Journal of Bacteriology and Virology 2011. Vol. 41, No. 4 p.313 318 http://dx.doi.org/10.4167/jbv.2011.41.4.313 Letter to the Editor Systemic Review for Efficacy of Human Papillomavirus Vaccines Ho Sun Park * Department of Microbiology, College of Medicine, Yeungnam University, Daegu, Korea Two human papillomavirus (HPV) vaccines (Gardasil and Cevarix TM ) were launched between 2006~2007. Clinical trials have been performed in several countries. However, it takes few decades to measure HPV vaccine efficacy for the protection of cervical cancer. Therefore, several surrogate markers such as seroconversion rate, presence of HPV DNA, and cytological/ histological abnormalities have been evaluated. Until now, long-term follow-up data for 5 years (Gardasil) and for 8.4 years (Cevarix) were available from international trials. However, only seroconversion rate at 4 weeks after vaccination and safety were evaluated in Korea. It is necessary to establish a reference laboratory and long-term follow-up monitoring system for the proper evaluation of HPV vaccines in Korea. Key Words: Human papillomavirus, Vaccine, Efficacy 서론 저자는인유두종바이러스백신의효과에대한메타분석논문인 'Efficacy of human papillomavirus vaccine: A systemic quantitative review. International Journal of Gynecological Cancer 2009:19;1166-76' 과인유두종바이러스백신의장기효과에대한논문인 'Long term protection against cervical infection with the human papillomavirus. Human Vaccines 2011:7;161-9' 를읽고이를중심으로이분야에대한요약과견해를아래와같이전달하고자합니다. 요약 인유두종바이러스 (human papilloma virus: HPV) 에대한두가지백신이현재약 100여개국에서허가를받아 HPV 관련질환의예방목적으로사용되고있다. HPV 백 Received: December 1, 2011/ Revised: December 6, 2011 Accepted: December 9, 2011 * Corresponding author: Ho Sun Park. Rm#407, Department of Microbiology, College of Medicine, Yeungnam University, 170 Hyeonchung-ro, Nam-gu, Daegu, 705-717, Korea. Phone: +82-53-620-4364, Fax: +82-53-653-6628 e-mail: hspark@ynu.ac.kr 신으로예방하고자하는주된질환인자궁경부암은 HPV 가감염되고수십년후에발생하므로백신의효과를단기간에측정할수없다. 따라서아직까지이백신들이얼마나오랜기간동안 HPV 감염및관련질환을방어할수있는지, 추가접종이필요한지등에대한정보가없는상태에서예방접종에대한가이드라인이제시되었다. Medeiros 등은 HPV 백신에대한무작위대조임상시험 (randomized controlled clinical trials: RCT) 결과들을 systemic review하여백신의효과와안전성, 면역원성에대한메타분석을실시하였고 (1), Romanowsky는최근까지실시된 HPV 백신의장기임상시험결과들에대한 systemic review를실시하여 2가백신인서바릭스는 8.4년, 4가백신인가다실은 5년까지의면역원성과 HPV 감염, 자궁경부병변에대한백신효과를확인하였다 (2). 지금까지발표된결과들을살펴보면백신접종전피험자의 HPV 감염유무나연령, 백신접종횟수, 백신효과측정을위한종말점 (end point), 추적기간등이매우다양하므로메타분석을위한연구의수가한정되고특히장기적인효과를보기에는아직까지자료가부족한실정이다. 그러므로 HPV 백신의효과를파악하기위해서는장기간에걸친면역원성과임상결과를모니터할수있는시스템이갖추어져야하며, 백신제조사에게장기간에걸친추적연구를하도록요구하여야한다고제시하였다 (2). 313
