子宫颈癌等人乳头瘤病毒相关疾病免疫预防专家共识(简版)Expert consensus on immunoprophylaxis of human papillomavirus-related diseases(abridged)
王华庆,王岩,王朝华,王亚敏,孙晓冬,许涤沙,李明珠,李燕,李智,余文周,余艳琴,岳晨妍,张小松,郭欣,胡尚英,赵方辉,赵超,赵昀,秦冉,夏昌发
摘要(Abstract):
子宫颈癌等人乳头瘤病毒(HPV)相关疾病已成为严重威胁人类健康的公共卫生问题。为响应消除子宫颈癌行动计划,本共识在世界卫生组织关于HPV疫苗立场文件(2017年)的基础上,结合国内外研究的最新进展,对HPV相关疾病的病原学、临床学、流行病学、疫苗学等方面进行综述,以提高专业人员HPV相关疾病的防控水平,为HPV疫苗的科学使用和发挥其最佳预防作用提供系统、全面的循证依据。
关键词(KeyWords): 人乳头瘤病毒;子宫颈癌;接种;免疫预防
基金项目(Foundation):
作者(Author): 王华庆,王岩,王朝华,王亚敏,孙晓冬,许涤沙,李明珠,李燕,李智,余文周,余艳琴,岳晨妍,张小松,郭欣,胡尚英,赵方辉,赵超,赵昀,秦冉,夏昌发
参考文献(References):
- [1] World Health Organization. WHO Director-General calls for all countries to take action to help end the suffering caused by cervical cancer[EB/OL].(2018-05-19)[2019-05-09]. https://www. who. int/reproductivehealth/call-toactionelimination-cervical-cancer/en/.
- [2] World Heal th Organizat ion. Human papi l lomavi rus vaccines:WHO posi t ion paper, May 2017[J]. Wkly Epidemiol Rec, 2017, 92(19):241-268. DOI:10. 1016/j.biologicals. 2009. 04. 005.
- [3] WANG JW, RODEN RBS. L2, the minor capsid protein of papillomavirus[J]. Virology, 2013, 445(112):175-186. DOI:10. 1016/j. virol. 2013. 04. 017.
- [4] BUCK CB, DAY PM, TRUS BL. The papillomavirus major capsid protein L1[J]. Virology, 2013, 445(112):169-174.DOI:10. 1016/j. virol. 2013. 05. 038.
- [5] BUCK CB, CHENG N, THOMPSON CD, et al.Arrangement of L2 within the papillomavirus capsid[J].Journal of Virology, 2008, 82(11):5190-5197. DOI:10. 1128/JVI. 02726-07.
- [6] UNCKELL F, STREECK RE, SAPP M. Generation and neutralization of pseudovirions of human papillomavirus type 33[J]. Journal of Virology, 1997, 71(4):2934-2939.DOI:10. 1016/S0166-0934(97)02181-2.
- [7] LIU X, CLEMENTS A, ZHAO K, et al. Structure of the human papillomavirus, E7 oncoprotein andits mechanism for inactivation of the retinoblastoma tumor suppressor[J]. J Biol Chem, 2006, 281(1):578-586. DOI:10. 1074/jbc.M508455200.
- [8] BONNEZ W, ROSE RC, BORKHUIS C, et al. Evaluation of temperature sensitivity of human papillomavi rus type 11 by using the human xenograf t severe combined immunodef iciency mouse model[J]. Journal of Clinical Microbiology, 1994, 32(6):1575-1577. DOI:10. 1002/jctb.280600215.
- [9] BACCARD-LONGèRE M, ALPHA-BAZIN B, CHYPRE C,et al. Fast solid support detection of human papillomavirus in invitro amplified DNA usi ng a DNP-ant i DNP monoclonal antibody couple[J]. Journal of Virological Methods, 1994, 46(1):29-38. DOI:10. 1016/0166-0934(94)90014-0.
- [10] STANLEY MA, PETT MR, COLEMAN N. HPV:f rom infection to cancer[J]. Biochemical Society. Transactions,2007, 35(Pt 6):1456-1460. DOI:10. 1042/BST0351456.
