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辛复宁对HPV感染相关的宫颈疾病疗效及对免疫的影响

·临床研究·辛复宁对ＨＰＶ感染相关的宫颈疾病疗效及对免疫的影响吴　帆　宋力雯　成佳景　丘　瑾　周健红＊同济大学附属第十人民医院（上海，２０００７２）摘　要　目的：探讨辛复宁治疗人乳头瘤病毒（ＨＰＶ）感染相关的宫颈疾病效果及其对免疫功能影响。

方法：选取２０１６年５月—２０１７年５月本院收治的ＨＰＶ感染患者９０例，随机数字表法分为对照组和观察组各４５例，对照组采用常规治疗，观察组在对照组基础上采用辛复宁治疗，观察两组治疗前后１个月机体Ｔ淋巴细胞亚群、免疫球蛋白和炎症因子变化，临床疗效及６个月后ＨＰＶ感染复发情况。

结果：宫颈局部ＣＤ３＋Ｔ细胞、ＣＤ８＋Ｔ细胞、ＣＤ４＋ＣＤ２５＋Ｔ细胞以及Ｆｏｘｐ３＋Ｔｒｅｇｓ、ＩｇＡ、ＩｇＧ和ＩｇＭ、Ｃ－反应蛋白（ＣＲＰ）、肿瘤坏死因子－（ＴＮＦ－）、干扰素（ＩＦＮ－）和白细胞介素－６（ＩＬ－６）等水平，治疗前两组无统计学差异（Ｐ＞０．０５），治疗后两组均有改善，且观察组改善程度优于对照组（Ｐ＜０．０５）；治疗６个月后观察组ＨＰＶ感染复发率（２．２％）低于对照组（１５．６％）（Ｐ＜０．０５）。

