今日の臨床サポート

HPVワクチン接種

著者: 鈴木光明 新百合ヶ丘総合病院 がんセンター

監修: 青木大輔 慶應義塾大学医学部産婦人科学教室

著者校正/監修レビュー済:2018/10/03
患者向け説明資料

概要・推奨   

  1. HPVワクチンは、ヒトパピローマウイルス(HPV)の殻(カプシド)の大部分を構成するL1タンパク質を遺伝子組み換え技術で生成した粒子(virus-like particles: VLP)を抗原として作られたサブユニットワクチンである。VLPは外観上はHPVのウイルス粒子とほぼ同様であるが、DNAを含まないので感染力も複製力もなく安全である()。現在GSK社(サーバリックス、2価ワクチン)とMSD社(ガーダシル、4価ワクチン)の2社からHPV16型と18型に起因する子宮頸癌の予防が確実視されているL1-VLPのカクテルワクチンが世界各国で承認・販売され、広く接種されている。また最近ではMSD社からGARDASIL 9(9価ワクチン、注:日本では未承認)が60カ国以上で承認され、米国では定期接種が始まっている。
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
鈴木光明 : 特に申告事項無し[2021年]
監修:青木大輔 : 講演料(アストラゼネカ株式会社,武田薬品工業株式会社,中外製薬株式会社),研究費・助成金など(アストラゼネカ株式会社,中外製薬株式会社,インサイト・バイオサイエンシズ・ジャパン合同会社)[2021年]

執筆のポンイト:
  1. 産婦人科診療ガイドライン/婦人科外来編2017
に基づき執筆を行った。

まとめ

概要  
  1. HPVワクチンは、ヒトパピローマウイルス(HPV)の殻(カプシド)の大部分を構成するL1タンパク質を遺伝子組み換え技術で生成した粒子(virus-like particles: VLP)を抗原として作られたサブユニットワクチンである。VLPは外観上はHPVのウイルス粒子とほぼ同様であるが、DNAを含まないので感染力も複製力もなく安全である[1][2][3][4]。現在GSK社(サーバリックス、2価ワクチン)とMSD社(ガーダシル、4価ワクチン)の2社からHPV16型と18型に起因する子宮頸癌の予防が確実視されているL1-VLPのカクテルワクチンが世界各国で承認・販売され、広く接種されている。また最近ではMSD社からGARDASIL 9(9価ワクチン、注:日本では未承認)が60カ国以上で承認され、米国では定期接種が始まっている。
 
HPV VLPの模式図

*:VLP (Virus Like Particle):ウイルス様粒子

出典

img1:  著者提供
 
 
 
  1. これらのワクチンを接種すると、自然感染で得られる数十倍もの中和抗体が産生される。免疫応答の増強により強力な血清抗体価が誘導できるため、高い抗体価が長期間にわたり持続し、性行為により侵入するHPVの子宮頸部上皮への感染をほぼ100%排除することができる[5][6]。しかしながら、これらのワクチンはすでに感染しているHPVの排除や異形成(CIN)の進行を遅らせたり、消滅させる治療ワクチンではない。したがって、最も効果的な接種時期は初交前と考えられる[5][6]
  1. 現在わが国では、サーバリックスとガーダシルの2つのワクチンが接種可能である。2009年10月にサーバリックスが承認され(ガーダシル:2011年7月承認)、まずは地方自治体主導で接種がスタートした。2009年12月には魚沼市が全額公費助成を決定し、翌2010年5月には大田原市が小学校での集団接種を開始した。これら地方自治体の動きを受け、厚生労働省は2012年11月に公費助成を決定し、翌2013年4月から本ワクチンは定期接種ワクチンとなり、12歳になる年度初日から16歳になる年度末日までの女児(小学6年~高校1年相当:※標準的な接種年齢は13歳になる年度初日から末日、中学1年)が公費助成を受けられるようになった[7][8]。これら2つのHPVワクチンの導入プログラムが適切に実施されれば、少なくとも70%の子宮頸癌の発症を予防すると期待される[9]
  1. その後、わが国において因果関係は不明だが、本ワクチン接種後に持続的な疼痛と運動障害などの有害事象報告がメディアから繰り返し報道された。これらの事例に対し、副反応に関する専門委員会(副反応検討部会)で緊急に検討された結果、定期接種の実施を中止するほどリスクが高いとは評価されなかったものの、「同副反応の発生頻度等がより明らかになり、国民に適切な情報提供ができるまでの間、定期接種を積極的に勧奨すべきではない」との判断により、定期接種化されて僅か2カ月後に厚生労働省は、本ワクチンの積極的な接種勧奨の一時中止を決定した[10]。当初は一時的な措置として早急な専門家による評価を実施する予定としていたが、以後現在(2017年10月現在)に至るまで、積極的な接種勧奨中止の状態が続いている。そのため公費助成対象である女性の70%以上が接種していた本ワクチンの接種率は急落し、現在は1%にも満たない低い接種率となっている[11]
  1. HPVワクチンが承認されて以降、厚生労働省ではHPVワクチンの副反応について専門家の会議による分析・評価が定期的に続けられ、問題とされている副反応の発生頻度が明らかとなった[12]。一方、HPVワクチン接種後に症状を訴える女性に対する適切な初期対応の実施を目的に、日本医師会・日本医学会より「HPVワクチン接種後に生じた症状に対する手引き」が2015年8月に公表された[13]。厚生労働省は、二次医療機関が適切に対応できるよう、各都道府県に1施設以上の協力医療機関を配置し、さらに専門医療機関に相談できる診療体制の整備を行った[14]。現在、これら協力医療機関、専門医療機関の一覧が厚生労働省のホームページに公開されている[15]。また、「HPVワクチン相談窓口」を設け、HPVワクチン接種に関する電話相談ができるようになっている。このようにHPVワクチン接種に伴う不安を医療体制ならびに心理的側面からも解消できるよう体制が整いつつある[15]
  1. 一方、世界保健機関(WHO)は、2014年より現在まで、HPVワクチンの安全性について注意深い検証とモニタリングを続け、ワクチン接種とそれに伴う多様な症状もしくは慢性疼痛などの疾患との間に生物学的・疫学的なエビデンスが認められず、日本でのHPVワクチンの勧奨中止を憂慮する旨の声明を重ねて発表している[16][17][18]。日本産科婦人科学会、日本産婦人科医会、日本小児科学会、予防接種推進専門協議会などの学術団体は、積極的接種勧奨の再開を求める声明を発信している[19]

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文献 

著者: R Kirnbauer, F Booy, N Cheng, D R Lowy, J T Schiller
雑誌名: Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12180-4.
Abstract/Text Infection by certain human papillomavirus types is regarded as the major risk factor in the development of cervical cancer, one of the most common cancers of women worldwide. Analysis of the immunogenic and structural features of papillomavirus virions has been hampered by the inability to efficiently propagate the viruses in cultured cells. For instance, it has not been established whether the major capsid protein L1 alone is sufficient for virus particle assembly. In addition, it is not known whether L1, L2 (the minor capsid protein), or both present the immunodominant epitopes required for induction of high-titer neutralizing antibodies. We have expressed the L1 major capsid proteins of bovine papillomavirus type 1 and human papillomavirus type 16 in insect cells via a baculovirus vector and analyzed their conformation and immunogenicity. The L1 proteins were expressed at high levels and assembled into structures that closely resembled papillomavirus virions. The self-assembled bovine papillomavirus L1, in contrast to L1 extracted from recombinant bacteria or denatured virions, also mimicked intact bovine papillomavirus virions in being able to induce high-titer neutralizing rabbit antisera. These results indicate that L1 protein has the intrinsic capacity to assemble into empty capsid-like structures whose immunogenicity is similar to infectious virions. This type of L1 preparation might be considered as a candidate for a serological test to measure antibodies to conformational virion epitopes and for a vaccine to prevent papillomavirus infection.