314 HS Park 해설 HPV는 100여종이상의바이러스가존재하며피부와점막에감염하여병변을유발한다. 점막상피에감염을유발하는 HPV는자궁경부암발생과의연관성에따라저위험군과고위험군으로분류된다. 저위험군 HPV는첨단콘딜로마나항문생식기사마귀와같은생식기사마귀, 호흡기인유두종증, 양성또는저등급자궁경부세포이상등을유발하며, 고위험군 HPV는자궁경부세포이상, 항문생식기암, 자궁경부암의원인이다. 자궁경부암은전세계적으로여성에서두번째많이발생하는암이며, 우리나라에서도여성암으로세번째로많이발생하는암이다 (3). 4가 (HPV6/11/16/18) 백신인가다실 (Gardasil, Merck, Whitehouse Station, NJ, USA) 은 2006년미국에서처음허가를받았고국내에서는 2007년부터사용되고있으며, 2 가 (HPV16/18) 백신인서바릭스 (Cevarix TM, GSK, Middlesex, UK) 는 2007년에오스트레일리아에서처음허가를받았고국내에서는 2008년부터사용되고있다. HPV 백신의 효과평가는궁극적으로는자궁경부암이나생식기사마귀등 HPV에유해유발되는질환의발생률로측정해야하나자궁경부암의발생은 HPV가감염되고수십년후에나타나므로장기적인추적을하지않고서는불가능하다. 따라서 HPV 백신의효과를평가하는방법으로백신관련 HPV의감염유무, 세포나조직학적이상, 항체가나항체양전율등과같은대리표지자들을측정한다. Medeiros 등은 HPV 백신의임상적효과와안전성및면역원성을평가하기위하여 9세에서 26세여성을대상으로실시한양측눈가림 RCT 연구들에대한 systemic review를하였다 (1). 이연구의주된목적을평가하기위하여필요한선택기준 (selection criteria) 들에합당한 6개의연구를대상으로메타분석을실시하였으며, 총 47,236명의피험자가분석에포함되었다 (Table 1) (4~9). 백신의임상적효과를측정하기위하여자궁경부, 외음, 질, 항문생식기에대한저등급평편상피내병변 (low grade squamous intraepithelial lesion: LSIL) 과고등급평편상피내병변 (Hi grade squamous intraepithelial lesion: HSIL) 의발생건수를측정하여백신효과를 odd ratio (OR) 로표현하였다. 서바릭스의백신투여군과대조군에각각약 10,000명이분 Table 1. Characteristics of clinical studies included in systemic review by Medeiros (Modified from Medeiros et al. Ref.1) Study ID References Sex: Enroll No. Age, yrs Vaccine valency (HPV Type) Periods (Area) Follow-up (Month) NCT00689741 (HPV-001) a 4 V 560 P 553 15~25 Bivalent (16, 18) 2003.11~2004.07 (Brazil, Canada, USA) 44 NCT00122681 (HPV-008) a PATRICIA 5 V 9,319 P 9,325 15~25 Bivalent (16, 18) 2004.05~2005.06 (14 countries) 14.8 NCT00128661 (HPV-009) a 6 V 3,727 P 3,739 18~25 Bivalent (16, 18) 2004.06~2005.12 (Costa Rica) 12 NCT00365378 (V501-005) b 7 V 1,193 P 1,198 16~23 Monovalent (16) 1998.10~1999.11 (USA) 48 NCT00092521 (V501-013) b FUTURE I 8 V 2,723 P 2,732 16~24 Quadrivalent (6, 11, 16, 18) 2002.01~2003.03 (16 countries) 36 NCT00092534 (V501-015) b FUTURE II 9 V 5,305 P 5,260 15~26 Quadrivalent (6, 11, 16, 18) 2002.06~2003.05 (13 countries) 48 a GSK protocol No. b Merck protocol No. NCT ID, ID of ClinicalTrials.gov; F, female; V, vaccine group; P, placebo group
Systemic Review for Efficacy of Human Papillomavirus Vaccines 315 Study identifier Table 2. Long-term clinical trials of the bivalent and quadrivalent HPV vaccines (modified from Romanowski Ref.2) Sex: age (years) Head-to-head trials (Bivalent Vs. Quadrivalent vaccine) Duration of follow-up currently reported Planned duration of follow-up References HPV-010 18~45 2 years 4 years 10, 11 Bivalent vaccine HPV-001/007/023 15~25 Up to 8.4 years after 1 st vaccination ~ 9.5 years 12, 13, 14 HPV-014 15~55 4 years Completed 15 HPV-013/025 10~14 4 years 10 years 16 HPV-012 10~25 4 years Completed 17 PATRICIA (HPV-008) Quadrivalent vaccine 15~25 4 years (average ~ 3.7 years after 1 st * Completed 18, 19, 20, 21 vaccination) V501-007 16~23 5 years Completed 22, 23 FUTURE I & FUTURE II (V501-013 & 015) 15~26 Average ~ 3.6 years after 1 st vaccination * Completed 8, 9, 24, 25, 