- [11] MOSCICKI AB, SCHIFFMAN M, BURCHELL A, et al.Updating the natural history of human papillomavirus and anogenital cancers[J]. Vaccine, 2012, 30(Suppl 5):24-33.DOI:10. 1016/j. vaccine. 2012. 05. 089.
- [12] MUNOZ N, BOSCH FX, CASTELLSAGUE X, et al.Against which human papillomavi rus types shall we vaccinate and screen? The international perspective[J].International Journal of Cancer, 2004, 111(2):278-285.DOI:10. 1002/ijc. 20244.
- [13] ZUNA ER, ALLEN AR MOORE EW, et al. Distribution of HPV geno types in 282 women with cervicallesions:evidence for three categories of intraepithelial lesions based on morphology and HPV type[J].Modern Pathology, 2006, 20(2):167-174. DOI:10. 1038/modpathol. 3800723.
- [14] GRAVITT PE. The known unknowns of HPV natural history[J]. The Journal of Clinical Investigation, 2011,121(12):4593-4599. DOI:10. 1172/JCI57149.
- [15] KAWANA K, YASUGI T, KANDA T, et al. Neutralizing antibodies against oncogenic human papillomavirus as a possible determinant of the fate of low-grade cervical intraepithelial neoplasia[J]. Biochemical and Biophysical Research Communications, 2002, 296(1):102-105. DOI:10.1016/S0006-291X(02)00843-4.
- [16] STANLEY MA. Epithelial cell responses to infection with human papillomavirus[J]. Clinical Microbiology Reviews,2012, 25(2):215-222. DOI:10. 1128/CMR. 05028-11.
- [17] ZUCKERMAN AJ. IARC monographs on the evaluation of carcinogenic risks to humans[J]. Journal of Clinical Pathology, 1995, 48(7):691. DOI:10. 1136/jcp. 48. 7. 691-a.
- [18] WAXMAN AG, CHELMOW D, DARRAGH TM, et al.Revised terminology for cervical histopathology and its implications for management of high-grade squamous intraepithelial lesions of the cervix[J]. Obstetrics and Gynecology, 2012, 120(6):1465-1471. DOI:10. 1097/aog.0b013e31827001d5.
- [19] KURMAN RJ, CARCANGIU ML, HERRINGTON CS, et al. WHO classif ication of tumours of female reproductive organs[M]. 4th edition. Lyon:IARC Press, 2014.
- [20] MCCREDIE MR, SHARPLES KJ, PAUL C, et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical int raepithelial neoplasia 3:a retrospective cohort study[J]. The Lancet Oncology, 2008,9(5):425-434. DOI:10. 1016/S1470-2045(08)70103-7.
- [21] AHO M, VESTERINEN E, MEYER B, et al. Natural history of vaginal intraepithelial neoplasia[J]. Cancer,1991, 68(1):195-197. DOI:10. 1002/1097-0142(19910701)68:13. 0. CO; 2-L.
- [22] American Society for Colposcopy and Cervical Pathology.Modern colposcopy textbook and atlas[M]. 3rd edition.California:Lippincott Williams&Wilkins, 2011.
- [23] JENTSCHKE M, HOFFMEISTER V, SOERGEL P, et al.Clinical presentation, treatment and outcome of vaginal intraepithelial neoplasia[J]. Arch Gynecol Obstet, 2016,293(2):415-419. DOI:10. 1007/s00404-015-3835-6.
- [24]魏丽惠.下生殖道上皮内病变的诊治和管理[M].北京:北京大学医学出版社, 2018.
- [25] SMITH JS, BACKES DM, HOOTS BE, et al. Human papillomavirus type-distribution in vulvar and vaginal cancers and their associated precursors[J]. Obstetrics and Gynecology, 2009, 113(4):917-924. DOI:10. 1097/aog.0b013e31819bd6e0.