结论：辛复宁可治疗ＨＰＶ感染相关的宫颈疾病疗效显著，感染复发更低，与患者机体Ｔ淋巴细胞亚群、免疫球蛋白和炎症因子等水平改善有关。

关键词　人乳头瘤病毒；宫颈疾病；辛复宁；Ｔ细胞亚群；免疫球蛋白；炎症因子；疗效Ｅｆｆｅｃｔ　ｏｆ　Ｘｉｎｆｕｎｉｎｇ　ｏｎ　ＨＰＶ　ｉｎｆｅｃｔｉｏｎ－ｒｅｌａｔｅｄ　ｃｅｒｖｉｃａｌ　ｄｉｓｅａｓｅｓ　ａｎｄ　ｉｔｓ　ｅｆｆｅｃｔ　ｏｎ　ｉｍｍｕｎｉｔｙＷＵ　Ｆａｎ，ＳＯＮＧ　Ｌｉｗｅｎ，ＣＨＥＮＤ　Ｊｉａｊｉｎｇ，ＱＩＵ　Ｊｉｎｇ，ＺＨＯＵ　ＪｉａｎｈｏｎｇＴｈｅ　Ｔｅｎｔｈ　Ｐｅｏｐｌｅ＇ｓ　Ｈｏｓｐｉｔａｌ　Ａｆｆｉｌｉａｔｅｄ　ｔｏ　Ｔｏｎｇｊｉ　Ｕｎｉｖｅｒｓｉｔｙ，Ｓｈａｎｇｈａｉ，２０００７２Ａｂｓｔｒａｃｔ　Ｏｂｊｅｃｔｉｖｅ：Ｔｏ　ｉｎｖｅｓｔｉｇａｔｅ　ｔｈｅ　ｔｈｅｒａｐｅｕｔｉｃ　ｅｆｆｅｃｔ　ｏｆ　Ｘｉｎｆｕｎｉｎｇ　ｏｎ　ｃｅｒｖｉｃａｌ　ｄｉｓｅａｓｅｓ　ｂｙ　ｈｕｍａｎ　ｐａｐｉｌｌｏｍａｖｉｒｕｓ（ＨＰＶ）ｉｎｆｅｃｔｅｄ，ａｎｄ　ｔｏ　ｓｔｕｄｙ　ｉｔｓ　ｅｆｆｅｃｔ　ｏｎ　ｉｍｍｕｎｉｔｙ　ｏｆ　ｐａｔｉｅｎｔｓ．Ｍｅｔｈｏｄｓ：９０ｗｏｍｅｎ　ｗｉｔｈ　ＨＰＶ　ｉｎｆｅｃｔｉｏｎ－ｒｅｌａｔｅｄ　ｃｅｒｖｉ－ｃａｌ　ｄｉｓｅａｓｅｓ　ｗｅｒｅ　ｄｉｖｉｄｅｄ　ｉｎｔｏ　ｔｈｅ　ｃｏｎｔｒｏｌ　ｇｒｏｕｐ　ａｎｄ　ｓｔｕｄｙ　ｇｒｏｕｐ　ｆｒｏｍ　Ｍａｙ　２０１６ｔｏ　Ｍａｙ　２０１７．Ｔｈｅ　ｗｏｍｅｎ　ｉｎ　ｃｏｎｔｒｏｌｇｒｏｕｐ　ｗｅｒｅ　ｔｒｅａｔｅｄ　ｂｙ　ｃｏｎｖｅｎｔｉｏｎａｌ　ｔｈｅｒａｐｙ，ａｎｄ　ｔｈｅ　ｗｏｍｅｎ　ｉｎ　ｓｔｕｄｙ　ｇｒｏｕｐ　ｗｅｒｅ　ｔｒｅａｔｅｄ　ｂｙ　Ｘｉｎｆｕｎｉｎｇ　ｅｘｃｅｐｔ　ｃｏｎｖｅｎ－ｔｉｏｎａｌ　ｔｈｅｒａｐｙ．Ｔｈｅ　ｓｉｔｕａｔｉｏｎ　ｏｆ　Ｔ　ｌｙｍｐｈｏｃｙｔｅ　ｓｕｂｓｅｔｓ，ａｎｄ　ｔｈｅ　ｃｈａｎｇｅ　ｏｆ　ｉｍｍｕｎｏｇｌｏｂｕｌｉｎ　ａｎｄ　ｉｎｆｌａｍｍａｔｏｒｙ　ｃｙｔｏｋｉｎｅｓｏｆ　ｗｏｍｅｎ　ｉｎ　ｔｈｅ　ｔｗｏ　ｇｒｏｕｐｓ　ｂｅｆｏｒｅ　ａｎｄ　１ｍｏｎｔｈ　ａｆｔｅｒ　ｔｒｅａｔｍｅｎｔ　ｗｅｒｅ　ｒｅｃｏｒｄｅｄ　ａｎｄ　ｃｏｍｐａｒｅｄ，ａｎｄ　ｔｈｅ　ｃｌｉｎｉｃａｌ　ｅｆｆｉｃａｃｙａｎｄ　ｒｅｃｕｒｒｅｎｃｅ　ｏｆ　ＨＰＶ　ｉｎｆｅｃｔｅｄ　ｏｆ　ｗｏｍｅｎ　ｉｎ　ｔｈｅ　ｔｗｏ　ｇｒｏｕｐｓ　ａｆｔｅｒ　６ｍｏｎｔｈｓ　ｗｅｒｅ　ａｌｓｏ　ｒｅｃｏｒｄｅｄ．