26, 27 * In the PATRICIA and FUTURE trials, case ascertainment for efficacy endpoints began after first vaccine dose in the TVC and ITT populations, and after the third vaccine dose in the ATP-E and per protocol populations (the day after the third dose in PATRICIA, and one month after the third dose in FUTURE). The studies were originally planned to last for 4 years, but the independent data and safety monitoring board recommend early termination so that women in the placebo group could receive the vaccine. 석에포함되었으며, Intention-to-treat (ITT) 분석시 OR는 LSIL에대하여 0.06, HSIL에대하여 0.09로매우좋은백신효과를보였다. 가다실은 LSIL에대한효과측정에서백신투여군과대조군이각각약 3,900명이참여하여 OR가 0.13으로나타났으며, HSIL에대한효과측정에는백신투여군과대조군이각각약 10,000명이참여하여 OR가 0.54로나타나 HSIL에대해서는그리좋은효과를나타내지못하였다. 그러나가다실의경우서바릭스에비하여더장기간추적연구를하였으므로위의결과만으로두백신의효과를비교할수는없다. 부작용에대한 OR는서바릭스가 1.35, 가다실이 1.16으로서바릭스가부작용이많았다 (1). Romanowski가리뷰하였던 HPV 백신의장기적효과에대한임상시험과관련논문을 Table 2에표시하였다 (2, 8~27). 가다실과서바릭스의비교임상시험이 1건, 서바릭스임상시험 8건, 가다실의임상시험 3건에대한총 20개의논문이포함되어있다. GSK에서가다실과서바릭스두백신의면역원성과안전성을비교하는임상시험 (GSK protocol: HPV-010) 을실시하여 2년간에걸친결과를보고하였다 (10, 11). 면역원 성측정에서는중화항체가와 ELISA 항체가, 메모리 B 세포, 점막항체가를측정하였다. 중화항체의기하평균항체가는서바릭스가가다실에비하여연령대에따라높게나타났다. ELISpot을이용한메모리 B 세포측정과자궁경부-질분비물내항체가도서바릭스에서조금높게나타났다. 주사부위의통증이나발적, 부종과같은부작용도서바릭스에서더많았다. 그러나두백신이포함하는항원종류에차이가있고면역원성측정방법도다르므로두백신을한회사의측정법으로만비교하는것은정확한비교가되지않는다. 또한아직까지이러한면역원성의차이가임상적으로도관련이있는지는불분명하다 (2). 서바릭스의장기면역원성측정임상시험 (GSK protocol: HPV-007/023) 에서백신접종당시자궁경부세포검사가정상이고, HPV16/18에대한항체음성, 14종의고위험 HPV DNA가음성이었던피험자 300여명을백신접종후 6.4년까지추적연구를실시한결과약 50여명의혈액을확보하여 pseudovirion-based neutralization assay로중화항체를측정한결과이들대부분양성이었고 (13), 8.4년까지도양성이었다 (14). 가다실은약 17,000여명이참여한다국적 3상임상시험인 FUTURE I과 II (Merck protocol:
316 HS Park V501-013/015) 에서접종 48개월까지추적하여각 HPV형에대한 2,300~2,800여명의항체를측정하였다. 각백신형에대하여각각한개의중화 epitope과반응하는항체만을측정하는 competitive luminex immunoassay (clia) 로분석한결과, 백신접종후 7개월에피험자의 99% 에서 4가지백신형에대하여항체양전이되었고 48개월까지도 HPV6/11/16에대한항체보유율은 89.7~98.4% 로매우높았다 (25). 그러나 HPV18 에대한항체보유율은 clia로측정한경우에는시간경과에따라 24개월에 71.6%, 48개월에 64.8% 로감소하였으나, 중화항체와비중화항체를모두측정할수있는 Total IgG LIA로측정한경우는 48 개월에 96.7% 로나타나항체측정방법에따라상당한차이가나타났다 (25). HPV 감염과자궁병변에대한서바릭스의효과는 433 명을 8.4년까지관찰한결과 HPV 16과 18의일시적감염에대해서는 95.1%, 12개월이상지속감염에대해서는 100%, LSIL 이상의병변에대해서는 94.6%, HSIL에대해서는 100% 의효과를보였다 (14). 18,000여명의피험자가참여한서바릭스의다국적임상시험인 PATRICIA (GSK protocol: HPV-008) 에서 34.9~39.4개월동안추적한결과 HPV16/18과관련된 HSIL에대한백신효과는백신접종전성경험이없고고위험 HPV 감염이없는피험자그룹 (total vaccinated cohort-naïve: TVC-naïve) 에서는 98.4%, 백신접종전 HPV16/18에대한항체가없고백신접종전과마지막접종때에 HPV DNA에음성인그룹 (according to protocol cohort for efficacy: APT-E) 에대해서는 92.9%, 백신접종당시 HPV DNA 유무와상관없이 1회이상백신을접종받은그룹 (total vaccinated cohort: TVC) 에서는 52.8% 였다. HPV16/18과관련된 cervical intraepithelial neoplasia 3등급이상 (CIN3+) 에대한백신의효과는 TVCnaïve에서는 100%, ATP-E에서 80%, TVC에서 33.6% 였다 (18). 