- [26]熊菊香,王沂峰,陈高文,等.人乳头瘤病毒与外阴癌的相关性研究[J].中国妇幼保健, 2015, 30(4):529-532. DOI:10.7620/zgfybj. j. issn. 1001-4411. 2015. 04. 13.
- [27] WRIGHT TC. Natural history of HPV inf ections[J]. J Fam Pract, 2009, 58(Suppl 9):S3-7.
- [28] HISHAM M, TOM B, TOM A, et al. Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer-systematic review and meta analysis of trends by time and region[J]. Head&Neck, 2012,35(5):747-755. DOI:10. 1002/hed. 22015.
- [29] ZHAO FH, TIGGELAAR SM, HU SY, et al. A multi-center survey of HPV knowledge and at titudes toward HPV vaccination among women, government of f icials, and medical personnel in China[J]. Asian Pacif ic Journal of Cancer Prevention, 2012, 13(5):2369-2378. DOI:10. 7314/APJCP. 2012. 13. 5. 2369.
- [30] ZHAO FH, FORMAN MR, BELINSON J, et al. Risk f actors for HPV inf ection and cervical cancer among unscreened women in a high-risk rural area of China[J].International Journal of Cancer, 2005, 118(2):442-448.DOI:10. 1002/ijc. 21327.
- [31] LUQUE AE, HITTI J, MWACHARI C, et al. Prevalence of human papillomavirus genotypes in HIV-1-inf ected women in Seattle, USA and Nairobi, Kenya:results f rom the Women’s HIV Interdisciplinary Network(WHIN)[J].International Journal of Infectious Diseases, 2010, 14(9):810-814. DOI:10. 1016/j. ijid. 2010. 03. 016.
- [32] ZHANG HY, TIGGELAAR SM, SAHASRABUDDHE VV, et al. HPV prevalence and cervical intraepithelial neoplasia among HIV-infected women in Yunnan province,China:a pilot study[J]. Asian Pacif ic Journal of Cancer Prevention, 2012, 13(1):91-96. DOI:10. 7314/APJCP. 2012.13. 1. 091.
- [33] KJAER SK, CHACKERIAN B, VAN DEN BRULE AJ, et al. High-risk human papillomavirus is sexually transmitted:evidence from a follow-up study of virgins starting sexual activity(intercourse)[J]. Cancer Epidemiology, Biomarkers&Prevention, 2001, 10(2):101-106.
- [34] ANNA-BARBARA M. Impac t of HPV i nf ec t ion in adolescent populat ions[J]. J Adolesc Heal th, 2005,37(Suppl 6):S3-9. DOI:10. 1016/j. jadohealth. 2005. 09.011.
- [35] VINODHINI K, SHANMUGHAPRIYA S, DAS BC, et al. Prevalence and risk factors of HPV infection among women from various provinces of the world[J]. Archives of Gynecology and Obstetrics, 2012, 285(3):771-777. DOI:10. 1007/s00404-011-2155-8.
- [36] BRAY F, FERLAY J, SOERJOMATARAM I, et al. Global cancer statistics 2018:Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J].Ca:a Cancer Journal for Clinicians, 2018, 68(6):394-424.DOI:10. 3322/caac. 21492.
- [37]孙可欣,郑荣寿,张思维,等. 2015年中国分地区恶性肿瘤发病和死亡分析[J].中国肿瘤, 2019, 28(1):1-11. DOI:10.11735/j. issn. 1004-0242. 2019. 01. A001.
- [38]胡尚英,郑荣寿,赵方辉,等. 1989至2008年中国女性子宫颈癌发病和死亡趋势分析[J].中国医学科学院学报, 2014,36(2):119-125. DOI:10. 3881/j. issn. 1000-503X. 2014. 02.001.
- [39] MARTEL C, PLUMMER M, VIGNAT J, et al. Worldwide burden of cancer attributable to HPV by site, country and HPV type[J]. Int J Cancer, 2017, 141(4):664-670. DOI:10.1002/ijc. 30716.