Ｒｅｓｕｌｔｓ：Ｂｅｆｏｒｅ　ｔｒｅａｔ－ｍｅｎｔ，ｔｈｅ　ｌｅｖｅｌｓ　ｏｆ　ＣＤ３＋Ｔ　ｃｅｌｌｓ，ＣＤ８＋Ｔ　ｃｅｌｌｓ，ＣＤ４＋ＣＤ２５＋Ｔ　ｃｅｌｌｓ，Ｆｏｘｐ３＋Ｔｒｅｇｓ，ＩｇＡ，ＩｇＧ　ａｎｄ　ＩｇＭ，Ｃ－ｒｅａｃｔｉｖｅｐｒｏｔｅｉｎ（ＣＲＰ），ｔｕｍｏｒ　ｎｅｃｒｏｓｉｓ　ｆａｃｔｏｒ　ａｌｐｈａ（ＴＮＦ－ａ），ｉｎｔｅｒｆｅｒｏｎ（ＩＦＮ）ａｎｄ　ｉｎｔｅｒｌｅｕｋｉｎ－６（ＩＬ－６）ｏｆ　ｗｏｍｅｎ　ｉｎ　ｂｏｔｈｇｒｏｕｐｓ　ｈａｄ　ｎｏ　ｓｉｇｎｉｆｉｃａｎｔ　ｄｉｆｆｅｒｅｎｔ（Ｐ＞０．０５）．Ａｆｔｅｒ　ｔｒｅａｔｍｅｎｔ，ａｌｌ　ａｂｏｖｅ　ｉｎｄｅｘｅｓ　ｏｆ　ｗｏｍｅｎ　ｉｎ　ｂｏｔｈ　ｇｒｏｕｐｓ　ｈａｄ　ｉｍ－ｐｒｏｖｅｄ，ａｎｄ　ｔｈｅ　ｃｈａｎｇｅｓ　ｏｆ　ａｌｌ　ａｂｏｖｅ　ｉｎｄｅｘｅｓ　ｏｆ　ｗｏｍｅｎ　ｉｎ　ｃｏｎｔｒｏｌ　ｇｒｏｕｐ　ｗｅｒｅ　ｓｉｇｎｉｆｉｃａｎｔ　ｂｅｔｔｅｒ　ｔｈａｎ　ｔｈｏｓｅ　ｏｆ　ｗｏｍｅｎ　ｉｎｃｏｎｔｒｏｌ　ｇｒｏｕｐ（Ｐ＜０．０５）．６ｍｏｎｔｈｓ　ａｆｔｅｒ　ｔｒｅａｔｍｅｎｔ，ｔｈｅ　ｉｎｃｉｄｅｎｃｅ　ｏｆ　ＨＰＶ　ｉｎｆｅｃｔｅｄ　ａｇａｉｎ　ｏｆ　ｗｏｍｅｎ　ｉｎ　ｃｏｎｔｒｏｌ　ｇｒｏｕｐｗａｓ　ｓｉｇｎｉｆｉｃａｎｔ　ｌｏｗｅｒ　ｔｈａｎ　ｔｈａｔ　ｏｆ　ｗｏｍｅｎ　ｉｎ　ｃｏｎｔｒｏｌ　ｇｒｏｕｐ（Ｐ＜０．０５）．Ｃｏｎｃｌｕｓｉｏｎ：Ｘｉｎｆｕｎｉｎｇ　ｃａｎ　ｂｅ　ｕｓｅｄ　ｔｏ　ｔｒｅａｔ　ＨＰＶｉｎｆｅｃｔｉｏｎ－ｒｅｌａｔｅｄ　ｃｅｒｖｉｃａｌ　ｄｉｓｅａｓｅｓ，ｗｈｉｃｈ　ｃａｎ　ｄｅｃｒｅａｓｅ　ｒａｔｅ　ｏｆ　ＨＰＶ　ｉｎｆｅｃｔｅｄ　ａｇａｉｎ　ｏｆ　ｗｏｍｅｎ　ｂｙ　ｉｍｐｒｏｖｉｎｇ　ｔｈｅ　ｌｅｖｅｌｓ　ｏｆＴ　ｌｙｍｐｈｏｃｙｔｅ　ｓｕｂｓｅｔｓ，ｉｍｍｕｎｏｇｌｏｂｕｌｉｎ，ａｎｄ　ｉｎｆｌａｍｍａｔｏｒｙ　ｃｙｔｏｋｉｎｅｓ．Ｋｅｙ　ｗｏｒｄｓ　Ｈｕｍａｎ　ｐａｐｉｌｌｏｍａｖｉｒｕｓ；Ｃｅｒｖｉｃａｌ　ｄｉｓｅａｓｅ；Ｘｉｎｆｕｎｉｎｇ；Ｔｃｅｌｌ　ｓｕｂｓｅｔｓ；Ｉｍｍｕｎｏｇｌｏｂｕｌｉｎ；Ｉｎｆｌａｍｍａｔｏｒｙ　ｃｙｔｏ－ｋｉｎｅｓ；Ｅｆｆｉｃａｃｙ人乳头瘤状病毒（ＨＰＶ）是引起人类宫颈病变ＤＯＩ：１０．３９６９／ｊ．ｉｓｓｎ．１００４－８１８９．２０１９．０３．０１１基金项目：国家自然科学基金青年项目（８１５０２４５１）；上海市科委自然科学基金项目（１５ＺＲ１４３２６００）收稿日期：２０１８－０３－３０　修回日期：２０１８－０９－２６＊通信作者：ｚｈｏｕｊｉａｎｈｏｎｇｘｉｎ＠１６３．ｃｏｍ的常见病毒，有７０多种亚型，ＨＰＶ－６、－１１、－４０、－４２与宫颈炎相关，ＨＰＶ－１６，－１８，－３１，－３３，－４５与宫颈上皮内瘤变相关，ＨＰＶ－１６和ＨＰＶ－１８是引起宫颈癌的高危型ＨＰＶ［１－２］。