가다실의장기임상효과를측정하기위하여백신을 3회모두접종받은피험자들을 5년까지추적하였다 (Merck protocol: V501-007). 235명의피험자들이추적되었고이들에서아무도 LSIL 이상의질병이발생하지않아이에대한백신의효과는 100% 였으며, HPV16의지속감염에대한효과는 96.6%, HPV18의지속감염에대한효과는 90.6% 였다 (22). 가다실의 FUTURE I과 II 임상시험에서백신접종전 14종의고위험군 HPV에대하여음성인 HPV-naïve population과 1회라도백신을접종받은 ITT population으로구분하여백신의효과를측정하였다. HPV- 16이나 18과관련된 LSIL에대해서 HPV-naïve population 에서는 97.2%, ITT population에서는 67.5% 의감소효과를나타내었고, CIN3에대해서 HPV-naïve population에서는 100%, ITT population에서는 43.5% 의감소효과가있었다 (25). 현재백신이나약물에대한임상시험이국내에서도많이이루어지고있다. 그러나잘디자인된임상시험을실시하여야만그약물에대한효과를정확하게평가할수있다. 최근에근거중심의학 (evidence-based medicine) 의중요성이강조됨에따라많은 systemic review가이루어지고있으나위의결과에서보는것처럼분석대상이어떠한그룹인지, 분석시어떠한기준을포함하고어떤기준을제외하느냐에따라분석결과가다르게나타나므로임상시험이나분석을주도하는주체에따라결과가다르게나타날수도있다. 비영리기관인 Cochrane library에서여러질환에대한치료나약물의효과등에대한 systemic review와메타분석결과들이보고되고있다. 그러나아직까지 HPV 백신에대한 Cochrane review는발표된것이없고논문으로발표된 systemic review도많지않다. 위의두 systemic review 논문을보면아직까지 HPV 백신의효과를평가하기에는비교가능한연구의수가너무적고, 장기적인효과에대한연구는초기에피험자수가많아도지속적으로추적할수있는피험자의수가현저히줄어드는문제점이있다. 그럼에도불구하고현재까지보고된 HPV 백신의효과에대한공통된결과는백신접종이전에백신형 HPV에대한감염이없었던피험자에서예방효과가좋고, 백신접종당시연령이낮을수록항체가가높았다 (15, 18, 25). 또한백신접종군에서백신에포함된 HPV형에의한고등급자궁경부병변발생률을 36개월까지추적관찰하였을때시간경과에따라대조군에비하여현저히낮았으나, 모든 HPV형에의한고등급자궁경부병변의발생률은크게차이가나지않았다 (9). 우리나라에서실시한 HPV 백신에대한임상시험중 ClinicalTrials.gov에등록되어있는것은가다실 2회, 서바릭스가 3회로총 5건이다 (28). 이시험들에서백신효과의일차종말점 (primary end point) 으로백신마지막접종 4주후항체양전율또는안전성만을측정하였을뿐 HPV 감염유무나세포 / 조직병변에대한검사는실시되지않았고현재진행중인시판후조사 (post-marketing
Systemic Review for Efficacy of Human Papillomavirus Vaccines 317 surveillance) 에서도안전성과반응원성만을조사하고있는실정이다 (29~31). 우리나라에서 HPV 백신의효과를제대로평가하려면백신을접종받은사람들과대조군에대한장기추적시스템을구축하여주기적으로면역원성측정및 HPV 감염유무검사, 세포및조직검사, 질병발생유무등을조사하여야하며, 그에선행하여두백신에대하여국제적으로표준화된면역원성측정법및감염된 HPV형을구별할수있는 reference lab의구축이필요하다. 참고문헌 1) Medeiros LR, Rosa DD, da Rosa MI, Bozzetti MC, Zanini RR. Efficacy of human papillomavirus vaccines: A systematic quantitative review. Int J Gynecol Cancer 2009;19:1166-76. 2) Romanowski B. Long term protection against cervical infection with the human papillomavirus: review of currently available vaccines. Hum Vaccin 2011;7:161-9. 3) Castlellsague X, de Sanjose S, Aguado T, Louie KS, Bruni L, Muñoz J, et al. HPV and Cervical cancer in the world 2007 Report. Vaccine 2007;25S:C1-26. 4) Harper DM, Franco EL, Wheeler CM, Moscicki AB, 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;367:1247-55. 5) Paavonen J, Jenkins D, Bosch FX, Naud P, Salmerón 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, randomised controlled trial. Lancet 2007;369:2161-70. 6) Hildesheim A, Herrero R, Wacholder S, Rodriguez AC, Solomon D, Bratti MC, et al. Effect of human papillomavirus 16/18 L1 Viruslike particle vaccine among young women with preexisting infection. a randomized trial. JAMA 2007; 298:743-53. 7) Mao C, Koutsky LA, Adult KA, Wheeler CM, Brown DR, Wiley DJ, et al. