ヒトパピローマウイルス（HPV）ワクチンの接種を逃した方へ～キャッチアップ接種のご案内～. https://www.mhlw.go.jp/stf/seisakunitsuite/bunya/kenkou/hpv_catch-up-vaccination.html（参照日2024年2月6日）.
R Kirnbauer, F Booy, N Cheng, D R Lowy, J T Schiller
Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic.
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.
Polly Roy, Rob Noad
Virus-like particles as a vaccine delivery system: myths and facts.
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.
Ian Frazer
Vaccines for papillomavirus infection.
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.
Mark Schiffman, Philip E Castle
Human papillomavirus: epidemiology and public health.
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.
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
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 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.
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
Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases.
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.
Anthony B Miller
Does HPV vaccination prevent cervical cancer?
South Asian J Cancer. 2013 Oct;2(4):198-9. doi: 10.4103/2278-330X.119894.
Abstract/Text
ヒトパピローマウイルス感染症の定期接種の対応について（勧告）厚生労働省（健康局長通知：平成25年06月14日）.
平成27年度予防接種実施率について：第18回厚生科学審議会予防接種・ワクチン分科会予防接種基本方針部会資料（平成29年4月27日）.
副反応追跡調査結果について：第15回厚生科学審議会予防接種・ワクチン分科会副反応検討部会資料（平成27年9月17日）.
HPVワクチン接種にかかる診療・相談：第11回厚生科学審議会予防接種・ワクチン分科会副反応検討部会資料（平成26年10月29日）.
Meeting of the Global Advisory Committee on Vaccine Safety, 7–8 June 2017.
Wkly Epidemiol Rec. 2017 Jul 14;92(28):393-402. Epub 2017 Jul 14.
Abstract/Text
Wakaba Fukushima, Megumi Hara, Yuri Kitamura, Masahiko Shibata, Yoshikazu Ugawa, Koichi Hirata, Akira Oka, Shinya Miyamoto, Susumu Kusunoki, Satoshi Kuwabara, Shuji Hashimoto, Tomotaka Sobue
A Nationwide Epidemiological Survey of Adolescent Patients With Diverse Symptoms Similar to Those Following Human Papillomavirus Vaccination: Background Prevalence and Incidence for Considering Vaccine Safety in Japan.
J Epidemiol. 2022 Jan 5;32(1):34-43. doi: 10.2188/jea.JE20210277. Epub 2021 Oct 30.
Abstract/Text
BACKGROUND: Since June 2013, Japan has suspended proactive recommendation of human papillomavirus (HPV) vaccination due to self-reported diverse symptoms, including pain and motor dysfunction, as possible serious adverse events following immunization. Although these symptoms may be seen in adolescents without HPV vaccination, their frequency, taking into account disease severity, has not been examined.
METHODS: A two-stage, descriptive, nationwide epidemiological survey was conducted in 2016, with a 6-month target period from July 1 to December 31, 2015, to estimate the prevalence and incidence of diverse symptoms among Japanese adolescents without HPV vaccination. Participants were 11,037 medical departments in hospitals selected nationwide by stratified random sampling. Eligible patients had to satisfy four criteria: (1) aged 12-18 years upon visiting hospital; (2) having at least one of four symptoms/disorders (pain or sensory dysfunction, motor dysfunction, autonomic dysfunction, or cognitive impairment); (3) symptoms/disorders persisting for at least 3 months; and (4) both criteria (2) and (3) influence attendance at school or work. We then extracted data of patients with diverse symptoms similar to those after HPV vaccination while considering opinions of doctors in charge.
RESULTS: Estimated 6-month period prevalence of diverse symptoms among girls aged 12-18 years without HPV vaccination was 20.2 per 100,000. Annual incidence was estimated to be 7.3 per 100,000.
CONCLUSION: Adolescent Japanese girls without HPV vaccination also visited hospitals with diverse symptoms similar to those following HPV vaccination. Our findings predict the medical demands for coincident diverse symptoms, which are temporally associated with but not caused by HPV vaccination of Japanese adolescents.
Sadao Suzuki, Akihiro Hosono
No association between HPV vaccine and reported post-vaccination symptoms in Japanese young women: Results of the Nagoya study.
Papillomavirus Res. 2018 Jun;5:96-103. doi: 10.1016/j.pvr.2018.02.002. Epub 2018 Feb 23.