PMID 1334560  Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12180-4.
著者: Polly Roy, Rob Noad
雑誌名: Hum Vaccin. 2008 Jan-Feb;4(1):5-12. Epub 2008 Jan 11.
Abstract/Text Vaccines against viral disease have traditionally relied on attenuated virus strains or inactivation of infectious virus. Subunit vaccines based on viral proteins expressed in heterologous systems have been effective for some pathogens, but have often suffered from poor immunogenicity due to incorrect protein folding or modification. In this review we focus on a specific class of viral subunit vaccine that mimics the overall structure of virus particles and thus preserves the native antigenic conformation of the immunogenic proteins. These virus-like particles (VLPs) have been produced for a wide range of taxonomically and structurally distinct viruses, and have unique advantages in terms of safety and immunogenicity over previous approaches. With new VLP vaccines for papillomavirus beginning to reach the marketplace we argue that this technology has now 'come-of-age' and must be considered a viable vaccine strategy.

PMID 18438104  Hum Vaccin. 2008 Jan-Feb;4(1):5-12. Epub 2008 Jan 11.
著者: Ian Frazer
雑誌名: Virus Res. 2002 Nov;89(2):271-4.
Abstract/Text Vaccines to prevent PV infection, utilising PV L1 virus like particles (VLPs) to induce neutralising antibody, are in clinical trial and show all the characteristics likely to be associated with success. Results warrant global planning for the deployment of VLP vaccines within a decade, as part of a program to prevent cervical cancer. Vaccines designed to treat existing PV infection by inducing therapeutic cellular immunity targeted to PV proteins are at a much earlier stage of development. The wide choice of potential and proposed antigens, routes and mechanisms of delivery, and possible treatment regimens suggest that, to move the field forward, surrogate markers allowing comparison of the relative efficacy of different vaccine approaches are required. These should be based on reduction in load of virus infection, and need to be validated in animal models or in man.

PMID 12445666  Virus Res. 2002 Nov;89(2):271-4.
著者: Mark Schiffman, Philip E Castle
雑誌名: Arch Pathol Lab Med. 2003 Aug;127(8):930-4. doi: 10.1043/1543-2165(2003)127<930:HPEAPH>2.0.CO;2.
Abstract/Text Approximately 15 types of human papillomavirus (HPV) infection cause virtually all cases of cervical cancer. Human papillomavirus 16 is the major type, accounting for approximately 50% of cases. The major steps of cervical carcinogenesis include HPV infection, viral persistence and progression to precancer (as opposed to viral clearance), and invasion. Human papillomavirus is the most common sexually transmitted infection. However, most HPV infections become undetectable by even sensitive HPV DNA testing within 1 to 2 years. The prevalence of infection peaks at young ages and declines thereafter, perhaps as the result of HPV type-specific acquired immunity. Most HPV infections are neither microscopically evident nor visible, making HPV DNA detection the diagnostic reference standard. Poorly defined immunologic factors are the major determinants of viral outcome. Smoking, multiparity, and long-term oral contraceptive use increase the risk of persistence and progression. Other sexually transmitted infections (eg, Chlamydia trachomatis), chronic inflammation, and nutritional factors might also play a role. Overt, long-term viral persistence in the absence of precancer is uncommon. New prevention strategies can be derived from the evolving knowledge of HPV carcinogenesis. Human papillomavirus vaccination is the ultimate prevention strategy, and large-scale trials are already underway. In the meantime, HPV DNA diagnostics are more sensitive although less specific than cytology, permitting a consideration of lengthened screening intervals. In terms of public health education, clinicians and patients will need to shift discussions of the mildly abnormal Papanicolaou test to consideration of HPV infection as a common sexually transmitted infection that rarely causes cervical cancer.

PMID 12873163  Arch Pathol Lab Med. 2003 Aug;127(8):930-4. doi: 10.104・・・
著者: J Paavonen, P Naud, J Salmerón, C M Wheeler, S-N Chow, D Apter, H Kitchener, X Castellsague, J C Teixeira, S R Skinner, J Hedrick, U Jaisamrarn, G Limson, S Garland, A Szarewski, B Romanowski, F Y Aoki, T F Schwarz, W A J Poppe, F X Bosch, D Jenkins, K Hardt, T Zahaf, D Descamps, F Struyf, M Lehtinen, G Dubin, HPV PATRICIA Study Group
雑誌名: Lancet. 2009 Jul 25;374(9686):301-14. doi: 10.1016/S0140-6736(09)61248-4. Epub 2009 Jul 6.
Abstract/Text BACKGROUND: The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was immunogenic, generally well tolerated, and effective against HPV-16 or HPV-18 infections, and associated precancerous lesions in an event-triggered interim analysis of the phase III randomised, double-blind, controlled PApilloma TRIal against Cancer In young Adults (PATRICIA). We now assess the vaccine efficacy in the final event-driven analysis.
METHODS: Women (15-25 years) were vaccinated at months 0, 1, and 6. Analyses were done in the according-to-protocol cohort for efficacy (ATP-E; vaccine, n=8093; control, n=8069), total vaccinated cohort (TVC, included all women receiving at least one vaccine dose, regardless of their baseline HPV status; represents the general population, including those who are sexually active; vaccine, n=9319; control, n=9325), and TVC-naive (no evidence of oncogenic HPV infection at baseline; represents women before sexual debut; vaccine, n=5822; control, n=5819). The primary endpoint was to assess vaccine efficacy against cervical intraepithelial neoplasia 2+ (CIN2+) that was associated with HPV-16 or HPV-18 in women who were seronegative at baseline, and DNA negative at baseline and month 6 for the corresponding type (ATP-E). This trial is registered with ClinicalTrials.gov, number NCT00122681.
FINDINGS: Mean follow-up was 34.9 months (SD 6.4) after the third dose. Vaccine efficacy against CIN2+ associated with HPV-16/18 was 92.9% (96.1% CI 79.9-98.3) in the primary analysis and 98.1% (88.4-100) in an analysis in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types (ATP-E cohort). Vaccine efficacy against CIN2+ irrespective of HPV DNA in lesions was 30.4% (16.4-42.1) in the TVC and 70.2% (54.7-80.9) in the TVC-naive. Corresponding values against CIN3+ were 33.4% (9.1-51.5) in the TVC and 87.0% (54.9-97.7) in the TVC-naive. Vaccine efficacy against CIN2+ associated with 12 non-vaccine oncogenic types was 54.0% (34.0-68.4; ATP-E). Individual cross-protection against CIN2+ associated with HPV-31, HPV-33, and HPV-45 was seen in the TVC.
INTERPRETATION: The HPV-16/18 AS04-adjuvanted vaccine showed high efficacy against CIN2+ associated with HPV-16/18 and non-vaccine oncogenic HPV types and substantial overall effect in cohorts that are relevant to universal mass vaccination and catch-up programmes.
FUNDING: GlaxoSmithKline Biologicals.