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia. a randomized controlled trial. Obstet Gynecol 2006;107:18-27. 8) Garland SM, Hernandez-Avila M, Wheeler CM, Perez G, Harper DM, Leodolter S, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007;356:1928-43. 9) FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915-27. 10) Einstein MH, Baron M, Levin MJ, Chatterjee A, Edwards RP, Zepp F, et al. Comparison of the immunogenicity and safety of Cervarix and Gardasil human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18-45 years. Hum Vaccin 2009;5:705-19. 11) Einstein MH. On behalf of the HPV-010 study group. Immunogenicity comparison of two prophylactic human papillomavirus (HPV) cervical cancer vaccines at month 24. Abstract and poster presented at the European Research Organisation on Genital Infection and Neoplasia, Monte Carlo, Monaco, 2010;17-20. 12) Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D, Schuind A, 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. Lancet 2004;364:1757-65. 13) GlaxoSmithKline Vaccine HPV-007 study group, Romanowski B, de Borba PC, Naud PS, Roteli-Martins CM, De Carvalho NS, et al. 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;374:1975-85. 14) Roteli-Martins CM, Naud P, Borba P, Teixeira J, De Carvalho N, Zahaf T, et al. Sustained Immunogenicity and Efficacy of the HPV-16/18 AS04-Adjuvanted Vaccine: Follow-up to 8.4 Years. Abstract presented at the 28th Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID), Nice, France 2010;4-8. 15) Schwarz TF, Spaczynski M, Schneider A, Wysocki J, Galaj A, Schulze K, et al. Long-term persistence of immune response to HPV-16/18 AS04-adjuvanted cervical cancer vaccine in women aged 15~55 years. Abstract presented at the Asia Oceania Research Organization on Genital Infections and Neoplasia, New Delhi, India 2010;26-8. 16) Schwarz TF, Huang LM, Rivera Medina DM, Valencia A, Yien LT, Behre U, et al. 4 year follow-up of immunogenicity and safety of adolescent girls vaccinated with the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine. Abstract presented at the 28th Annual Meeting of the European Society
318 HS Park for Paediatric Infectious Diseases (ESPID), Nice, France 2010; 4-8. 17) Petaja T. The HPV-012 study group. Long-term persistence of immune response to HPV-16/18 AS04-adjuvanted cervical cancer vaccine in preteen/adolescent girls and young women. Abstract presented at the European Research Organisation on Genital Infection and Neoplasia, Monte Carlo, Monaco 2010; 17-20. 18) Paavonen J, Naud P, Salmerón J, Wheeler CM, Chow SN, Apter D, et al. Efficacy of human papillomavirus (HPV)- 16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet 2009;374:301-14. 