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1 Focused Issue of This Month Kyung Hyo Kim, MD Department of Pediatrics, Ewha Womans University College of Medicine E mail : kaykim@ewha.ac.kr J Korean Med Assoc 2008; 51(2): Vaccination has had a major effect on protection of humans against disease. The human papillomavirus (HPV) vaccine is the most recent breakthrough in the vaccine development, which provides an exceptional opportunity for cancer prevention through vaccination. The prophylactic quadrivalent vaccine using L1 virus like particles (VLPs) of HPV 6, 11, 16, and 18 is now available in Korea, and the bivalent vaccine containing VLPs of HPV16 and HPV18 is available in other countries. Results from the phase IIb and III trials show that these two HPV vaccines are safe and well tolerated. They offer HPV naive women a very high level of efficacy against persistent infection and cervical intra epithelial lesions associated with the HPV types included in the vaccine. The quadrivalent vaccine has also been shown to protect against vulvar and vaginal lesions and genital warts caused by types 6 and 11. Recent studies on both vaccines indicate there is a high level of cross protection against infections associated with other related oncogenic HPV types, which are responsible for a further 10% of cervical cancers globally. The Korean Society of Pediatrics has developed guidelines for the use of the prophylactic HPV vaccine for the prevention of cervical intraepithelial neoplasia and cervical cancer. They address the use of prophylactic HPV vaccines, including who should be vaccinated and at what age, as well as a summary of policy and implementation issues. With the introduction of the vaccines, general issues have to be raised such as duration of protection after vaccination, data on different immunization schedules, data on infants and young children, cross protection, impact on cervical cancer screening, vaccination of males, potential replacement infection and vaccine compatibility. This review provides an up to date summary of recent studies and available information concerning HPV vaccination. Keywords : Papillomavirus vaccines; Guideline Abstract 144

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4 Table 1. Efficacy data from Phase randomised controlled trials of human papillomavirus vaccines Vaccine Cervarix Gardasil Gardasil Vaccine Population Analysed Disease HPV Types Number of Endpoint Patients Efficacy (cases in v:c) modified intention to treat CIN2+or AIS 16 or 18 V: 7, % analysis C: 7,838 (2:21) Per protocol susceptible CIN2+or AIS 16 or 18 V: 8,579 99% population C: 8,550 (1:85) Unrestricted susceptible CIN2+or AIS 16 or 18 V: 9,729 98% population C: 9,737 (3:121) Intention to treat CIN2+or AIS 16 or 18 V: 10,291 44% population C: 10,292 (142:255) Intention to treat CIN2+or AIS Any type V: 10,291 18% population C: 10,292 (394:483) Per protocol susceptible Condyloma 6, 11, 16, 18 V: 2, % population C: 2,279 (0:48) unrestricted susceptible Condyloma 6, 11, 16, 18 V: 2,667 96% population C: 2,684 (3:67) Intention to treat Condyloma 6, 11, 16, 18 V: 2,723 76% population C: 2,732 (21:86) Intention to treat Condyloma Any type V: 2,723 51% population C: 2,732 (55~111) CI* 53.4, , , , 55 7, 29 92, 100 * 97.9% CI reported for Paavonen, et al (33), 95% CI reported for Future 2 Study (34) and Garland, et al (35) : Defined as This analysis assesses prophylactic efficacy I women uninfected sith the indivdual HPV type at study entry (day O). The total vaccinated cohort included women who had prevalent infection with oncogenic HPV often with several types, as well as low grade cytological abnormalities at study entry and who received at least one vaccine dose. : Defined as all women who were serongative and PCR negative to HPV 16, HPV 18 or both at day 1, including those who received incomplete vaccination regimens. were exposed to HPV 16/18 before receiving three doses or who had major protocol violations. : Defined as subjects who were seronegative and HPV DNA negative on PCR analysis for HPV6, HPV11, HPV16 or HPV18 at day 1: were included even if protocol violations were present: were included even if results on cervical cytologic examinations at day 1 were abnormal. V: vaccine group. C: control group. CIN2+: cervical intraepithelial neoplasia grade 2 or more severe, AIS: adenocarcinoma in situ 86, 99 61, 86 32,

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6 ( mmu/ml ) Immunogenicity Bridge Efficacy Program Age at Enrollment (Years) Abbreviation: GMT; geometric mean titer, CI; confidence interval Source: Merck, unpublished data, Presented at ACIP meeting, February 2006 Figure 1. Serum anti HPV 6 antibody titers after quadrivalent HPV vaccination by age at enrollment. Immunogenicity bridge study was done in female 9~15 year of age and efficacy program was done in female 16~23 year of age. 149