HPV感染的慢病管理

HPV感染的慢病管理
黄华钰;曹育春;谷志超
【期刊名称】《皮肤科学通报》
【年(卷),期】2024(41)1
【摘要】目前HPV的感染在全球人群中普遍存在,并且HPV感染人体后很难被彻底清除,因此由HPV感染所诱发的多种慢性疾病如病毒疣、宫颈上皮内瘤变、呼吸道乳头状瘤等往往存在着很高的复发率,给患者乃至社会均带来了沉重负担。

因此,需要对HPV感染所诱发的慢性疾病进行科学规范的管理,进而降低HPV感染率与疾病复发率、缩短病程,从而有效促进HPV的防治工作。

本文就HPV感染的慢病管理的必要性、具体方法及其意义进行综述。

【总页数】6页(P100-105)
【作者】黄华钰;曹育春;谷志超
【作者单位】华中科技大学同济医学院附属同济医院皮肤科
【正文语种】中文
【中图分类】R752.5
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宫颈癌的相关免疫治疗及进展

宫颈癌的相关免疫治疗及进展尹博，丁鉴夷，杨美琴，韩凌斐△【摘要】宫颈癌是最常见的妇科恶性肿瘤，严重威胁女性健康。

高危型人乳头瘤病毒（human papillomavirus ，HPV ）持续感染是宫颈癌的主要危险因素。

近年来，HPV 疫苗在宫颈癌预防方面取得了良好的效果，免疫治疗也成为了宫颈癌治疗的新模式，尤其对于手术、放化疗效果不佳和术后转移及晚期复发的患者，免疫治疗尤为重要。