Abstract/Text
Nagoya City introduced free HPV vaccination in 2010 and in April 2013 the Ministry of Health, Labour and Welfare included the HPV vaccine in the National Immunization Program. However, in June 2013, the Ministry suspended proactive recommendation of the vaccine after unconfirmed reports of adverse events. To investigate any potential association between the vaccine and reported symptoms, Nagoya City conducted a questionnaire-based survey. Participants were 71,177 female residents of Nagoya City born between April 2, 1994 and April 1, 2001. The anonymous postal questionnaire investigated the onset of 24 symptoms (primary outcome), associated hospital visits, frequency, and influence on school attendance. Totally, 29,846 residents responded. No significant increase in occurrence of any of the 24 reported post-HPV vaccination symptoms was found. The vaccine was associated with increased age-adjusted odds of hospital visits for "abnormal amount of menstrual bleeding" (OR: 1.43, 95% CI: 1.13-1.82), "irregular menstruation" (OR: 1.29, 95% CI: 1.12-1.49), "severe headaches" (OR: 1.19, 95% CI: 1.02-1.39), and chronic, persisting "abnormal amount of menstrual bleeding" (OR 1.41, 95% CI: 1.11-1.79). No symptoms significantly influenced school attendance and no accumulation of symptoms was observed. The results suggest no causal association between the HPV vaccines and reported symptoms.
Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
Human papillomavirus vaccines: WHO position paper, May 2017.
Wkly Epidemiol Rec. 2017 May 12;92(19):241-68. Epub 2017 May 12.
Abstract/Text
サーバリックス添付文書 GSK株式会社 2014年9月改訂 （第9版）.
ガーダシル添付文書 MSD株式会社 2013年6月改訂 （第4版）.
シルガード9水性懸濁筋注シリンジ. https://www.info.pmda.go.jp/go/pack/631341CG1023_1_06/（参照日：2024年2月6日）.
日本産婦人科学会/日本産婦人科医会 編集・監修：産婦人科診療ガイドライン 婦人科外来編 2023; 52-59.
Julia Ml Brotherton, Dorota M Gertig, Cathryn May, Genevieve Chappell, Marion Saville
HPV vaccine impact in Australian women: ready for an HPV-based screening program.
Med J Aust. 2016 Mar 21;204(5):184-184e1. doi: 10.5694/mja15.01038.
Abstract/Text
Julia M L Brotherton, A Marion Saville, Cathryn L May, Genevieve Chappell, Dorota M Gertig
Human papillomavirus vaccination is changing the epidemiology of high-grade cervical lesions in Australia.
Cancer Causes Control. 2015 Jun;26(6):953-4. doi: 10.1007/s10552-015-0568-6. Epub 2015 Mar 25.
Abstract/Text
Elaine W Flagg, Elizabeth A Torrone, Hillard Weinstock
Ecological Association of Human Papillomavirus Vaccination with Cervical Dysplasia Prevalence in the United States, 2007-2014.
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.
Ross L Cameron, Kimberley Kavanagh, D Cameron Watt, Chris Robertson, Kate Cuschieri, Syed Ahmed, Kevin G Pollock
The impact of bivalent HPV vaccine on cervical intraepithelial neoplasia by deprivation in Scotland: reducing the gap.
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.
Eva Herweijer, Karin Sundström, Alexander Ploner, Ingrid Uhnoo, Pär Sparén, Lisen Arnheim-Dahlström
Quadrivalent HPV vaccine effectiveness against high-grade cervical lesions by age at vaccination: A population-based study.
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 75% (IRR = 0.25, 95%CI = 0.18-0.35) for those initiating vaccination before age 17, and 46% (IRR = 0.54, 95%CI = 0.46-0.64) and 22% (IRR = 0.78, 95%CI = 0.65-0.93) 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.
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
Assessment of herd immunity and cross-protection after a human papillomavirus vaccination programme in Australia: a repeat cross-sectional study.
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.
Lauri E Markowitz, Gui Liu, Susan Hariri, Martin Steinau, Eileen F Dunne, Elizabeth R Unger
Prevalence of HPV After Introduction of the Vaccination Program in the United States.
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.
D Mesher, K Soldan, R Howell-Jones, K Panwar, P Manyenga, M Jit, S Beddows, O N Gill
Reduction in HPV 16/18 prevalence in sexually active young women following the introduction of HPV immunisation in England.