7 Kim KH Table 2. Summary of HPV clia geometric mean titers by age among subjects who received GARDASIL Age group 9 to 17 yrs(n = 56) 18 to 23 yrs(n = 61) GMT 95% CI GMT 95% CI Assay (clia) Time Point n (mmu/ml) n (mmu/ml) Anti HPV 6 Preimmune 56 <8 <8, <8 59 <8 <8, <8 Postimmune , 1, , Anti HPV 11 Preimmune 56 <8 <8, <8 59 <8 <8, <8 Postimmune 56 1, ,024.2, 1, , Anti HPV 16 Preimmune 56 <12 <12, <12 60 <12 <12, <12 Postimmune 56 8, ,023.6, 11, , ,376.4, 4,835.4 Anti HPV 18 Preimmune 56 <8 <8, <8 59 <8 <8, <8 Postimmune 55 1, , 1, , : The all HPV type specific naive subjects immunogenicity population includes all subjects who received all 3 vaccinations and were seronegative at Day 1 for the relevant HPV type(s) N: Number of subjects with the indicated age group; n: Number of subjects contributing to the analysis CI: Confidence interval; clia: Competitive Luminex immunoassay; GMT: Geometric mean titer; mmu: Milli Merck units Anogenital warts Oncogenic types Figure 2. Papillomavirus phylogenetic tree. Oncogenic types Warts on hands and feet 150

8 Table 3. Data of cross protection against non vaccine human papillomavirus types from randomised controlled trials Vaccine Disease endpoint HPV Types 45 PI: 12m 31 PI: 12m Number of Patients Vaccine Efficacy (cases in v:c) CI* V: 6, % C: 6,747 (10:25) 2.6, 85.2 V: 3, % C: 3,601 (3:8) 93.2, 95.4 V: 6, % C: 6,667 (47:74) 0.5, 59.5 V: 3, % C: 3,568 (15:17) 115.2, 63.6 Cervarix Gardasil PI: 12m PI: 12m V: 6, % C: 6,736 (31:49) 9.9, 64.0 V: 3, % C: 3,603 (6:11) 91.8, 86.5 V: 6, % C: 6,573 (79:116) 3.5, 51.9 V: 3, % C: 3,508 (16:30) 12.3, 75.8 V: 6, % 132.1, C: 6,734 (43:33) PI: 12m V: 3, % 372.0, 78.4 C: 3,601 (6:6) V: 6, % 31, 33, 35, 39, 45, 51, C: 6,804 (505:554) 5.1, , 56, 58, 59 V: 3, PI: 12m C: 3,632 (100:137) 0.5, % 9, 38 31, 33, 45, 52, 58 CIN1+ or AIS 19% 1, 33 CIN1+ or AIS 31 or 45 CIN2+ or AIS CIN1+ or AIS 31, 33, 45,52, 58 CIN2+ or AIS CIN1+ or AIS CIN2+ or AIS V: 1,036 45% C: 1,029 (41:73) V: 4,616 45% C: 4,675 (23:42) V: 4,616 62% C: 4,675 (8:21) V: 1, % C: 1,029 (109:148) V: 4,616 33% C: 4,675 (66:99) V: 4,616 43% C: 4,675 (27:48) V: 4,616 27% 31, 33, 35, 39,45, 51, C: 4,675 (135:185) 52, 56, 58, 59 V: 4,616 38% C: 4,675 (38:62) *: 97.9% Confidence intervals reported for Paavonen, et al (33), 95% CI reported for Brown (47) V: group. C: control group. PI: persistent infection. CIN1+: cervical intraepithelial neoplasia grade 1 or more severe. CIN2+: cervical intraepithelial neoplasia grade 2 or more severe. AIS: adenocarcinoma in situ 18.3, , 68 10, , , 52 7, 66 8, 42 6,