PMID 19586656  Lancet. 2009 Jul 25;374(9686):301-14. doi: 10.1016/S014・・・
著者: Suzanne M Garland, Mauricio Hernandez-Avila, Cosette M Wheeler, Gonzalo Perez, Diane M Harper, Sepp Leodolter, Grace W K Tang, Daron G Ferris, Marc Steben, Janine Bryan, Frank J Taddeo, Radha Railkar, Mark T Esser, Heather L Sings, Micki Nelson, John Boslego, Carlos Sattler, Eliav Barr, Laura A Koutsky, Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I Investigators
雑誌名: N Engl J Med. 2007 May 10;356(19):1928-43. doi: 10.1056/NEJMoa061760.
Abstract/Text BACKGROUND: A phase 3 trial was conducted to evaluate the efficacy of a prophylactic quadrivalent vaccine in preventing anogenital diseases associated with human papillomavirus (HPV) types 6, 11, 16, and 18.
METHODS: In this randomized, placebo-controlled, double-blind trial involving 5455 women between the ages of 16 and 24 years, we assigned 2723 women to receive vaccine and 2732 to receive placebo at day 1, month 2, and month 6. The coprimary composite end points were the incidence of genital warts, vulvar or vaginal intraepithelial neoplasia, or cancer and the incidence of cervical intraepithelial neoplasia, adenocarcinoma in situ, or cancer associated with HPV type 6, 11, 16, or 18. Data for the primary analysis were collected for a per-protocol susceptible population of women who had no virologic evidence of HPV type 6, 11, 16, or 18 through 1 month after administration of the third dose.
RESULTS: The women were followed for an average of 3 years after administration of the first dose. In the per-protocol population, those followed for vulvar, vaginal, or perianal disease included 2261 women (83%) in the vaccine group and 2279 (83%) in the placebo group. Those followed for cervical disease included 2241 women (82%) in the vaccine group and 2258 (83%) in the placebo group. Vaccine efficacy was 100% for each of the coprimary end points. In an intention-to-treat analysis, including those with prevalent infection or disease caused by vaccine-type and non-vaccine-type HPV, vaccination reduced the rate of any vulvar or vaginal perianal lesions regardless of the causal HPV type by 34% (95% confidence interval [CI], 15 to 49), and the rate of cervical lesions regardless of the causal HPV type by 20% (95% CI, 8 to 31).
CONCLUSIONS: The quadrivalent vaccine significantly reduced the incidence of HPV-associated anogenital diseases in young women. (ClinicalTrials.gov number, NCT00092521 [ClinicalTrials.gov].).

Copyright 2007 Massachusetts Medical Society.
PMID 17494926  N Engl J Med. 2007 May 10;356(19):1928-43. doi: 10.1056・・・
著者: Anthony B Miller
雑誌名: South Asian J Cancer. 2013 Oct;2(4):198-9. doi: 10.4103/2278-330X.119894.
Abstract/Text
PMID 24455625  South Asian J Cancer. 2013 Oct;2(4):198-9. doi: 10.4103・・・
著者:
雑誌名: Wkly Epidemiol Rec. 2017 Jul 14;92(28):393-402. Epub 2017 Jul 14.
Abstract/Text
PMID 28707463  Wkly Epidemiol Rec. 2017 Jul 14;92(28):393-402. Epub 20・・・
著者:
雑誌名: Wkly Epidemiol Rec. 2017 May 12;92(19):241-68. Epub 2017 May 12.
Abstract/Text
PMID 28530369  Wkly Epidemiol Rec. 2017 May 12;92(19):241-68. Epub 201・・・
著者: Julia M L Brotherton, A Marion Saville, Cathryn L May, Genevieve Chappell, Dorota M Gertig
雑誌名: Cancer Causes Control. 2015 Jun;26(6):953-4. doi: 10.1007/s10552-015-0568-6. Epub 2015 Mar 25.
Abstract/Text
PMID 25804857  Cancer Causes Control. 2015 Jun;26(6):953-4. doi: 10.10・・・
著者: Elaine W Flagg, Elizabeth A Torrone, Hillard Weinstock
雑誌名: Am J Public Health. 2016 Dec;106(12):2211-2218. doi: 10.2105/AJPH.2016.303472. Epub 2016 Oct 13.
Abstract/Text OBJECTIVES: To examine prevalence of low- and high-grade cervical lesions over time in a large cohort of US female adolescents and women.
METHODS: We used health care claims data from 9 million privately insured female patients aged 15 to 39 years to estimate annual prevalence of cytologically detected cervical low-grade (LSIL) and high-grade squamous intraepithelial lesions (HSIL) and high-grade histologically detected cervical intraepithelial neoplasia grades 2 and 3 (CIN2+) during 2007 through 2014. We restricted analyses to those who received cervical cancer screening in a given calendar year.
RESULTS: Prevalence of HSIL and CIN2+ decreased significantly for those aged 15 to 19 years. Average annual percent change in prevalence in this group during 2007 through 2014 for HSIL and CIN2+ was -8.3% and -14.4%, respectively (P < .001 for both estimates). Prevalence of HSIL and CIN2+ also decreased significantly for women aged 20 to 24 years. No decreases were seen in women aged 25 to 39 years.
CONCLUSIONS: Decreases in high-grade lesions reflected their greater association with human papillomavirus types 16 and 18, compared with low-grade lesions, providing ecological evidence of population effectiveness of human papillomavirus vaccination among young, privately insured women.