- [40] PATEL H, WAGNER M, SINGHAL P, et al. Systematic review of the incidence and prevalence of genital warts[J].BMC Infect Dis, 2013, 13:39. DOI:10. 1186/1471-2334-13-39.
- [41] International Agency for Research on Cancer. Human papillomavirus and related diseases in the world[R]. Lyon:IARC, 2019.
- [42] BRUNI L, DIAZ M, CASTELLSAGUE X, et al. Cervical human papillomavirus prevalencein 5 continents:metaanalysis of 1 million women with normal cytological f indings[J]. J Infect Dis, 2010, 202(12):1789-1799. DOI:10. 1086/657321.
- [43] ZHAO FH, ADAM KL, HU SY, et al. Prevalence of human papillomavirus and cervical intraepithelial neoplasia in China:a pooled analysis of 17 population-based studies[J].Int J Cancer, 2012, 131(12):2929-2938. DOI:10. 1002/ijc.27571.
- [44] BAO YP, LI N, SMITH JS, et al. Human papillomavirus type-distribution in the cervix of Chinese women:a metaanalysis[J]. Int J STD AIDS, 2008, 19(2):106-111. DOI:10.1258/ijsa. 2007. 007113.
- [45] ZHANG R, VELICER C, CHEN W, et al. Human papilloma virusgeno type distribution in cervical intraepithelial neoplasia grades 1 or worse among 4215Chinese women in a population-based study[J]. Cancer Epidemiol, 2013, 37(6):939-945. DOI:10. 1016/j. canep.2013. 10. 005.
- [46] CHEN W, MOLIJN A, ENQI W, et al. The variable clinicopa t ho logica lcategories and role of huma n papillomavirus in cervical adenocarcinoma:a hospital based nation-wide multi-center retrospective study across China[J]. Int J Cancer, 2016, 139(12):2687-2697. DOI:10.1002/ijc. 30401.
- [47] CHEN W, ZHANG X, MOLI JN A, et al. Huma n papillomavirus type-dist ribution in cervical cancer in China:the importance of HPV 16 and 18[J]. Cancer Causes Control, 2009, 20(9):1705-1713. DOI:10. 1007/s10552-009-9422-z.
- [48] INSINGA RP, YE X, SINGHAL PK, et al. Healthcare resource use and costs associated with cervical, vaginal and vulvar cancers in a large U. S. health plan[J]. Gynecol Oncol, 2008, 111(2):188-196. DOI:10. 1016/j. ygyno. 2008.07. 032.
- [49] BA L L EGOOI J E N M, K OOPMA NSCH A P M A,TJOKROWARDOJO AJ, et al. Care and costs for advanced cervical cancer[J]. Eur J Cancer, 1992, 28a(10):1703-1708.DOI:10. 1016/0959-8049(92)90072-A.
- [50] HAILU A, MARIAM DH. Pat ient side cost and i ts predictors for cervical cancer in Ethiopia:a cross sectional hospital based study[J]. BMC Cancer, 2013, 13:69. DOI:10. 1186/1471-2407-13-69.
- [51]王敏珍.女性常见恶性肿瘤疾病负担趋势性分析及预测研究[D].兰州:兰州大学, 2010.
- [52]魏巧玲.恶性肿瘤疾病负担研究[D].厦门:厦门大学, 2009.
- [53]朱洁,金萍妹,华伟,等. 15348例宫颈癌不同治疗方式的住院费用研究[J].中国医院管理, 2017, 37(2):58-60.
- [54] LANG HC, WU SL. Lifetime costs of the top f ive cancers in Taiwan[J]. Eur J Health Econ, 2012, 13(3):347-353.DOI:10. 1007/s10198-011-0307-1.
- [55] HILLEMANNS P, BREUGELMANS JG, GIESEKING F,et al. Estimation of the incidence of genital warts and the cost of illness in Germany:a cross-sectional study[J].BMC Infect Dis, 2008, 8(1):76. DOI:10. 1186/1471-2334-8-76.
- [56] MERITO M, LARGERON N, COHET C, et al. Treatment patterns and associated costs for genital warts in Italy[J]. Curr Med Res Opin, 2008, 24(11):3175-3183. DOI:10.1185/03007990802485694.