免疫治疗的策略主要包括免疫检查点抑制剂、疫苗治疗、树突状细胞免疫疗法和过继细胞免疫疗法。

目前，相关的免疫疗法在宫颈癌及其癌前病变治疗的研究中均取得了不错的疗效。

综述宫颈癌中的免疫治疗进展，并对今后的研究方向做出展望，从而为宫颈癌的临床治疗和基础研究提供依据。

【关键词】宫颈肿瘤；免疫疗法；乳头状瘤病毒科；乳头状瘤病毒疫苗；治疗Related Immunotherapy and Progress of Cervical Cancer YIN Bo,DING Jian -yi,YANG Mei -qin,HAN Ling -fei.Department of Gynecology,Shanghai First Maternity and Infant Hospital Affiliated to Tongji University,Shanghai 201204,ChinaCorresponding author:HAN Ling-fei,E-mail:******************【Abstract 】Cervical cancer is the most common gynecological malignant tumor,which is a serious threat to women ′s health.High-risk human papillomavirus (HPV)persistent infection is the main risk factor of the cervical cancer.In recent years,HPV vaccine has achieved favorable results in the prevention of cervical cancer.Immunotherapy has also become a new pattern of treatment of cervical cancer,especially for patients with poor effect of surgery,radiotherapy and chemotherapy,postoperative metastasis and late recurrence.The strategies of immunotherapy mainly include immune checkpoint inhibitors,vaccine therapy,dendritic cell immunotherapy and adoptive cellular immunotherapy.At present,the related immunotherapy has achieved good results in the treatment of cervical cancer and its precancerous lesions.This article will describe the progress of immunotherapy in cervical cancer,and look forward to the future research direction,so as to provide a basis for clinical treatment and fundamental research of cervical cancer.【Keywords 】Uterine cervical neoplasms;Immunotherapy;Papillomaviridae;Papillomavirus vaccines;Therapy（J Int Obstet Gynecol ，2021，48：628-633）·综述·基金项目：国家自然科学基金（81972422）作者单位：201204上海，同济大学附属第一妇婴保健院妇科通信作者：韩凌斐，E-ma ｉｌ：ｌ*****************△审校者DOI:10.12280/gjfckx.20210116从世界范围来看，宫颈癌已成为妇女第四大常见的癌症死亡原因，是主要的健康威胁之一[1]。