PMID 27736208  Am J Public Health. 2016 Dec;106(12):2211-2218. doi: 10・・・
著者: Ross L Cameron, Kimberley Kavanagh, D Cameron Watt, Chris Robertson, Kate Cuschieri, Syed Ahmed, Kevin G Pollock
雑誌名: J Epidemiol Community Health. 2017 Oct;71(10):954-960. doi: 10.1136/jech-2017-209113. Epub 2017 Jul 29.
Abstract/Text BACKGROUND: Cervical cancer disproportionately affects women from lower socioeconomic backgrounds. A human papillomavirus (HPV) vaccination programme was introduced in Scotland in 2008 with uptake being lower and inequitable in a catch-up cohort run for the first three years of the programme compared with the routine programme. The socioeconomic differences in vaccine uptake have the potential to further increase the inequality gap in regards to cervical disease.
METHODS: Vaccination status was linked to demographic, cytological and colposcopic data, which are routinely collected by the Scottish HPV surveillance system. Incidence rates and relative risk of cervical intraepithelial neoplasia (CIN) 1, 2 and 3 in unvaccinated and vaccinated women were stratified by birth year and deprivation status using Poisson regression.
RESULTS: Women who received three doses of HPV vaccine have significantly decreased risk of CIN 1, 2 and 3. Vaccine effectiveness was greater in those women from the most deprived backgrounds against CIN 2 and 3 lesions. Compared with the most deprived, unvaccinated women, the relative risk of CIN 3 in fully vaccinated women in the same deprivation group was 0.29 (95% CI 0.2 to 0.43) compared with 0.62 (95% CI 0.4 to 0.97) in vaccinated women in the least-deprived group.
CONCLUSIONS: The HPV vaccine is associated with significant reductions in both low-grade and high-grade CIN for all deprivation categories. However, the effect on high-grade disease was most profound in the most-deprived women. These data are welcoming and allay the concern that inequalities in cervical cancer may persist or increase following the introduction of the vaccine in Scotland.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
PMID 28756395  J Epidemiol Community Health. 2017 Oct;71(10):954-960. ・・・
著者: Eva Herweijer, Karin Sundström, Alexander Ploner, Ingrid Uhnoo, Pär Sparén, Lisen Arnheim-Dahlström
雑誌名: Int J Cancer. 2016 Jun 15;138(12):2867-74. doi: 10.1002/ijc.30035. Epub 2016 Mar 9.
Abstract/Text Human papillomavirus (HPV) types 16/18, included in HPV vaccines, contribute to the majority of cervical cancer, and a substantial proportion of cervical intraepithelial neoplasia (CIN) grades 2/3 or worse (CIN2+/CIN3+) including adenocarcinoma in situ or worse. The aim of this study was to quantify the effect of quadrivalent HPV (qHPV) vaccination on incidence of CIN2+ and CIN3+. A nationwide cohort of girls and young women resident in Sweden 2006-2013 and aged 13-29 (n = 1,333,691) was followed for vaccination and histologically confirmed high-grade cervical lesions. Data were collected using the Swedish nationwide healthcare registers. Poisson regression was used to calculate incidence rate ratios (IRRs) and vaccine effectiveness [(1-IRR)x100%] comparing fully vaccinated with unvaccinated individuals. IRRs were adjusted for attained age and parental education, and stratified on vaccination initiation age. Effectiveness against CIN2+ was 64% (IRR = 0.36, 95%CI = 0.27–0.47) for those initiating vaccination before age 17, and 25% (IRR = 0.75, 95%CI = 0.66–0.86) and 14% (IRR = 0.86, 95%CI = 0.73–1.01) for those initiating vaccination at ages 17–19, and at ages 20–29, respectively. Vaccine effectiveness against CIN3+ was similar to vaccine effectiveness against CIN2+. Results were robust for both women participating to the organized screening program and for women at prescreening ages. We show high effectiveness of qHPV vaccination on CIN2+ and CIN3+ lesions, with greater effectiveness observed in girls younger at vaccination initiation. Continued monitoring of impact of HPV vaccination in the population is needed in order to evaluate both long-term vaccine effectiveness and to evaluate whether the vaccination program achieves anticipated effects in prevention of invasive cervical cancer.

© 2016 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
PMID 26856527  Int J Cancer. 2016 Jun 15;138(12):2867-74. doi: 10.1002・・・
著者: Sepehr N Tabrizi, Julia M L Brotherton, John M Kaldor, S Rachel Skinner, Bette Liu, Deborah Bateson, Kathleen McNamee, Maria Garefalakis, Samuel Phillips, Eleanor Cummins, Michael Malloy, Suzanne M Garland
雑誌名: Lancet Infect Dis. 2014 Oct;14(10):958-66. doi: 10.1016/S1473-3099(14)70841-2. Epub 2014 Aug 5.
Abstract/Text BACKGROUND: After the introduction of a quadrivalent human papillomavirus (HPV) vaccination programme in Australia in April, 2007, we measured the prevalence of vaccine-targeted and closely related HPV types with the aim of assessing direct protection, cross-protection, and herd immunity.
METHODS: In this repeat cross-sectional study, we recruited women aged 18-24 years who attended Pap screening between October, 2005, and July, 2007, in three major metropolitan areas of Australia to form our prevaccine-implementation sample. For our postvaccine-implementation sample, we recruited women aged 18-24 years who attended Pap screening in the same three metropolitan areas from August, 2010, to November, 2012. We compared the crude prevalence of HPV genotypes in cervical specimens between the prevaccine and the postvaccine implementation groups, with vaccination status validated against the National HPV Vaccination Program Register. We estimated adjusted prevalence ratios using log linear regression. We estimated vaccine effectiveness both for vaccine-targeted HPV types (16, 18, 6, and 11) and non-vaccine but related HPV types (31, 33, and 45).
FINDINGS: 202 women were recruited into the prevaccine-implementation group, and 1058 were recruited into the postvaccine-implementation group. Crude prevalence of vaccine-targeted HPV genotypes was significantly lower in the postvaccine-implementation sample than in the prevaccine-implementation sample (58 [29%] of 202 vs 69 [7%] of 1058; p<0·0001). Compared with the prevaccine-implementation sample, adjusted prevalence ratios for vaccine-targeted HPV genotypes were 0·07 (95% CI 0·04-0·14; p<0·0001) in fully vaccinated women and 0·65 (0·43-0·96; p=0·03) in unvaccinated women, which suggests herd immunity. No significant declines were noted for non-vaccine-targeted HPV genotypes. However, within the postvaccine-implementation sample, adjusted vaccine effectiveness against vaccine-targeted HPV types for fully vaccinated women compared with unvaccinated women was 86% (95% CI 71-93), and was 58% (26-76) against non-vaccine-targeted but related genotypes (HPV 31, 33, and 45).
INTERPRETATION: 6 years after the initiation of the Australian HPV vaccination programme, we have detected a substantial fall in vaccine-targeted HPV genotypes in vaccinated women; a lower prevalence of vaccine-targeted types in unvaccinated women, suggesting herd immunity; and a possible indication of cross-protection against HPV types related to the vaccine-targeted types in vaccinated women.
FUNDING: Australian National Health and Medical Research Council and Cancer Council Victoria.

Copyright © 2014 Elsevier Ltd. All rights reserved.
PMID 25107680  Lancet Infect Dis. 2014 Oct;14(10):958-66. doi: 10.1016・・・
著者: Lauri E Markowitz, Gui Liu, Susan Hariri, Martin Steinau, Eileen F Dunne, Elizabeth R Unger
雑誌名: Pediatrics. 2016 Mar;137(3):e20151968. doi: 10.1542/peds.2015-1968. Epub 2016 Feb 22.
Abstract/Text BACKGROUND: Since mid-2006, human papillomavirus (HPV) vaccination has been recommended for females aged 11 to 12 years and through 26 years if not previously vaccinated.
METHODS: HPV DNA prevalence was analyzed in cervicovaginal specimens from females aged 14 to 34 years in NHANES in the prevaccine era (2003-2006) and 4 years of the vaccine era (2009-2012) according to age group. Prevalence of quadrivalent HPV vaccine (4vHPV) types (HPV-6, -11, -16, and -18) and other HPV type categories were compared between eras. Prevalence among sexually active females aged 14 to 24 years was also analyzed according to vaccination history.
RESULTS: Between the prevacccine and vaccine eras, 4vHPV type prevalence declined from 11.5% to 4.3% (adjusted prevalence ratio [aPR]: 0.36 [95% confidence interval (CI): 0.21-0.61]) among females aged 14 to 19 years and from 18.5% to 12.1% (aPR: 0.66 [95% CI: 0.47-0.93]) among females aged 20 to 24 years. There was no decrease in 4vHPV type prevalence in older age groups. Within the vaccine era, among sexually active females aged 14 to 24 years, 4vHPV type prevalence was lower in vaccinated (≥1 dose) compared with unvaccinated females: 2.1% vs 16.9% (aPR: 0.11 [95% CI: 0.05-0.24]). There were no statistically significant changes in other HPV type categories that indicate cross-protection.
CONCLUSIONS: Within 6 years of vaccine introduction, there was a 64% decrease in 4vHPV type prevalence among females aged 14 to 19 years and a 34% decrease among those aged 20 to 24 years. This finding extends previous observations of population impact in the United States and demonstrates the first national evidence of impact among females in their 20s.