19) Paavonen J, Naud P, Salmeró, J, Wheeler CM, Chow SN, Apter D, et al. End-of-study results of PATRICIA: a phase III efficacy study of HPV-16/18 AS04-adjuvanted vaccine in young women. Abstract presented at the International Papillomavirus Conference, Montreal, Canada 2010;3-8. 20) Naud P. The HPV PATRICIA study group. Cross-protective efficacy of the AS04-adjuvanted HPV-16/18 vaccine against oncogenic HPV-31, -33 and -45. Abstract presented at the European Research Organisation on Genital Infection and Neoplasia, Monte Carlo, Monaco 2010;17-20. 21) Romanowski B. On behalf of the PARTICIA study group. Efficacy of the HPV-16/18 AS04-adjuvanted vaccine against non-vaccine oncogenic HPV types: end-of-study results. Abstract presented at the International Papillomavirus Conference, Montreal, Canada 2010;3-8. 22) Villa LL, Costa RL, Petta CA, Andrade RP, Paavonen J, Iversen OE, et al. 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;95:1459-66. 23) Olsson SE, Villa LL, Costa RL, Petta CA, Andrade RP, Malm C, 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. Vaccine 2007;25:4931-9. 24) Joura EA, Kjaer SK, Wheeler CM, Sigurdsson K, Iversen OE, Hernandez-Avila M, et al. HPV antibody levels and clinical efficacy following administration of a prophylactic quadrivalent HPV vaccine. Vaccine 2008;26:6844-51. 25) Muñoz N, Kjaer SK, Sigurdsson K, Iversen OE, 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;102:325-39. 26) Brown DR, Kjaer SK, Sigurdsson K, Iversen OE, Hernandez- Avila M, Wheeler CM, et al. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in generally HPV-naive women aged 16-26 years. J Infect Dis 2009;199:926-35. 27) Wheeler CM, Kjaer SK, Sigurdsson K, Iversen OE, Hernandez- Avila M, Perez G, et al. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in sexually active women aged 16-26 years. J Infect Dis 2009;199:936-44. 28) Park HS. Plan for the evaluation of effectiveness of vaccines which does not included in national immunization program. Study Report. Korea Food and Drug Administration 2011; 64-5. 29) Kang S, Kim KH, Kim YT, Kim YT, Kim JH, Song YS, et al. Safety and immunogenicity of a vaccine targeting human papillomavirus types 6, 11, 16 and 18: a randomized, placebocontrolled trial in 176 Korean subjects. Int J Gynecol Cancer 2008;18:1013-9. 30) Kim YJ, Kim KT, Kim JH, Cha SD, Kim JW, Bae DS, et al. Vaccination with a human papillomavirus (HPV)-16/18 AS04- adjuvanted cervical cancer vaccine in Korean girls aged 10~ 14 years. J Korean Med Sci 2010;25:1197-204. 31) Kim SC, Song YS, Kim YT, Kim YT, Ryu KS, Gunapalaiah B, et al. Human papillomavirus 16/18 AS04-adjuvanted cervical cancer vaccine: immunogenicity and safety in 15-25 years old healthy Korean women. J Gynecol Oncol 2011;22: 67-75.