9 Kim KH Table 4. Global policy recommendations for human papillomavirus vaccine Country Female Male Funding Primary cohort Catch up cohorts Recommended Primary cohort Public /Private sector Age (yr) Algeria 12~13 9~11, 14~26 9~15 No Argentina 11~15 17~26 9~10, 16 Private Australia 12~13 14~26 Public Austria 9~15 16~26 9~15 No Belgium 10~13 14~15 16~26 Public & Private Bermuda 11~12 9~10, 13~26 Private Canada 9~26 Public for 12~14 Cyprus 9~15 16~26 9~15 No Czeck Rep. 9~18 Private Denmark 12 13~15 Public France 14 15~23 Public & Private Germany 12~17 18~26 Private Greece 12~15 16~26 Public for 12~15 Greenland 11~15 11~15 No Hong Kong 9~26 No Israel 9~26 Public Italy 12 15, 18, 25 No Lichtenstein 9~26 Public Luxemburg 11~12 13~18 No New Zealand 9~26 9~15 No Norway 11~12 13~16 No Poland 9~26 No Slovakia 12 Public Spain 11~14 Public Sweden 13~17 Private Switzerland 11~14 15~19 20~26 No The Netherlands 9~26 9~15 Private UK 12~13 14~18 Public USA 11~12 9~10, 13~18 19~26 Public & Private Abbreviations: P; primary cohort 152

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11 Kim KH 11. Lowy DR, Schiller JT. Prophylactic human papillomavirus vaccines. J Clin Invest 2006; 116: Pollack AE, Balkin M, Edouard L, Cutts F, Broutet N. WHO/ UNFPA Working Group on Sexual and Reproductive Health and HPV Vaccines. Ensuring access to HPV vaccines through integrated services: a reproductive health perspective. Bull World Health Organ 2007; 85: Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER. Centers for Disease Control and Prevention (CDC); Advisory Committee on Immunization Practices (ACIP). Quadrivalent : Recommendations of the Advisory Committee on Immunization Practices(ACIP). MMWR Recomm Rep 2007; 56(RR 2): American Academy of Pediatrics Committee on Infectious Diseases. Recommended immunization schedules for children and adolescents United States, Pediatrics 2007; 119: Saslow D, Castle PE, Cox JT, Davey DD, Einstein MH, Ferris DG, Goldie SJ, Harper DM, Kinney W, Moscicki AB, Noller KL, Wheeler CM, Ades T, Andrews KS, Doroshenk MK, Kahn KG, Schmidt C, Shafey O, Smith RA, Partridge EE; Gynecologic Cancer Advisory Group, Garcia F. American Cancer Society Guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin 2007; 57: Kim KH, Kim JH, Park SE, Shin SH, Oh SH, Lee HJ, Jo DS, Choi EH, Hur JK, Hong YJ, The Committee on Infectious Diseases, The Korean Pediatric Society. Human Papillomavirus Vaccine. Korean J Pediatr 2007; 50:

12 17. Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998; 338: Moscicki AB, Shiboski S, Broering J, Powell K, Clayton L, Jay N, Darragh TM, Brescia R, Kanowitz S, Miller SB, Stone J, Hanson E, Palefsky J. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women. J Pediatr 1998; 132: Ho GY, Burk RD, Klein S, Kadish AS, Chang CJ, Palan P, Basu J, Tachezy R, Lewis R, Romney S. Persistent genital human papillomavirus infection as a risk factor for persistent cervical dysplasia. J Natl Cancer Inst 1995; 87: Schiffman M, Kjaer SK. Natural history of anogenital human papillomavirus infection and neoplasia. J Natl Cancer Inst Monogr 2003; 31: de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur HH. Classification of papillomaviruses. Virology 2004; 324: Bonnez W, Reichman RC. Papillomaviruses. In: Mandell GL, Bennet JE, Dolin R, eds. Principles and practice of Infectious Disease. 6th ed. Elsevior Inc., 2005: Muñoz N, Bosch FX, de Sanjosé S, Herrero R, Castellsague X, Shah KV, Snijders PJ, Meijer CJ; International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003; 348: Clifford G, Franceschi S, Diaz M, Muñoz N, Villa LL. Chapter 3: HPV type distribution in women with and without cervical neoplastic diseases. Vaccine 2006; 24(S3): Duensing S, Munger K. Mechanisms of genomic instability in human cancer: insights from studies with human papillomavirus oncoproteins. Int J Cancer 2004; 109: Stanley M. Immune responses to human papillomavirus. Vaccine 2006; 24: S16-S Carter JJ, Koutsky LA, Hughes JP, Lee SK, Kuypers J, Kiviat N, Galloway DA. Comparison of human papillomavirus types 16, 18, and 6 capsid antibody responses following incident infection. J Infect Dis 2000; 181: Winer RL, Lee SK, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol 2003; 157: Manhart LE, Holmes KK, Koutsky LA, Wood TR, Kenney DL, Feng Q, Kiviat NB. Human papillomavirus infection among sexually active young women in the United States: implications for developing a vaccination strategy. Sex Transm Dis 2006; 33: Watts DH, Koutsky LA, Holmes KK, Goldman D, Kuypers J, Kiviat NB, Galloway DA. Low risk of perinatal transmission of human papillomavirus: results from a prospective cohort study. Am J Obstet Gynecol 1998; 178: Moscicki AB, Schiffman M, Kjaer S, Villa LL. Updating the natural history of HPV and anogenital cancer. Vaccine 2006; 24: S Castellsague X, Munoz N. Cofactors in human papillomavirus carcinogenesis role of parity, oral contraceptives, and tobacco smoking. J Natl Cancer Inst Monogr 2003; 31: Ministry of Health and Welfare Annual Report of the Korea Central Cancer Registry (Published in 2003). 24. Korea National Statistical Office. Annual Report on the Cause of Death Statistics (published in 2005). 25. Shin HR, Lee DH, Herrero R, Smith JS, Vaccarella S, Hong SH, Jung KY, Kim HH, Park UD, Cha HS, Park S, Touze A, Muñoz N, Snijders PJ, Meijer CJ, Coursaget P, Franceschi S. Prevalence of human papillomavirus infection in women in Busan, South Korea. Int J Cancer 2003; 103: Shin HR, Franceschi S, Vaccarella S, Roh JW, Ju YH, Oh JK, Kong HJ, Rha SH, Jung SI, Kim JI, Jung KY, van Doorn LJ, Quint W. Prevalence and determinants of genital infection with papillomavirus, in female and male university students in Busan, South Korea. J Infect Dis 2004; 190: Shin HR, Seoh K, Song KJ, Park EC, Choi GS, Lee HY, Oh JK, Kim BK, Kim JY. A report of investigation of disease burden associated with human papillomavirus infection in Korea. Korean Center for Disease Control and Prevention (published in 2007). 28. Stanley M, Lowy DR, Frazer I. Prophylactic vaccines: underlying mechanisms. Vaccine 2006; 24: S Kahn JA. Vaccination as a prevention strategy for human papillomavirus related diseases. J Adolesc Health 2005; 37 (S6): S Noad R, Roy P. Virus like particles as immunogens. Trends Microbiol 2003; 11: Kim YT. Prophylactic vaccine for cervical carcinoma. J Korean Med Assoc 2007; 50: Ahn WS. Recent concepts for human papillomavirus vaccine. J Korean Med Assoc 2007; 50: Paavonen J, Jenkins D, Bosch FX, Naud P, Salmeron J, Wheeler CM, Chow SN, Apter DL, Kitchener HC, Castellsague X, de Carvalho NS, Skinner SR, Harper DM, Hedrick JA, Jaisamrarn U, Limson GA, Dionne M, Quint W, Spiessens B, Peeters P, Struyf F, Wieting SL, Lehtinen MO, Dubin G; HPV PATRICIA study group. Efficacy of a prophylactic adjuvanted bivalent L1 virus like particle vaccineagainst infection with human papillomavirus types 16 and 18 in young women: aninterim analysis of a phase III double blind, randomised controlled trial. Lancet 2007; 369: Ault KA; Future II Study Group. Effect of prophylactic human papillomavirus L1 virus like particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials. Lancet 2007; 369: Garland SM, Hernandez Avila M, Wheeler CM, Perez G, Harper DM, Leodolter S, Tang GW, Ferris DG, Steben M, Bryan J, Taddeo FJ, Railkar R, Esser MT, Sings HL,Nelson M, Boslego J, Sattler C, Barr E, Koutsky LA; Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007; 356:

13 Kim KH 36. Villa LL, Costa RL, Petta CA, Andrade RP, Paavonen J, Iversen OE, Olsson SE, Høye J, Steinwall M, Riis Johannessen G, Andersson Ellstrom A, Elfgren K, KroghG, Lehtinen M, Malm C, Tamms GM, Giacoletti K, Lupinacci L, Railkar R, Taddeo FJ, Bryan J, Esser MT, Sings HL, Saah AJ, Barr E. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus like particle vaccine through 5 years of follow up. Br J Cancer 2006; 95: Olsson SE, Villa LL, Costa RL, Petta CA, Andrade RP, Malm C, Iversen OE, Høye J, Steinwall M, Riis Johannessen G, Andersson Ellstrom A, Elfgren K, von Krogh G, Lehtinen M, Paavonen J, Tamms GM, Giacoletti K, Lupinacci L, Esser MT, Vuocolo SC, Saah AJ, Barr E. Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus like particle (VLP) vaccine. Vaccine 2007; 25: Harper DM, Franco EL, Wheeler CM, Moscicki AB, Romanowski B, Roteli Martins CM, Jenkins D, Schuind A, Costa Clemens SA, Dubin G; HPV Vaccine Study group. Sustained efficacy up to 4.5 years of a bilvalent L1virus like particle vaccine against human papillomavirus types 16 and 18: follow up from a randomised control trial. Lancet 2006; 367: Opalka D, Lachman CE, MacMullen SA, Jansen KU, Smith JF, Chirmule N, Esser MT. Simultaneous quantitation of antibodies to neutralizing epitopes on virus like particles for human papillomavirus types 6, 11, 16, and 18 by a multiplexed luminex assay. Clin Diagn Lab Immunol 2003; 10: Dias D, Van Doren J, Schlottmann S, Kelly S, Puchalski D, Ruiz W, Boerckel P, Kessler J, Antonello JM, Green T, Brown M, Smith J, Chirmule N, Barr E, Jansen KU, Esser MT. Optimization and validation of a multiplexed luminex assay to quantify antibodies to neutralizing epitopes on human papillomaviruses 6, 11, 16, and 18. Clin Diagn Lab Immunol 2005; 12: Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D, Schuind A, Zahaf T, Innis B, Naud P, De Carvalho NS, Roteli Martins CM, Teixeira J, Blatter MM, Korn AP, Quint W, Dubin G; GlaxoSmithKline HPV Vaccine Study Group. 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. Lancet 2004; 364: Reisinger KS, Block SL, Lazcano Ponce E, Samakoses R, Esser MT, Erick J, Puchalski D, Giacoletti KE, Sings HL, Lukac S, Alvarez FB, Barr E. Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus like particle vaccine in preadolescents and adolescents: a randomized controlled trial. Pediatr Infect Dis J 2007; 26: Block SL, Nolan T, Sattler C, Barr E, Giacoletti KE, Marchant CD, Castellsagué X, Rusche SA, Lukac S, Bryan JT, Cavanaugh PF Jr, Reisinger KS; Protocol 016 Study Group. Comparison of the immunogenicity and reactogenicity of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus like particle vaccine in male and female adolescents and young adult women. Pediatrics 2006; 118: Villa LL, Ault KA, Giuliano AR, Costa RL, Petta CA, Andrade RP, Brown DR, Ferenczy A, Harper DM, Koutsky LA, Kurman RJ, Lehtinen M, Malm C, Olsson SE, Ronnett BM, Skjeldestad FE, Steinwall M, Stoler MH, Wheeler CM, Taddeo FJ, Yu J, Lupinacci L, Railkar R, Marchese R, Esser MT, Bryan J, Jansen KU, Sings HL, TammsGM, Saah AJ, Barr E. Immunologic responses following administration of a vaccine targeting human papillomavirus types 6, 11, 16, and 18. Vaccine 2006; 24: Kang S, Kim KH, Kim YT, Kim YT, Kim JH, Song YS, Shin SH, Ryu HS, Han JW, Kang JH, Park SY. Safety and immunogenicity of a vaccine targeting human papillomavirus types 6, 11, 16 and 18: a randomized, placebo controlled trial in 176 Korean subjects. Int J Gynecol Cancer Munoz N, Castellsagué X, de González AB, Gissmann L. Chapter 1: HPV in the etiology of human cancer. Vaccine 2006; 24(S3): Brown D, for the FUTURE Study Group. HPV Type 6/11/16/18 Vaccine: First analysis of cross protection against persistent infection, cervical intraepithelial neoplasia (CIN), and adenocarcinoma in situ (AIS) caused by oncogenic HPV types in addition to 16/18. ICAAC Chicago. September Food and Drug Administration. Product approval information licensing action [package insert]. Gardasil (quadrivalent human papillomavirus types 6, 11, 16, 18). Merck & Co., Whitehouse Station, NJ. Available at HPVmer060806LB.pdf. 49. Preparing for the introduction of HPV vaccines, Policy and programme guidance for countries. products/hpvmer htm 50. Soldan K, Dillner J. Comparable strategies needed to evaluate human papillomavirus vaccine efficiency across Europe. Euro Surveill 2006; 11: E Kudjawu Y, Lévy Bruhl D, Celentano LP, O Flanagan D, Salmaso S, Lopalco P, Mullins N, Bacci S; VENICE working group. The current status of HPV and rotavirus vaccines in national immunisation schedules in the EU preliminary results of a VENICE survey. Euro Surveill 2007; 12: E Howell Jones R. Human papillomavirus vaccination: the United Kingdom s recommendation and update on European licensure and efficacy data. Euro Surveill 2007; 12: E

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R