Copyright © 2016 by the American Academy of Pediatrics.
PMID 26908697  Pediatrics. 2016 Mar;137(3):e20151968. doi: 10.1542/ped・・・
著者: D Mesher, K Soldan, R Howell-Jones, K Panwar, P Manyenga, M Jit, S Beddows, O N Gill
雑誌名: Vaccine. 2013 Dec 17;32(1):26-32. doi: 10.1016/j.vaccine.2013.10.085. Epub 2013 Nov 6.
Abstract/Text BACKGROUND: Reduction in the prevalence of vaccine type HPV infection in young women is an early indication of the impact of the HPV immunisation programme and a necessary outcome if the subsequent impact on cervical cancer is to be realised.
METHODS: Residual vulva-vaginal swab (VVS) specimens from young women aged 16-24 years undergoing chlamydia screening in community sexual health services (formerly known as family planning clinics), general practice (GP), and youth clinics in 2010-2012 were submitted from 10 laboratories in seven regions around England. These specimens were linked to demographic and sexual behaviour data reported with the chlamydia test, anonymised, and tested for type-specific HPV DNA using a multiplex PCR and Luminex-based genotyping test. Estimated immunisation coverage was calculated and findings were compared to a baseline survey conducted prior to the introduction of HPV immunisation in 2008.
RESULTS: A total of 4664 eligible specimens were collected and 4178 had a valid test result. The post-immunisation prevalence of HPV 16/18 infection was lowest in this youngest age group (16-18 years) and increased with age. This increase with age was a reversal of the pattern seen prior to immunisation and was inversely associated with estimates of age-specific immunisation coverage (65% for 16-18 year olds). The prevalence of HPV 16/18 infection in the post-immunisation survey was 6.5% amongst 16-18 year olds, compared to 19.1% in the similar survey conducted prior to the introduction of HPV immunisation.
CONCLUSIONS: These findings are the first indication that the national HPV immunisation programme is successfully preventing HPV 16/18 infection in sexually active young women in England. The reductions seen suggest, for the estimated coverage, high vaccine effectiveness and some herd-protection benefits. Continued surveillance is needed to determine the effects of immunisation on non-vaccine HPV types.

Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.
PMID 24211166  Vaccine. 2013 Dec 17;32(1):26-32. doi: 10.1016/j.vaccin・・・
著者: Nobuyoshi Ozawa, Kiyoshi Ito, Toru Tase, Hirohito Metoki, Nobuo Yaegashi
雑誌名: Tohoku J Exp Med. 2016 Oct;240(2):147-151. doi: 10.1620/tjem.240.147.
Abstract/Text Prevention of cervical cancer has been unsuccessful in Japan because of low rates of cancer screening and vaccination. The Vaccine Adverse Review Committee of the Japanese Government investigated 2,475 adverse events and reported 617 (6.9/100,000) severe cases and 176 (2.0/100,000) cases with chronic pain. The proactive recommendation for human papillomavirus (HPV) vaccination has been suspended since June 2013. In this study, we examined vaccination rate and incidence of abnormal cervical cytology in women aged 20 to 24 years attending cancer screening in Miyagi. Among the 3,272 women who underwent a health check in the fiscal year 2014 (April 2014-March 2015), 332 (10.2%) received a HPV vaccination. The HPV vaccination rates were 42.3%, 10%, 17.5%, 3.8% and 4.0% in women aged 20, 21, 22, 23 and 24 years, respectively. The rates of atypical squamous cells of undetermined significance (ASC-US) or worse were 2.41% (8/332) in women with HPV vaccination and 5.03% (148/2,940) in those without HPV vaccination, indicating a significant decrease in vaccinated women (p = 0.03). ASC-US cases were referred to HPV DNA tests. In addition, the rates of high grade squamous intraepithelial lesion (HSIL) or worse were 0.30% (1/332) in women with HPV vaccination and 0.82% (24/2,940) in those without HPV vaccination, showing the marginal decrease in women who were vaccinated (p = 0.3). Thus, this study indicates that HPV vaccination is associated with a reduction in the incidence of cervical abnormalities, suggesting a need for scientific discussion of reinstatement of proactive recommendation for HPV vaccine in Japan.

PMID 27746423  Tohoku J Exp Med. 2016 Oct;240(2):147-151. doi: 10.1620・・・
著者: Hidenori Tanaka, Hiromitsu Shirasawa, Dai Shimizu, Naoki Sato, Noriaki Ooyama, Osamu Takahashi, Yukihiro Terada
雑誌名: J Obstet Gynaecol Res. 2017 Oct;43(10):1597-1601. doi: 10.1111/jog.13419. Epub 2017 Jul 14.
Abstract/Text AIM: To examine the effect that human papillomavirus (HPV) vaccination has had in Akita Prefecture, by comparing cervical cytology results from women aged 20-24 years with or without HPV vaccination.
METHODS: We examined cervical cytology results from 2425 subjects who underwent cervical cancer screening under the jurisdiction of the Akita Foundation for Healthcare between January 2014 and October 2016. We compared the prevalence of cytologic abnormalities among women aged 20-24 years with or without HPV vaccination.
RESULTS: The rate of atypical squamous cells of undetermined significance (ASC-US) or worse was 0.242% (1/413) with HPV vaccination, and 2.04% (41/2012) without HPV vaccination. Overall, the prevalence of abnormal cytology results was significantly lower in women aged 20-24 years who had received an HPV vaccination than in those who had not (P = 0.011). The reduction in the rate of abnormal cervical cytology results by HPV vaccination was 88.1%.
CONCLUSION: Within a 4-year-5-year period following vaccination, women aged 20-24 years who received an HPV vaccination had significantly lower rates of abnormal cervical cytology results than those who did not receive the vaccine.