- [57] MIZUKAMI A, KAISE T, VAN KRIEKINGE G. Resource use and cost of treating human papillomavirus-related lesions in Japanese women[J]. Value Health Reg Issues,2018, 15:56-62. DOI:10. 1016/j. vhri. 2017. 07. 009.
- [58] WOODHALL SC, JIT M, SOLDAN K, et al. The impact of geni t a l war ts:loss of quali ty of lif e and cost of treatment in eight sexual health clinics in the UK[J].Sex Transm Inf ect, 2011, 87(6):458-463. DOI:10. 1136/sextrans-2011-050073.
- [59] MARRA F, OGILVIE G, COLLEY L, et al. Epidemiology and costs associated with genital warts in Canada[J]. Sex Transm Infect, 2009, 85(2):111-115. DOI:10. 1136/sti. 2008.030999.
- [60] DESAI S, WETTEN S, WOODHALL SC, et al. Genital warts and cost of care in England[J]. Sex Transm Infect,2011, 87(6):464-468. DOI:10. 1136/sti. 2010. 048421.
- [61] T ERMR U NGR UA NGL ERT W, HAVA NOND P,KHEMAPECH N, et al. Model for predicting the burden and cost of treatment in cervical cancer and HPV-related diseases in Thailand[J]. Eur J Gynaecol Oncol, 2012,33(4):391-394. DOI:DOI:10. 1159/000335489.
- [62] LEE TS, KOTHARI-TALWAR S, SINGHAL PK, et al.A cross-sectional study estimating the burden of illness related to genital warts in South Korea[J]. BMJ Open,2017, 7(6):e014217. DOI:10. 1136/bmjopen-2016-014217.
- [63]郝晓刚.长治地区尖锐湿疣的临床流行病学研究[D].太原:山西医科大学, 2009.
- [64] WHO. Comprehensive cervical cancer control:a guide to essential practice[EB/OL].(2015-11-25)[2019-05-01].https://www.who.int/immunization/hpv/plan/hpv_vaccine_intro_guide_c4gep_who_2013. pdf.
- [65]中华预防医学会妇女保健分会.子宫颈癌综合防控指南[M].北京:人民卫生出版社, 2017.
- [66] WINER RL, HUGHES JP, FENG Q, et al. Condom use and the risk of genital human papillomavirus infection in young women[J]. N Engl J Med, 2006, 354(25):2645-2654. DOI:10. 1056/NEJMoa053284.
- [67] SáNCHE Z-AL EMáN M A, URIBE-SALAS F J,LAZCANO-PONCE EC, et al. Human papillomavirus incidence and risk factors among Mexican female college students[J]. Sex Transm Dis, 2011, 38(4):275-278. DOI:10.1097/OLQ. 0b013e3181feae89.
- [68]孟龄婷,高丽,岳婷,等.生殖道HPV感染与阴道混合性感染相关危险因素的研究[J].实用妇产科杂志, 2018, 34(1):30-34.
- [69] GRAY RH, SERWADDA D, KONG X, et a l. Ma le circumcision decreases acquisition and increases clearance of high-risk human papillomavirus in HIV-negative men:a randomized trial in Rakai, Uganda[J]. J Infect Dis, 2010,201(10):1455-1462. DOI:10. 1086/652184.
- [70] INGLIS S, SHAW A, KOENIG S. Chapt e r 11:HPV vaccines:commercial research&development[J]. Vaccine,2006, 24(Suppl 3):99-105. DOI:10. 1016/j. vaccine. 2006.05. 119.
- [71] MONIE A, HUNG CF, RODEN R, et al. Cervar ix:a vaccine for the prevent ion of HPV 16, 18-associated cervical cancer[J]. Biologics, 2008, 2(1):97-105. DOI:10.2147/BTT. S1877.
