine encoding calreticulin linked to a tumor antigen. J Clin Invest 2001; 108:669-678.

100. Chen C-H, Wang T-L, Hung C-F, Yang Y, Young RA, Pardoll DM, et al. Enhancement of DNA vaccine potency by linkage of antigen gene to an HSP70 gene. Cancer Res 2000; 60:1035-1042.

101. Kim TW, Hung C-F, Ling M, Juang J, He L, Hardwick JM, et al. Enhancing DNA vaccine potency by coadministration of DNA encoding antiapoptotic proteins. J Clin Invest 2003; 112:109-117.

102. Leachman SA, Tigelaar RE, Shlyankevich M, Slade MD, Irwin M, Chang E, et al. Granulocytemacrophage colony–stimulating factor priming plus papillomavirus E6 DNA vaccination: Effects on papilloma formation and regression in the cottontail rabbit papillomavirus–rabbit model. J Virol 2000; 74:8700-8708.

103. Tan J, Yang N-S, Turner JG, Niu G-L, Maassab HF, Sun J, et al. Interleukin-12 cDNA skin transfection potentiates human papillomavirus E6 DNA vaccine-induced antitumor immune response. Cancer Gen Ther 1999; 6:331-339.

104. Liu WJ, Gao F, Zhao KN, Zhao W, Fernando GJG, Thomas R, et al. Codon modified human papillomavirus type 16 E7 DNA vaccine enhances cytotoxic T-lymphocyte induction and anti-tumor activity. Virol 2002; 301:43-52.

105. 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; 77:4928-4937.

106. Klencke B, Matijevic M, Urban RG, Lathey JL, Lynne Hedley M, Berry M, et al. Encapsulated plasmid DNA treatment for human papillomavirus 16-associated anal dysplasia: a phase I study of ZYC1011. Clin Cancer Res 2002; 8:1028-1037.

107. Hung C-F, Tsai Y-C, He L, Wu T-C. DNA vaccines encoding Ii-PADRE generates potent PADRE-specific CD4+ T-cell immune responses and enhances vaccine potency. Mol Ther 2007; 15:1211-1219.

108. Brulet J-M, Maudoux F, Thomas S, Thielemans K, Burny A, Leo O, et al. DNA vaccine encoding endosometargeted human papillomavirus type 16 E7 protein generates CD4+ T cell-dependent protection. Eur J Immunol 2007; 37:376–384.

109. Smith HA, Klinman DM. The regulation of DNA vaccines. Curr Opin Biotech 2001; 12:299-303.

110. Hasan UA, Abai AM, Harper DR, Wren BW, Morrow WJW. Nucleic acid immunization: concepts and techniques associated with third generation vaccines. J Immun Meth 1999; 229:1-22.

111. Berglund P, Smerdou C, Fleeton MN, Tubulekas I, Liljestrom p. Enhancing immune responses using suicidal DNA vaccines. Nature Biotech 1998; 16:562-565.

112. Greenstone HL, Nieland JD, De Visser KE, DE Bruijn MLH, Kirbnbauer R, Roden RBS, et al. Chimeric papillomavirus virus-like particles elicit anti tumor immunity against the E7 oncoprotein in an HPV16 tumor model. Proc Natl Acad Sci 1998; 95:1800-1805.

113. Qian J, Dong y, Pang Y-YS, Ibrahim R, Berzofsky JA. Schiller JT, et al. Combined prophylactic and therapeutic cancer vaccine: Enhancing CTL responses to HPV16 E2 using a chimeric VLP in HLA-A2 mice. Int J Cancer 2006; 118:3022–3023.

114. Chen C-H, Wang T-L, Hung C-F, Pardoll DM, Wu T-C. Boosting with recombinant vaccinia increases HPV- 16 E7–specific T cell precursor frequencies of HPV-16 E7–expressing DNA vaccines. Vaccine 2000; 18:2015- 2022.

115. Kowalczyk DW, Wlazlo AP, Shane S, Ertl HCJ. Vaccine regimen for prevention of sexually transmitted infections with human papillomavirus type 16. Vaccine 2001; 19:3583-3590.