© 2017 Japan Society of Obstetrics and Gynecology.
PMID 28707725  J Obstet Gynaecol Res. 2017 Oct;43(10):1597-1601. doi: ・・・
著者: Koji Matsumoto, Nobuo Yaegashi, Takashi Iwata, Kasumi Yamamoto, Minoru Nagashima, Toshiaki Saito, Kimio Ushijima, Fumiaki Takahashi, Kiichiro Noda, Hiroyuki Yoshikawa
雑誌名: Int J Cancer. 2017 Oct 15;141(8):1704-1706. doi: 10.1002/ijc.30855. Epub 2017 Jul 12.
Abstract/Text
PMID 28657110  Int J Cancer. 2017 Oct 15;141(8):1704-1706. doi: 10.100・・・
著者: Lisen Arnheim-Dahlström, Björn Pasternak, Henrik Svanström, Pär Sparén, Anders Hviid
雑誌名: BMJ. 2013 Oct 9;347:f5906. doi: 10.1136/bmj.f5906. Epub 2013 Oct 9.
Abstract/Text OBJECTIVE: To assess the risk of serious adverse events after vaccination of adolescent girls with quadrivalent human papillomavirus (qHPV) vaccine.
DESIGN: Register based cohort study.
SETTING: Denmark and Sweden, October 2006 to December 2010.
PARTICIPANTS: 997,585 girls aged 10-17, among whom 296,826 received a total of 696,420 qHPV vaccine doses.
MAIN OUTCOME MEASURES: Incident hospital diagnosed autoimmune, neurological, and venous thromboembolic events (53 different outcomes) up to 180 days after each qHPV vaccine dose. Only events with at least five vaccine exposed cases were considered for further assessment. Rate ratios adjusted for age, country, calendar year, and parental country of birth, education, and socioeconomic status were estimated, comparing vaccinated and unvaccinated person time. For outcomes where the rate ratio was significantly increased, we regarded three criteria as signal strengthening: analysis based on 20 or more vaccine exposed cases (reliability), rate ratio 3.0 or more (strength), and significantly increased rate ratio in country specific analyses (consistency). We additionally assessed clustering of events in time and estimated rate ratios for a risk period that started on day 181.
RESULTS: Among the 53 outcomes, at least five vaccine exposed cases occurred in 29 and these were analysed further. Whereas the rate ratios for 20 of 23 autoimmune events were not significantly increased, exposure to qHPV vaccine was significantly associated with Behcet's syndrome, Raynaud's disease, and type 1 diabetes. Each of these three outcomes fulfilled only one of three predefined signal strengthening criteria. Furthermore, the pattern of distribution in time after vaccination was random for all three and the rate ratios for these outcomes in the period from day 181 after vaccination were similar to the rate ratios in the primary risk period. The rate ratios for five neurological events were not significantly increased and there were inverse associations with epilepsy (rate ratio 0.66, 95% confidence interval 0.54 to 0.80) and paralysis (0.56, 0.35 to 0.90). There was no association between exposure to qHPV vaccine and venous thromboembolism (0.86, 0.55 to 1.36).
CONCLUSIONS: This large cohort study found no evidence supporting associations between exposure to qHPV vaccine and autoimmune, neurological, and venous thromboembolic adverse events. Although associations for three autoimmune events were initially observed, on further assessment these were weak and not temporally related to vaccine exposure. Furthermore, the findings need to be interpreted considering the multiple outcomes assessed.

PMID 24108159  BMJ. 2013 Oct 9;347:f5906. doi: 10.1136/bmj.f5906. Epub・・・
著者: Nikolai Madrid Scheller, Henrik Svanström, Björn Pasternak, Lisen Arnheim-Dahlström, Karin Sundström, Katharina Fink, Anders Hviid
雑誌名: JAMA. 2015 Jan 6;313(1):54-61. doi: 10.1001/jama.2014.16946.
Abstract/Text IMPORTANCE: Case reports have suggested a link between human papillomavirus (HPV) vaccination and development of multiple sclerosis and other demyelinating diseases.
OBJECTIVE: To investigate if quadrivalent HPV (qHPV) vaccination is associated with an increased risk of multiple sclerosis and other demyelinating diseases.
DESIGN, SETTING, AND PARTICIPANTS: Using nationwide registers we identified a cohort of all females aged 10 years to 44 years in Denmark and Sweden, followed up from 2006 to 2013, information on qHPV vaccination, and data on incident diagnoses of multiple sclerosis and other demyelinating diseases. The primary analysis used a cohort design including vaccinated and unvaccinated study participants. A secondary analysis used a self-controlled case-series design including only cases. Both analyses used a 2-year risk period following vaccination.
EXPOSURES: Information on qHPV vaccination was obtained through the national vaccination and prescription registers.
MAIN OUTCOMES AND MEASURES: The primary outcomes were multiple sclerosis and a composite end point of other demyelinating diseases. Incidence rate ratios were estimated using Poisson regression, comparing rates of events in the 2-year risk periods following vaccination and in unvaccinated time periods.
RESULTS: The study included 3,983,824 females, among whom 789,082 received a total of 1,927,581 qHPV vaccine doses. During follow-up, 4322 multiple sclerosis cases and 3300 cases of other demyelinating diseases were identified, of which 73 and 90, respectively, occurred within the risk period. In the cohort analysis, there was no increased risk of multiple sclerosis (crude incidence rates, 6.12 events/100,000 person-years [95% CI, 4.86-7.69] and 21.54 events/100,000 person-years [95% CI, 20.90-22.20] for the vaccinated and unvaccinated periods; adjusted rate ratio, 0.90 [95% CI, 0.70-1.15]) or other demyelinating diseases (crude incidence rates, 7.54 events/100,000 person-years [95% CI, 6.13-9.27] and 16.14 events/100,000 person-years [95% CI, 15.58-16.71]; adjusted rate ratio, 1.00 [95% CI, 0.80-1.26]) associated with qHPV vaccination. Similarly, no increased risk was found using the self-controlled case-series design (multiple sclerosis: incidence ratio, 1.05 [95% CI, 0.79-1.38]; other demyelinating diseases: incidence ratio, 1.14 [95% CI, 0.88-1.47]).
CONCLUSIONS AND RELEVANCE: In this study with nationwide coverage of 2 Scandinavian countries, qHPV vaccination was not associated with the development of multiple sclerosis or other demyelinating diseases. These findings do not support concerns about a causal relationship between qHPV vaccination and demyelinating diseases.

PMID 25562266  JAMA. 2015 Jan 6;313(1):54-61. doi: 10.1001/jama.2014.1・・・
著者: Ulla Bonde, Jan Stener Joergensen, Ronald F Lamont, Ole Mogensen
雑誌名: Hum Vaccin Immunother. 2016 Aug 2;12(8):1960-1964. doi: 10.1080/21645515.2016.1160178. Epub 2016 May 12.
Abstract/Text Millions of doses of HPV vaccine have been administered globally. Inadvertent administration of HPV vaccine during pregnancy occurs given that the main recipients of the vaccine are fertile young women, who might be unaware of their pregnancy at the time of their vaccination. To investigate the subject of HPV vaccine and pregnancy , the databases of PubMed and Embase were searched to find the relevant literature published in English within the last 10 y. Most of the evidence pertaining to fetal adverse events following HPV vaccination relates to spontaneous miscarriage. None of the relevant studies found any significantly increased rate of spontaneous abortion in the overall analyses. There was no indication of other HPV vaccine-associated adverse events in pregnancy or immediately post-conception.