- [72] GOVAN VA. A novel vaccine for cer v ical cancer:quadrivalent human papillomavirus(types 6, 11, 16 and 18)recombinant vaccine(Gardasil)[J]. Ther Clin Risk Manag,2008, 4(1):65-70. DOI:10. 2147/TCRM. S856.
- [73] LUXEMBOURG A, MOELLER E. 9-Valent human papillomavirusvaccin e:a review of the clinical development program[J]. Exper t Rev Vaccines, 2017,16(11):1119-1139. DOI:10. 1080/14760584. 2017. 1383158.
- [74] MARKOWITZ LE, LIU G, HARIRI S, et al. Prevalence of HPV af ter introduction of the vaccination program in the United States[J]. Pediatrics, 2016, 137(3):e20151968. DOI:10. 1542/peds. 2015-1968.
- [75]国家药品监督管理局.进口药品注册信息[EB/OL].[2019-05-30]. http://app1.sfda.gov.cn/datasearchcnda/face3/base.jsp?tableId=36&tableName=TABLE36&title=进口药品&b cId=152904858822343032639340277073.
- [76]国家药品监督管理局药品审评中心.药物临床试验登记与信息公示平台[EB/OL].[2019-05-01]. http://www.chinadrugtrials.org.cn/.
- [77] NGAN HY, CHEUNG AN, TAM KF, e t al. Human papillomavirus-16/18 AS04-ad juvanted cervical cancer vaccine:immunogenicity and safety in healthy Chinese women f rom Hong Kong[J]. Hong Kong Med J, 2010,16(3):171-179.
- [78] BHATLA N, SURI V, BASU P, et al. Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine in healthy Indian women[J]. J Obstet Gynaecol Res, 2010, 36(1):123-132. DOI:10. 1111/j.1447-0756. 2009. 01167. x.
- [79] ZHU F, LI J, HU Y, et al. Immunogenicity and saf ety of the HPV-16/18 AS04-ad juvanted vaccine in healthy Chinese girls and women aged 9 to 45 years[J]. Hum Vaccin Immunother, 2014, 10(7):1795-1806. DOI:10. 4161/hv. 28702.
- [80] SCHWARZ TF, SPACZYNSKI M, SCHNEIDER A, et al.Immunogenicity and tolerability of an HPV-16/18 AS04-adjuvanted prophylactic cervical cancer vaccine in women aged 15-55 years[J]. Vaccine, 2009, 27(4):581-587. DOI:10. 1016/j. vaccine. 2008. 10. 088.
- [81] KHATUN S, AKRAM HUSSAIN SM, CHOWDHURY S, et al. Saf ety and immunogenicity prof ile of human papillomavirus-16/18 AS04 ad juvant cer vical cancer vaccine:a randomized cont rol led t r ial i n heal thy adolescent girls of Bangladesh[J]. Jpn J Clin Oncol, 2012,42(1):36-41. DOI:10. 1093/jjco/hyr173.
- [82] KIM YJ, KIM KT, KIM JH, et al. Vaccination with a human papillomavirus(HPV)-16/18 AS04-ad juvanted cervical cancer vaccine in Korean girls aged 10-14 years[J]. J Korean Med Sci, 2010, 25(8):1197-1204. DOI:10.3346/jkms. 2010. 25. 8. 1197.
- [83] PUTHANAKIT T, HUANG LM, CHIU CH, et al.Randomized open trial comparing 2-dose regimens of the human papillomavirus 16/18 AS04-adjuvanted vaccine in girls aged 9-14 years versus a 3-dose regimen in women aged 15-25 years[J]. J Inf ect Dis, 2016, 214(4):525-536.DOI:10. 1093/infdis/jiw036.
- [84] DONKEN R, SCHURINK-VAN’T KLOOSTER TM,SCHEPP RM, et al. Immune responses af ter 2 versus3 doses of HPV vaccinat ion up to 4(1/2)years af ter vaccination:an observational study among dutch routinely vaccinated girls[J]. J Inf ect Dis, 2017, 215(3):359-367.DOI:10. 1093/infdis/jiw588.