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.
Change to single dose HPV vaccine. https://www.health.gov.au/ministers/the-hon-mark-butler-mp/media/change-to-single-dose-hpv-vaccine（参照日：2024年2月6日）.
Aimée R Kreimer, Tania Cernuschi, Helen Rees, Julia M L Brotherton, Carolina Porras, John Schiller
Public health opportunities resulting from sufficient HPV vaccine supply and a single-dose vaccination schedule.
J Natl Cancer Inst. 2023 Mar 9;115(3):246-249. doi: 10.1093/jnci/djac189.
Abstract/Text
Many countries with the highest burdens of cervical cancer have not yet offered human papillomavirus (HPV) vaccines to most of their age-eligible girls, who as adults also have limited or no access to effective cervical cancer screening or treatment. There are now 2 complementary developments that could make HPV vaccines more accessible and affordable: 1) the current and projected increases in HPV vaccine supply; and 2) the permissive recommendation for single-dose HPV vaccination schedules. This change in policy paired with the healthier HPV vaccine supply is an incredible opportunity to facilitate rapid access and expansion of HPV vaccination. Female adolescent vaccination including multiage cohorts must be prioritized. In the coming decades, this is the most cost-effective approach to avert millions of projected cervical cancer cases, which account for most HPV-related cancers globally.
Published by Oxford University Press 2022.
Jiayao Lei, Alexander Ploner, K Miriam Elfström, Jiangrong Wang, Adam Roth, Fang Fang, Karin Sundström, Joakim Dillner, Pär Sparén
HPV Vaccination and the Risk of Invasive Cervical Cancer.
N Engl J Med. 2020 Oct 1;383(14):1340-1348. doi: 10.1056/NEJMoa1917338.
Abstract/Text
BACKGROUND: The efficacy and effectiveness of the quadrivalent human papillomavirus (HPV) vaccine in preventing high-grade cervical lesions have been shown. However, data to inform the relationship between quadrivalent HPV vaccination and the subsequent risk of invasive cervical cancer are lacking.
METHODS: We used nationwide Swedish demographic and health registers to follow an open population of 1,672,983 girls and women who were 10 to 30 years of age from 2006 through 2017. We assessed the association between HPV vaccination and the risk of invasive cervical cancer, controlling for age at follow-up, calendar year, county of residence, and parental characteristics, including education, household income, mother's country of birth, and maternal disease history.
RESULTS: During the study period, we evaluated girls and women for cervical cancer until their 31st birthday. Cervical cancer was diagnosed in 19 women who had received the quadrivalent HPV vaccine and in 538 women who had not received the vaccine. The cumulative incidence of cervical cancer was 47 cases per 100,000 persons among women who had been vaccinated and 94 cases per 100,000 persons among those who had not been vaccinated. After adjustment for age at follow-up, the incidence rate ratio for the comparison of the vaccinated population with the unvaccinated population was 0.51 (95% confidence interval [CI], 0.32 to 0.82). After additional adjustment for other covariates, the incidence rate ratio was 0.37 (95% CI, 0.21 to 0.57). After adjustment for all covariates, the incidence rate ratio was 0.12 (95% CI, 0.00 to 0.34) among women who had been vaccinated before the age of 17 years and 0.47 (95% CI, 0.27 to 0.75) among women who had been vaccinated at the age of 17 to 30 years.
CONCLUSIONS: Among Swedish girls and women 10 to 30 years old, quadrivalent HPV vaccination was associated with a substantially reduced risk of invasive cervical cancer at the population level. (Funded by the Swedish Foundation for Strategic Research and others.).
Copyright © 2020 Massachusetts Medical Society.
Milena Falcaro, Alejandra Castañon, Busani Ndlela, Marta Checchi, Kate Soldan, Jamie Lopez-Bernal, Lucy Elliss-Brookes, Peter Sasieni
The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study.
Lancet. 2021 Dec 4;398(10316):2084-2092. doi: 10.1016/S0140-6736(21)02178-4. Epub 2021 Nov 3.
Abstract/Text
BACKGROUND: Human papillomavirus (HPV) immunisation with a bivalent vaccine (Cervarix) was introduced in England, UK, in Sept 1, 2008: routine vaccination was offered to girls aged 12-13 years with a catch-up programme for females aged 14-18 years in 2008-10. We quantified the early effect of this immunisation programme on cervical cancer and cervical carcinoma in situ, namely grade 3 cervical intraepithelial neoplasia (CIN3), registrations.