PMID 27172372  Hum Vaccin Immunother. 2016 Aug 2;12(8):1960-1964. doi:・・・
著者: Nikolai M Scheller, Björn Pasternak, Ditte Mølgaard-Nielsen, Henrik Svanström, Anders Hviid
雑誌名: N Engl J Med. 2017 Mar 30;376(13):1223-1233. doi: 10.1056/NEJMoa1612296.
Abstract/Text BACKGROUND: The quadrivalent human papillomavirus (HPV) vaccine is recommended for all girls and women 9 to 26 years of age. Some women will have inadvertent exposure to vaccination during early pregnancy, but few data exist regarding the safety of the quadrivalent HPV vaccine in this context.
METHODS: We assessed a cohort that included all the women in Denmark who had a pregnancy ending between October 1, 2006, and November 30, 2013. Using nationwide registers, we linked information on vaccination, adverse pregnancy outcomes, and potential confounders among women in the cohort. Women who had vaccine exposure during the prespecified time windows were matched for propensity score in a 1:4 ratio with women who did not have vaccine exposure during the same time windows. Outcomes included spontaneous abortion, stillbirth, major birth defect, small size for gestational age, low birth weight, and preterm birth.
RESULTS: In matched analyses, exposure to the quadrivalent HPV vaccine was not associated with significantly higher risks than no exposure for major birth defect (65 cases among 1665 exposed pregnancies and 220 cases among 6660 unexposed pregnancies; prevalence odds ratio, 1.19; 95% confidence interval [CI], 0.90 to 1.58), spontaneous abortion (20 cases among 463 exposed pregnancies and 131 cases among 1852 unexposed pregnancies; hazard ratio, 0.71; 95% CI, 0.45 to 1.14), preterm birth (116 cases among 1774 exposed pregnancies and 407 cases among 7096 unexposed pregnancies; prevalence odds ratio, 1.15; 95% CI, 0.93 to 1.42), low birth weight (76 cases among 1768 exposed pregnancies and 277 cases among 7072 unexposed pregnancies; prevalence odds ratio, 1.10; 95% CI, 0.85 to 1.43), small size for gestational age (171 cases among 1768 exposed pregnancies and 783 cases among 7072 unexposed pregnancies; prevalence odds ratio, 0.86; 95% CI, 0.72 to 1.02), or stillbirth (2 cases among 501 exposed pregnancies and 4 cases among 2004 unexposed pregnancies; hazard ratio, 2.43; 95% CI, 0.45 to 13.21).
CONCLUSIONS: Quadrivalent HPV vaccination during pregnancy was not associated with a significantly higher risk of adverse pregnancy outcomes than no such exposure. (Funded by the Novo Nordisk Foundation and the Danish Medical Research Council.).

PMID 28355499  N Engl J Med. 2017 Mar 30;376(13):1223-1233. doi: 10.10・・・
著者: Maddalena D'Addario, Shelagh Redmond, Pippa Scott, Dianne Egli-Gany, A Ximena Riveros-Balta, Ana Maria Henao Restrepo, Nicola Low
雑誌名: Vaccine. 2017 May 19;35(22):2892-2901. doi: 10.1016/j.vaccine.2017.03.096. Epub 2017 Apr 25.
Abstract/Text Simpler schedules for human papillomavirus (HPV) vaccine delivery could improve vaccine coverage and the effectiveness of cervical cancer prevention. The objective of this study was to systematically review evidence about the effects of two-dose compared with three-dose schedules for human papillomavirus (HPV) vaccine and to describe the uptake of two-dose HPV vaccination schedules globally. We searched PubMed, the Cochrane Central Registry of Controlled Trials, trials registers, and manufacturers' databases from their earliest date to February 2016. We selected randomised controlled trials and controlled clinical trials that directly compared HPV vaccine schedules with two or three doses. We extracted data on immunological and clinical outcomes and used meta-analysis where appropriate. We also described the use of two-dose HPV vaccine schedules globally. We screened 1464 items and included seven eligible noninferiority trials in 11 countries. In randomised comparisons amongst adolescent girls (three trials), geometric mean concentrations (GMC) of antibodies against HPV16 and HPV18 were non-inferior or inconclusive, up to 24months after a two-dose compared with a three-dose schedule. One trial with a clinical outcome found no persistent HPV infections occurred after either two or three doses. In non-randomised comparisons, GMC were non-inferior or superior in adolescent girls receiving the two-dose schedule compared with women receiving the three-dose schedule for at least 21months after vaccination. By February 2017, 23 low and middle income and 25 high income countries had adopted a two-dose HPV vaccination schedule. A two-dose HPV vaccine schedule provides satisfactory immunological outcomes in adolescent girls, but uptake globally is limited, particularly in countries with the highest burden of cervical cancer.

Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.
PMID 28455170  Vaccine. 2017 May 19;35(22):2892-2901. doi: 10.1016/j.v・・・
著者: Beatriz Serrano, Laia Alemany, Sara Tous, Laia Bruni, Gary M Clifford, Thomas Weiss, Francesc Xavier Bosch, Silvia de Sanjosé
雑誌名: Infect Agent Cancer. 2012 Dec 29;7(1):38. doi: 10.1186/1750-9378-7-38. Epub 2012 Dec 29.
Abstract/Text UNLABELLED:
BACKGROUND: Information on human papillomavirus (HPV) type distribution is necessary to evaluate the potential impact of current and future HPV vaccines. We estimated the relative contribution (RC) to invasive cervical cancer (ICC) and precancerous cervical lesions of the nine HPV types (HPV 6/11/16/18/31/33/45/52/58) included in an HPV vaccine currently under development.
METHODS: Estimations on ICC were based on an international study of 8,977 HPV positive cases and estimations on precancerous cervical lesions were extracted from a published meta-analysis including 115,789 HPV positive women. Globocan 2008 and 2010 World Population Prospects were used to estimate current and future projections of new ICC cases.
RESULTS: RC of the 9 HPV types in ICC was 89.4%, with 18.5% of cases positive for HPV 31/33/45/52/58. Regional variations were observed. RCs varied by histology, ranging between 89.1% in squamous cell carcinomas (SCC) and 95.5% in adenocarcinomas (ADC). HPV 16/18/45 were detected in 94.2% of ADC. RC of the 9 types altogether decreased with age (trend test p < 0.0001), driven by the decrease in older ages of HPV 16/18/45. In contrast, the RC of HPV 31/33/52/58 increased with age. Due to population growth alone, projected estimates of ICC cases attributable to the 9 types are expected to rise from 493,770 new cases in 2012 to 560,887 new cases in 2025.The RCs of individual high risk HPV types varied by cytological and histological grades of HPV-positive precancerous cervical lesions, and there was an under representation of HPV 18 and 45 compared to ICC.
CONCLUSIONS: The addition of HPV 31/33/45/52/58 to HPV types included in current vaccines could prevent almost 90% of ICC cases worldwide. If the nine-valent vaccine achieves the same degree of efficacy than previous vaccines, world incidence rates could be substantially reduced.