WHO对HPV疫苗的指导原则

WHO/BS/06.2050 - FinalENGLISH ONLYEXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATIONGeneva, 23 to 27 October 2006GUIDELINES TO ASSURE THE QUALITY, SAFETY ANDEFFICACY OF RECOMBINANT HUMAN PAPILLOMAVIRUSVIRUS-LIKE PARTICLE VACCINES© World Health Organization 2006All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: permissions@who.int).The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. The named authors [editors] alone are responsible for the views expressed in this publication.Adopted by the 57th meeting of the WHO Expert Committee on Biological Standardization, 23-27 October2006. A definitive version of this document, which will differ from this version in editorial but not scientificdetails, will be published in the WHO Technical Report Series.WHO/BS/06.2050 - FinPage 2IntroductionGeneral considerationsSpecial considerationsPart A. Guidelines on manufacturingA.1DefinitionsA.2 General manufacturing recommendationsA.3Control of source materialsA.4Control of HPV antigen vaccine productionA.5Control of purified monovalent antigen bulkA.6Adsorbed monovalent antigen bulkA.7Final vaccine bulkA.8 Filling and containersA.9 Control tests on final vaccine lotA.10 RecordsA.11 Retained samplesA.12 LabellingA.13 Distribution and transportA.14 Stability testing, storage and expiry datePart B. Nonclinical evaluation of recombinant HPV VLP vaccinesB.1Pharmacological studiesB.2Safety Pharmacology studiesB.3Toxicology studiesPart C. Clinical evaluation of recombinant HPV VLP vaccinesC.1 Immune responses to the vaccineC.2 Studies of protective efficacyC.3 Bridging efficacy by means of immunogenicity dataC.4 Vaccine safetyC.5 Post-marketing studies and surveillancePart D. Guidelines for national regulatory authoritiesD.1GeneralD.2 Release and certificationAuthorsAcknowledgementsReferencesAppendix 1Model summary protocol for manufacturing and control of recombinant human papillomavirus virus-like particle vaccineAppendix 2Model certificate for the release of recombinant human papillomavirus virus-like particle vaccineWHO/BS/06.2050 - FinPage 3 IntroductionWHO convened two meetings in Geneva, 23-24 March and 28 - 30 August, 2006, where scientific experts, regulatory professionals and other stakeholders met todevelop guidelines for prophylactic human papillomavirus (HPV) vaccines. Thisdocument is intended to provide background and guidance to national regulatoryauthorities (NRAs) and vaccine manufacturers on the production, quality controland evaluation of the safety and efficacy of recombinant HPV virus-like particle(VLP) vaccines.This document sets out the guidance on product manufacture and qualityassessment in part A. In addition, guidance specific to the nonclinical and clinical evaluation of recombinant HPV vaccines is provided in Part B and Part C,respectively. This document should be read in conjunction with all relevant WHO guidelines including those on nonclinical (1) and clinical evaluation (2) ofvaccines. The following text is written in the form of guidelines instead ofrecommendations. Guidelines allow greater flexibility than recommendations with respect to expected future developments in the field. This guidance is based onthe experience of the products developed so far, as described below, and mayneed to be updated in view of future developments.General considerationsHPV is a small, non-enveloped deoxyribonucleic acid (DNA) virus. The circular, double-stranded viral genome is approximately 8-kb in length. The genomeencodes for 6 early proteins responsible for virus replication and 2 late proteins,L1 and L2, which are the viral structural proteins. L1 is the major structuralprotein. L1 proteins associate to form pentameric structures called capsomers.Mature virus particles are comprised of 72 capsomers arranged in icosahedralsymmetry. The minor capsid protein, L2, is present in as many as 72 moleculesper mature virus particle. L2 is not required for particle formation. HPVinfection, replication and particle maturation occurs in the stratified squamousepithelia of skin and mucous membranes, with virus spread occurring by skin-to-skin contact.Over 100 different types of HPV have been identified and molecularlycharacterized. These HPVs cause a variety of diseases in humans ranging frombenign warts to cancer of the epithelia (including the cervix, vagina, vulva, anusand oropharynx). Those HPV types associated with the development of cancerare called high risk for oncogenicity. Other HPV types, such as HPV types 6 and11 associated with genital warts, are considered low risk for oncogenicity.The majority of HPV infections by both high and low risk types are oftenasymptomatic, self-limiting and resolve spontaneously, presumably due to thehost immune response. In some instances, persistent infection by the high risktypes may ultimately progress to invasive carcinoma at the site of infection,WHO/BS/06.2050 - FinPage 4mainly of the genital tract, if not detected and treated appropriately. The interval between the acquisition of HPV infection and malignant progression usually takes about 10 years or longer. High risk HPV types can be detected in virtually allcases of cervical cancer, and it is generally accepted that the persistent viralinfection is necessary for the development of cancer (3). The basis forprogression to invasive carcinoma is not well defined. However, environmentaland physiological co-factors may increase the risk for cancer development inpersistently infected persons.The International Agency for Research on Cancer (IARC) has currently definedthirteen high risk HPV types that are associated with cancers in humans (4).Distribution and prevalence of these HPV types in cancer cases is generallyconsistent around the world. Two of the high risk HPV types, 16 and 18, account for approximately 70% of all cervical cancers globally (4). Most other genitalcancers, such as cancers of the vagina and anus are also associated with persistent HPV infection. In addition, these HPVs are associated with a fraction of cancers of the vulva, penis, and oropharynx. The incidence of cervical cancer issignificantly higher than all other HPV related cancers, and is