- [85] MUGO N, ANSAH NA, MARINO D, et al. Evaluation of safety and immunogenicity of a quadrivalent human papillomavirus vaccine in healthy f emales between 9and 26 years of age in Sub-Saharan Af rica[J]. Hum Vaccin Immunother, 2015, 11(6):1323-1330. DOI:10.1080/21645515. 2015. 1008877.
- [86] LI R, LI Y, RADLEY D, et al. Safety and immunogenicity of a vaccine targeting human papillomavirus types 6, 11,16 and 18:a randomized, double-blind, placebo-controlled trial in Chinese males and f emales[J]. Vaccine, 2012,30(28):4284-4291. DOI:10. 1016/j. vaccine. 2012. 02. 079.
- [87] KANG S, K IM KH, KIM YT, et al. Safety and immunogeni city of avaccinetargeting huma n papillomavirus types 6, 11, 16 and 18:a randomized,placebo-controlled trial in 176 Korean subjects[J]. Int J Gynecol Cancer, 2008, 18(5):1013-1019. DOI:10. 1111/j.1525-1438. 2007. 01123. x.
- [88] REISINGER KS, BLOCK SL, LAZCANO-PONCE E, et al.Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like par ticle vaccine in preadolescents and adolescents:a randomized controlled trial[J]. Pediatr Infect Dis J, 2007,26(3):201-209. DOI:10. 1097/01. inf. 0000253970. 29190.5a.
- [89] MU袿Z N, MANALASTAS R JR, PITISUTTITHUM P, et al. Safety, immunogenicity, and eff icacy of quadrivalent human papillomavirus(types 6, 11, 16, 18)recombinant vaccine in women aged 24-45 years:a randomised, doubleblind trial[J]. Lancet, 2009, 373(9679):1949-1957. DOI:10.1016/S0140-6736(09)60691-7.
- [90] DOBSON SR, MCNE I L S, DION NE M, et al.Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women:a randomized clinical trial[J]. JAMA, 2013, 309(17):1793-1802. DOI:10.1001/jama. 2013. 1625.
- [91] VESIKARI T, BRODSZKI N, VAN DAMME P, e t al. A randomized, double-blind, phaseⅢstudy of the immunogenicity and safety of a 9-valent human papillomavirus L1 virus-like par t icle vaccine(V503)versus Gardasil(R)in 9-15-year-old girls[J]. Pediatr Infect Dis J, 2015, 34(9):992-998. DOI:10. 1097/INF.0000000000000773.
- [92] VAN DAMME P, MEIJER C, KIENINGER D, et al. A phaseⅢclinical study to compare the immunogenicity and safety of the 9-valent and quadrivalent HPV vaccines in men[J]. Vaccine, 2016, 34(35):4205-4212. DOI:10.1016/j. vaccine. 2016. 06. 056.
- [93] IVERSEN OE, MIRANDA MJ, ULIED A, et al.Immunogenicity of the 9-valent HPV vaccine using 2-dose regimens in girls and boys vs a 3-dose regimen in women[J]. JAMA, 2016, 316(22):2411-2421. DOI:10. 1001/jama.2016. 17615.
- [94] GARCIA-SICILIA J, SCHWARZ TF, CARMONA A, et al.Immunogenicity and safety of human papillomavirus-16/18AS04-adjuvanted cervical cancer vaccine coadministered with combined diphtheria-tetanus-acellular per tussisinactivated poliovirus vaccine to girls and young women[J]. J Adolesc Health, 2010, 46(2):142-151. DOI:10. 1016/j.jadohealth. 2009. 11. 205.
- [95] PEDERSEN C, BREINDAHL M, AGGARWAL N, et al. Randomized t r ial:immunogenici ty and saf ety of coadministered human papi l loma v i rus-16/18 AS04-ad juvanted vaccine and combined hepat i t is A and B vaccine in girls[J]. J Adolesc Health, 2012, 50(1):38-46.DOI:10. 1016/j. jadohealth. 2011. 10. 009.
- [96] WHEELER CM, HARVEY BM, PICHICHERO ME, et al.Immunogenicit