PMID 23273245  Infect Agent Cancer. 2012 Dec 29;7(1):38. doi: 10.1186/・・・
著者: Warner K Huh, Elmar A Joura, Anna R Giuliano, Ole-Erik Iversen, Rosires Pereira de Andrade, Kevin A Ault, Deborah Bartholomew, Ramon M Cestero, Edison N Fedrizzi, Angelica L Hirschberg, Marie-Hélène Mayrand, Angela Maria Ruiz-Sternberg, Jack T Stapleton, Dorothy J Wiley, Alex Ferenczy, Robert Kurman, Brigitte M Ronnett, Mark H Stoler, Jack Cuzick, Suzanne M Garland, Susanne K Kjaer, Oliver M Bautista, Richard Haupt, Erin Moeller, Michael Ritter, Christine C Roberts, Christine Shields, Alain Luxembourg
雑誌名: Lancet. 2017 Nov 11;390(10108):2143-2159. doi: 10.1016/S0140-6736(17)31821-4. Epub 2017 Sep 5.
Abstract/Text BACKGROUND: Primary analyses of a study in young women aged 16-26 years showed efficacy of the nine-valent human papillomavirus (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine against infections and disease related to HPV 31, 33, 45, 52, and 58, and non-inferior HPV 6, 11, 16, and 18 antibody responses when compared with quadrivalent HPV (qHPV; HPV 6, 11, 16, and 18) vaccine. We aimed to report efficacy of the 9vHPV vaccine for up to 6 years following first administration and antibody responses over 5 years.
METHODS: We undertook this randomised, double-blind, efficacy, immunogenicity, and safety study of the 9vHPV vaccine study at 105 study sites in 18 countries. Women aged 16-26 years old who were healthy, with no history of abnormal cervical cytology, no previous abnormal cervical biopsy results, and no more than four lifetime sexual partners were randomly assigned (1:1) by central randomisation and block sizes of 2 and 2 to receive three intramuscular injections over 6 months of 9vHPV or qHPV (control) vaccine. All participants, study investigators, and study site personnel, laboratory staff, members of the sponsor's study team, and members of the adjudication pathology panel were masked to vaccination groups. The primary outcomes were incidence of high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, invasive cervical carcinoma), vulvar disease (vulvar intraepithelial neoplasia grade 2/3, vulvar cancer), and vaginal disease (vaginal intraepithelial neoplasia grade 2/3, vaginal cancer) related to HPV 31, 33, 45, 52, and 58 and non-inferiority (excluding a decrease of 1·5 times) of anti-HPV 6, 11, 16, and 18 geometric mean titres (GMT). Tissue samples were adjudicated for histopathology diagnosis and tested for HPV DNA. Serum antibody responses were assessed by competitive Luminex immunoassay. The primary evaluation of efficacy was a superiority analysis in the per-protocol efficacy population, supportive efficacy was analysed in the modified intention-to-treat population, and the primary evaluation of immunogenicity was a non-inferiority analysis. The trial is registered with ClinicalTrials.gov, number NCT00543543.
FINDINGS: Between Sept 26, 2007, and Dec 18, 2009, we recruited and randomly assigned 14 215 participants to receive 9vHPV (n=7106) or qHPV (n=7109) vaccine. In the per-protocol population, the incidence of high-grade cervical, vulvar and vaginal disease related to HPV 31, 33, 45, 52, and 58 was 0·5 cases per 10 000 person-years in the 9vHPV and 19·0 cases per 10 000 person-years in the qHPV groups, representing 97·4% efficacy (95% CI 85·0-99·9). HPV 6, 11, 16, and 18 GMTs were non-inferior in the 9vHPV versus qHPV group from month 1 to 3 years after vaccination. No clinically meaningful differences in serious adverse events were noted between the study groups. 11 participants died during the study follow-up period (six in the 9vHPV vaccine group and five in the qHPV vaccine group); none of the deaths were considered vaccine-related.
INTERPRETATION: The 9vHPV vaccine prevents infection, cytological abnormalities, high-grade lesions, and cervical procedures related to HPV 31, 33, 45, 52, and 58. Both the 9vHPV vaccine and qHPV vaccine had a similar immunogenicity profile with respect to HPV 6, 11, 16, and 18. Vaccine efficacy was sustained for up to 6 years. The 9vHPV vaccine could potentially provide broader coverage and prevent 90% of cervical cancer cases worldwide.
FUNDING: Merck & Co, Inc.

Copyright © 2017 Elsevier Ltd. All rights reserved.
PMID 28886907  Lancet. 2017 Nov 11;390(10108):2143-2159. doi: 10.1016/・・・
著者: Elmar A Joura, Anna R Giuliano, Ole-Erik Iversen, Celine Bouchard, Constance Mao, Jesper Mehlsen, Edson D Moreira, Yuen Ngan, Lone Kjeld Petersen, Eduardo Lazcano-Ponce, Punnee Pitisuttithum, Jaime Alberto Restrepo, Gavin Stuart, Linn Woelber, Yuh Cheng Yang, Jack Cuzick, Suzanne M Garland, Warner Huh, Susanne K Kjaer, Oliver M Bautista, Ivan S F Chan, Joshua Chen, Richard Gesser, Erin Moeller, Michael Ritter, Scott Vuocolo, Alain Luxembourg, Broad Spectrum HPV Vaccine Study
雑誌名: N Engl J Med. 2015 Feb 19;372(8):711-23. doi: 10.1056/NEJMoa1405044.
Abstract/Text BACKGROUND: The investigational 9-valent viruslike particle vaccine against human papillomavirus (HPV) includes the HPV types in the quadrivalent HPV (qHPV) vaccine (6, 11, 16, and 18) and five additional oncogenic types (31, 33, 45, 52, and 58). Here we present the results of a study of the efficacy and immunogenicity of the 9vHPV vaccine in women 16 to 26 years of age.
METHODS: We performed a randomized, international, double-blind, phase 2b-3 study of the 9vHPV vaccine in 14,215 women. Participants received the 9vHPV vaccine or the qHPV vaccine in a series of three intramuscular injections on day 1 and at months 2 and 6. Serum was collected for analysis of antibody responses. Swabs of labial, vulvar, perineal, perianal, endocervical, and ectocervical tissue were obtained and used for HPV DNA testing, and liquid-based cytologic testing (Papanicolaou testing) was performed regularly. Tissue obtained by means of biopsy or as part of definitive therapy (including a loop electrosurgical excision procedure and conization) was tested for HPV.
RESULTS: The rate of high-grade cervical, vulvar, or vaginal disease irrespective of HPV type (i.e., disease caused by HPV types included in the 9vHPV vaccine and those not included) in the modified intention-to-treat population (which included participants with and those without prevalent infection or disease) was 14.0 per 1000 person-years in both vaccine groups. The rate of high-grade cervical, vulvar, or vaginal disease related to HPV-31, 33, 45, 52, and 58 in a prespecified per-protocol efficacy population (susceptible population) was 0.1 per 1000 person-years in the 9vHPV group and 1.6 per 1000 person-years in the qHPV group (efficacy of the 9vHPV vaccine, 96.7%; 95% confidence interval, 80.9 to 99.8). Antibody responses to HPV-6, 11, 16, and 18 were noninferior to those generated by the qHPV vaccine. Adverse events related to injection site were more common in the 9vHPV group than in the qHPV group.
CONCLUSIONS: The 9vHPV vaccine prevented infection and disease related to HPV-31, 33, 45, 52, and 58 in a susceptible population and generated an antibody response to HPV-6, 11, 16, and 18 that was noninferior to that generated by the qHPV vaccine. The 9vHPV vaccine did not prevent infection and disease related to HPV types beyond the nine types covered by the vaccine. (Funded by Merck; ClinicalTrials.gov number, NCT00543543).

PMID 25693011  N Engl J Med. 2015 Feb 19;372(8):711-23. doi: 10.1056/N・・・

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