METHODS: In this observational study, we used an extension of the age-period-cohort Poisson model to estimate the relative risk of cervical cancer in three vaccinated cohorts compared with earlier cohorts that were not eligible for HPV vaccination. Data from a population-based cancer registry were extracted on Jan 26, 2021, and were assessed for diagnoses of cervical cancer and CIN3 from Jan 1, 2006 to June 30, 2019 in women aged 20-64 years and who were a resident in England. We used three vaccinated cohorts to account for differences in the school year in which the vaccine was offered and its national coverage. Adjustment for confounding was made using information on changes in cervical screening policy and historical events that affected cervical cancer incidence. Results were compared across models with different adjustments for confounders.
FINDINGS: We used data from a total of 13·7 million-years of follow-up of women aged 20 years to younger than 30 years. The estimated relative reduction in cervical cancer rates by age at vaccine offer were 34% (95% CI 25-41) for age 16-18 years (school year 12-13), 62% (52-71) for age 14-16 years (school year 10-11), and 87% (72-94) for age 12-13 years (school year 8), compared with the reference unvaccinated cohort. The corresponding risk reductions for CIN3 were 39% (95% CI 36-41) for those offered at age 16-18 years, 75% (72-77) for age 14-16 years, and 97% (96-98) for age 12-13 years. These results remained similar across models. We estimated that by June 30, 2019 there had been 448 (339-556) fewer than expected cervical cancers and 17 235 (15 919-18 552) fewer than expected cases of CIN3 in vaccinated cohorts in England.
INTERPRETATION: We observed a substantial reduction in cervical cancer and incidence of CIN3 in young women after the introduction of the HPV immunisation programme in England, especially in individuals who were offered the vaccine at age 12-13 years. The HPV immunisation programme has successfully almost eliminated cervical cancer in women born since Sept 1, 1995.
FUNDING: Cancer Research UK.
Crown Copyright © 2021 Published by Elsevier Ltd. All rights reserved.
Susanne K Kjaer, Christian Dehlendorff, Federica Belmonte, Louise Baandrup
Real-World Effectiveness of Human Papillomavirus Vaccination Against Cervical Cancer.
J Natl Cancer Inst. 2021 Oct 1;113(10):1329-1335. doi: 10.1093/jnci/djab080.
Abstract/Text
BACKGROUND: The primary goal of human papillomavirus (HPV) vaccination is to reduce morbidity and mortality from HPV-associated disease, especially cervical cancer. We determined the real-world effectiveness of HPV vaccination against cervical cancer.
METHODS: The study included women aged 17-30 years living in Denmark October 2006-December 2019. From nationwide registries, information on HPV vaccination and cervical cancer diagnoses were retrieved. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) for cervical cancer according to vaccination status were estimated using Poisson regression with HPV vaccination treated as a time-varying variable and stratified by age at vaccination. We adjusted for attained age, education, and ethnicity. To address the effect of prevalent disease, different buffer periods were used, with 1-year buffer period as primary analysis.
RESULTS: The cohort comprised 867 689 women. At baseline, 36.3% were vaccinated at age 16 years and younger, and during follow-up, 19.3% and 2.3% were vaccinated at ages 17-19 years and 20-30 years, respectively. For women vaccinated at ages 16 years and younger or 17-19 years, the IRRs of cervical cancer were 0.14 (95% CI = 0.04 to 0.53) and 0.32 (95% CI = 0.08 to 1.28), respectively, compared with unvaccinated women. In women aged 20-30 years at vaccination, the incidence rate was higher than among unvaccinated women (IRR = 1.19, 95% CI = 0.80 to 1.79) but slightly decreased with increasing buffer period (IRR = 0.85, 95% CI = 0.55 to 1.32, with 4-year buffer period).
CONCLUSION: HPV vaccine effectiveness against cervical cancer at the population level is high among girls vaccinated younger than age 20 years. The lack of immediate effect in women vaccinated at age 20-30 years points to the importance of early age at vaccination.
© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.
厚生労働省健康局結核感染症課「ヒトパピローマウイルス感染症の定期接種に関するリーフレットについて」別添3 医療従事者向けリーフレット（子宮頸がん予防）ワクチンの接種に当たって～医療従事者の方へ～（平成26年7月16日）.
