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): 144-157 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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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: 7,788 90.4% 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: 2,261 100% 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, 99.3 93, 100 93, 100 31, 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, 65 147
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( mmu/ml ) 1600 1500 1300 1100 900 700 Immunogenicity Bridge Efficacy Program 500 9 1011121314151617181920212223 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
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 55 906.5 654.2, 1,256.1 59 379.1 270.5, 531.4 Anti HPV 11 Preimmune 56 <8 <8, <8 59 <8 <8, <8 Postimmune 56 1,376.4 1,024.2, 1,849.7 59 763.6 587.4, 992.7 Anti HPV 16 Preimmune 56 <12 <12, <12 60 <12 <12, <12 Postimmune 56 8,302.6 6,023.6, 11,443.8 60 3,389.8 2,376.4, 4,835.4 Anti HPV 18 Preimmune 56 <8 <8, <8 59 <8 <8, <8 Postimmune 55 1,352.0 959.5, 1,905.1 58 589.8 423.2, 822.0 : 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
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: 6,724 59.9% C: 6,747 (10:25) 2.6, 85.2 V: 3,584 62.3% C: 3,601 (3:8) 93.2, 95.4 V: 6,615 36.1% C: 6,667 (47:74) 0.5, 59.5 V: 3,527 10.8% C: 3,568 (15:17) 115.2, 63.6 Cervarix Gardasil PI: 12m PI: 12m 33 52 V: 6,702 36.5% C: 6,736 (31:49) 9.9, 64.0 V: 3,574 45.1% C: 3,603 (6:11) 91.8, 86.5 V: 6,532 31.6% C: 6,573 (79:116) 3.5, 51.9 V: 3,489 46.5% C: 3,508 (16:30) 12.3, 75.8 V: 6,688 31.4% 132.1, 24.7 58 C: 6,734 (43:33) PI: 12m V: 3,563 1.1% 372.0, 78.4 C: 3,601 (6:6) V: 6,773 9.0% 31, 33, 35, 39, 45, 51, C: 6,804 (505:554) 5.1, 21.2 52, 56, 58, 59 V: 3,611 27.1 PI: 12m C: 3,632 (100:137) 0.5, 46.8 25% 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: 1,036 27.8% 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, 63.4 6, 68 10, 85 6.9, 442.2 8, 52 7, 66 8, 42 6, 60 151
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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