The present status and significance in implementation of prophylactic human papillomavirus vaccine in Japan

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1 The present status and significance in implementation of prophylactic human papillomavirus vaccine in Japan Toshiyuki SASAGAWA human papillomavirus ; HPV HPV16, HPV HPV HPV HPV HPV 20 HPV HPV16, 18 DNA zur Hausen HPV HPV HPV HPV 2008 zur Hausen HPV16, 18 1 Hausen HPV HPV HPV HPV16 HPV HPV Associate Professor in Reproduction & Perinatology, Kanazawa Medical University (1-1 Daigaku, uchinada-machi, Kahoku-gun, Isikawa)

2 HPV HPV cervical intraepithelial neoplasia ; CINcervical cancer SC-junctionHPV 2 HPV E7 DNA HPV DNA E1, E2 E4 E4 L1 capsomere HPV-DNA 72 capsomere 20 E4 HPV HPV reproductive infection CIN grade 1 CIN1 HPV HPV CIN garde 2, 3CIN2, 3 HPV E6, E7 abortive infection HPV16 E6, E7 CIN2, 3 3 HPV Dendritic cell ; DC MacrophageB antigen presenting cell ; APC HPV HPV HPV lytic infection Viremnia DC APC Toll like ReceporTLR IL1, IL6, TNF-α cytokine storm

3 HPV 4 DC DC T DC T HPV HPV APC HPV HPV 4 APC Langerhans HPV16 L1L2-VLP 5 HPV16 E6, E7 IFN- α, β 6, 7 IFN HPV IFN-α, β HPV 2 HPV HPV 1990 virus-like particle ; VLP VLP Zhou HPV16 VLP 8 VLP NIH Kirumbauer HPV16 L1 VLP 9 ICRF Crawford Pushko CIN1 10 HPV16 L1 L zur Hausen HPV16 B27-HPV16 L1 HPV16-VLP 11 HPV Koutsky 1998

HPV1 HPV6 16 VLP 11 HPV16 -VLP HPV16 100

Cervarix GARDASIL GSK HPV16, 18 2 HPV16,

11, 16, 18 HPV1618 VIN 23 VaIN 2399 100 14

4 HPV1 HPV6 16 VLP 11 HPV16 -VLP HPV HPV HPV HPV16 VLP APC GSK 2 HPV-VLP GSK Cervarix GARDASIL GSK HPV16, 18 2 HPV16, 18 HPV6, 11 4 HPV16, HPV16, 18 GARDASIL 5.5 HPV16, 18 HPV-VLP CIN23 AIS HPV6, 11, 16, 18 HPV1618 VIN 23 VaIN CervarixGSK HPV16, 18 CIN HPV HPV16, 18 CIN HPV HPV 7

5 4.5yrs 5.5yrs HPV-VLP CIN2 HPV HPV 20 4 GRDASIL HPV 16 HPV HPV-VLP HPV HPV HPV16, 18 Cervarix HPV45, HPV31, HPV33, HPV , 36.1, 36.5, GARDASIL 18 HPV HPV HPV HPV16, 18 HPV 8 20 HPV 8 7 HPV16, 18 HPV16, 18 HPV HPV16, HPV16, HPV16, HPV HPV16, HPV HPV16, 18 HPV1618, N235

6 23 HPV HPV HPV HPV HPV HPV HPV-DNA HPV- DNA 5 1 Durst M, Gissmann L, Ikenberg H et al.: A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc Natl Acad Asi, USA : , HPV : , Sasagawa T, Inoue M, Inoue H, Yutsudo M, Tanizawa O, Hakura A. Induction of uterine cervical neoplasia in mice by human papillomavirus type 16 E6-E7 genes. Cancer Res : , HPV : 69-81, Fausch SC, Fahey LM, Da Silva DM et al.: Human papillomavirus can escape immune recognition through Langerhans cell phosphoinositide 3-kinase activation. J Immunol. Jun 1 ; 11: , Ronco LV, Karpova AY, Vidal M et al.: Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. Genes Dev. Jul 1 ; 13: , Barnard P, McMillan NA. The human papillomavirus E7 oncoprotein abrogates signaling mediated by interferonalpha. Virology. Jul 5 ; 2: , Zhou J, Sun XY, Stenzel DJ et al.: Expression of vaccinia recombinant HPV 16 L1 and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles. Virology : , Kirnbauer R, Taub J, Greenstone H et al.: Efficient self-

7 assembly of human papillomavirus type 16 L1 and L1-L2 into virus-like particles. J Virol : , Pushko P, Sasagawa T, Cuzick J et al.: Sequence variation in the capsid protein genes of human papillomavirus type 16. J Gen Virol. Apr ; Pt 4: , Sasagawa T, Pushko P, Steers G et al.: Synthesis and assembly of virus-like particles of human papillomaviruses type 6 and type 16 in fission yeast Schizosaccharomyces pombe. Virology : , Koutsky LA, Ault KA, Wheeler CM et al.: Proof of Principle Study Investigators. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med : , Harper DM, Franco EL, Wheeler CM, et al.: HPV Vaccine Study group. 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. Apr 15 ; 9518: , Garland SM, Hernandez-Avila M, Wheeler CM, et al.: Females United to Unilaterally Reduce EndoEctocervical DiseaseFUTUREI Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med : , Harper DM. Impact of vaccination with Cervarixtrade markon subsequent HPV-1618 infection and cervical disease in women years of age. Gynecol Oncol : 11-17, Olsson SE, Villa LL, Costa RL et al.: Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirushpvtypes L1 virus-like particlevlpvaccine. Vaccine Jun 21 ; 26: Epub 2007 Apr Paavonen J, Jenkins D, Bosch FX et al.: Efficacy of a prophylactice adjuvanted bivalent L1 virus-like particle vaccine against infection with human papillomavirus types 16 and 18 in young women : n interim analysis of a phase III double? blind, randamised control trial, HPV PATRICIA study group, Lancet, : , Brown DR, Kjaer SK, Sigurdsson K et al.: The impact of quadrivalent human papillomavirushpv ; types 6, 11, 16, and 18L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in generally HPV-naive women aged years. J Infect Dis. Apr 1 ; 7: , Sasagawa T, Yamazaki H, Dong YZ, Satake S, Tateno M, Inoue M. Immunogloburins A and G responses against virus-like particlesvlpof human papillomavirus type 16 in women with cervical cancer and cervical intraepithelial lesions. Int J Cancer : , Descamps D, Hardt K, Spiessens B et al.: Safety of human papillomavirushpv-1618 AS04-adjuvanted vaccine for cervical cancer prevention : a pooled analysis of 11 clinical trials. Hum Vaccin May ; 5: Epub 2009 May Miura S, Matsumoto K, Oki A et al.: Do we need a different strategy for HPV screening and vaccination in East Asia? Int J Cancer : , Sasagawa T, Basha W, Yamazaki H et al. High-risk and multiple human papillomavirus infections associated with cervical abnormalities in Japanese women. Cancer Epidemiol Biomarkers Prev : 45-52, Marra F, Cloutier K, Oteng B et al.: Effectiveness and cost effectiveness of human papilllomavirusu vaccine : a systemic review. Pharmacoeconomics, : 91-93, HPV : , 2007.

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