Lisen Arnheim-Dahlström, Björn Pasternak, Henrik Svanström, Pär Sparén, Anders Hviid
Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study.
BMJ. 2013 Oct 9;347: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.
Nikolai Madrid Scheller, Henrik Svanström, Björn Pasternak, Lisen Arnheim-Dahlström, Karin Sundström, Katharina Fink, Anders Hviid
Quadrivalent HPV vaccination and risk of multiple sclerosis and other demyelinating diseases of the central nervous system.
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.
Ulla Bonde, Jan Stener Joergensen, Ronald F Lamont, Ole Mogensen
Is HPV vaccination in pregnancy safe?
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.
Nikolai M Scheller, Björn Pasternak, Ditte Mølgaard-Nielsen, Henrik Svanström, Anders Hviid
Quadrivalent HPV Vaccination and the Risk of Adverse Pregnancy Outcomes.
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.).
各部会の審議状況について：第7回厚生科学審議会予防接種・ワクチン分科会資料（平成27年10月29日）.
全国疫学調査結果 （子宮頸がんワクチンの有効性と安全性の評価に関する疫学研究）：第23回 副反応検討部会（2016年12月26日開催）.
Silvina Arrossi, Sarah Temin, Suzanne Garland, Linda O'Neal Eckert, Neerja Bhatla, Xavier Castellsagué, Sharifa Ezat Alkaff, Tamika Felder, Doudja Hammouda, Ryo Konno, Gilberto Lopes, Emmanuel Mugisha, Rául Murillo, Isabel C Scarinci, Margaret Stanley, Vivien Tsu, Cosette M Wheeler, Isaac Folorunso Adewole, Silvia de Sanjosé
Primary Prevention of Cervical Cancer: American Society of Clinical Oncology Resource-Stratified Guideline.
J Glob Oncol. 2017 Oct;3(5):611-634. doi: 10.1200/JGO.2016.008151. Epub 2017 Mar 17.
Abstract/Text
Purpose: To provide resource-stratified (four tiers), evidence-based recommendations on the primary prevention of cervical cancer globally.
Methods: The American Society of Clinical Oncology convened a multidisciplinary, multinational panel of oncology, obstetrics/gynecology, public health, cancer control, epidemiology/biostatistics, health economics, behavioral/implementation science, and patient advocacy experts. The Expert Panel reviewed existing guidelines and conducted a modified ADAPTE process and a formal consensus-based process with additional experts (consensus ratings group) for one round of formal ratings.
Results: Existing sets of guidelines from five guideline developers were identified and reviewed; adapted recommendations formed the evidence base. Five systematic reviews, along with cost-effectiveness analyses, provided evidence to inform the formal consensus process, which resulted in agreement of ≥ 75%.
Recommendations: In all resource settings, two doses of human papillomavirus vaccine are recommended for girls age 9 to 14 years, with an interval of at least 6 months and possibly up to 12 to 15 months. Individuals with HIV positivity should receive three doses. Maximal and enhanced settings: if girls are age ≥ 15 years and received their first dose before age 15 years, they may complete the series; if no doses were received before age 15 years, three doses should be administered; in both scenarios, vaccination may be through age 26 years. Limited and basic settings: if sufficient resources remain after vaccinating girls age 9 to 14 years, girls who received one dose may receive additional doses between age 15 and 26 years. Maximal, enhanced, and limited settings: if ≥ 50% coverage in the priority female target population, sufficient resources, and cost effectiveness, boys may be vaccinated to prevent other noncervical human papillomavirus-related cancers and diseases. Basic settings: vaccinating boys is not recommended.
It is the view of the American Society of Clinical Oncology that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement but not replace local guidelines.
Maddalena D'Addario, Shelagh Redmond, Pippa Scott, Dianne Egli-Gany, A Ximena Riveros-Balta, Ana Maria Henao Restrepo, Nicola Low
Two-dose schedules for human papillomavirus vaccine: Systematic review and meta-analysis.
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.
Beatriz Serrano, Laia Alemany, Sara Tous, Laia Bruni, Gary M Clifford, Thomas Weiss, Francesc Xavier Bosch, Silvia de Sanjosé
Potential impact of a nine-valent vaccine in human papillomavirus related cervical disease.
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.
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
Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16-26 years: a randomised, double-blind trial.
Lancet. 2017 Sep 5;. 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.
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
A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women.
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).