the second mostcommon cancer among women worldwide.Low risk HPV types cause genital warts, recurrent respiratory papillomatosis(RRP), and low grade cervical dysplasia. The lifetime risk of genital wartsexceeds 10%. While not malignant, these lesions are associated with physical and psychological morbidity. They are also difficult to treat. RRP is a devastating,albeit rare, disease that manifests as recurrent, rapidly growing benign laryngealtumors that require frequent excision to prevent airway obstruction. HPV 6 and 11 are responsible for over 90% of genital warts and RRP cases, and 9 to 12% of low grade cervical dysplastic lesions.Identification of a viral agent such as HPV as a major cause of diseases impliesthat prophylactic vaccines or interventions against the viral agent should preventthe disease(s) it causes. Initial studies in animal models showed that inoculationwith species-specific papillomaviruses induced an immune response thatconferred protection against homologous virus challenge. However, nativepapillomaviruses are not good substrates for vaccine development as they cannot be grown easily in culture. Subsequent studies were initiated on the production of viral particles from expression of the structural proteins in heterologousexpression systems, such as yeast or baculovirus vectors. Results showed thatexpression of L1 alone led to the production of VLPs which morphologicallyresemble the authentic HPV virions but contain no viral DNA. These VLPs areproduced by self-assembly of the L1 protein when expressed in a heterologouscell substrate and are the basis for the vaccines considered in this document. Inanimal studies, VLPs were shown to protect against high dose experimentalinfection by homologous virus. HPV VLPs are highly immunogenic in mice orrabbits, and the resulting antibodies have been shown to be neutralizing and typerestricted when tested in a pseudovirion neutralization assay. Immunization withWHO/BS/06.2050 - FinPage 5 denatured particles does not result in the production of neutralizing antibodies, orprotect from experimental virus challenge, indicating that neutralizing epitopesare conformation dependent. Protection in animals has also been demonstratedthrough passive transfer of antibodies in serum.Neutralizing antibodies are probably the primary mediator of this protection. L1is not expressed in the basal keratinocytes in which infection is thought to bemaintained and regression of established lesions was not observed after VLPvaccination. Therefore, it seems unlikely that cell-mediated immunity (CMI) isinvolved as a direct effector mechanism of protection (5).The specific assays that have been developed to evaluate the immune responseinclude: VLP-based enzyme immunoassay (EIA), competitive immunoassay with labeled neutralizing monoclonal antibodies, hemagglutination inhibition (HAI),and in vitro neutralization.The development of these guidelines has been driven by the acquired experiencewith the two vaccines developed thus far. These vaccines are both made up ofrecombinant protein L1 VLPs and they contain adjuvant in order to stabilize theintegrity of the L1 VLPs and also to enhance immunogenicity. The productsdiffer in the types of HPV L1 proteins included as antigens, substrates used forproduction, adjuvant properties and in the final formulation. These two vaccinesare:1) A bivalent vaccine comprised of oncogenic HPV types 16 and 18 VLPsreassembled from L1 protein expressed and purified from insect cells infectedwith a recombinant baculovirus. This vaccine is formulated with a noveladjuvant, AS04, which contains aluminium hydroxide and monophosphoryllipid A (MPL); and2) A tetravalent vaccine comprised of the low risk HPV types 6 and 11 and theoncogenic HPV types 16 and 18. Type specific L1 proteins for this vaccineare expressed and purified from yeast cells containing L1 expression plasmids.The VLPs are adsorbed to an amorphous aluminium hydroxyphosphatesulfate-containing adjuvant.It is possible that a vaccine produced in mammalian cells may be developed in the future.Special considerationsThere are several special considerations that need to be addressed in themanufacturing, non-clinical and clinical development of these vaccine products.WHO/BS/06.2050 - FinPage 6VLPs are complex biological products and will need to be assessed at variouslevels.With respect to manufacturing and product quality the following items should beconsidered:1)The bivalent vaccine expressed from recombinant baculovirus in insect cells isthe first vaccine to be developed in this host expression system. Testing ofthis cell substrate may have some unique requirements;2) A novel adjuvant which has not previously been experienced on a global scaleis used in the formulation of the bivalent vaccine. The immunostimulant isMPL which is a detoxified form of lipid A derived from thelipopolysaccharide (LPS) isolated from bacterial cell walls of the Gramnegative bacterium Salmonella minnesota R595. While detoxified, MPL wasshown to retain the capacity of the natural LPS compound to act as animmunostimulant by potentiating cellular and humoral adaptive immuneresponses;3)L1 protein in its native form is not glycosylated. For the two current vaccinesglycosylation during production on a cell substrate is not an issue. HPV L1VLP vaccines produced in new or different cell substrates should be assessedfor glycosylation status;4)Disassembly and reassembly of the L1 capsomers may contribute topurification of the product and lead to more stable VLPs;5)Purified L1 VLP preparations will have to be characterized biochemically andimmunologically, to determine L1 concentration, purity and assembly state;and6)Current HPV vaccines are manufactured in single dose presentations withoutthe addition of preservative. In the future, the availability of multi-dosevaccine vials would facilitate the adoption of innovative vaccination strategiestargeting pre-adolescents and adolescents in developing countries. If thesevaccines do not contain preservative, the use of such vaccine vials should betime-restricted as is the case of reconstituted vaccines such as BacillusCalmette-Guérin (BCG) and measles-containing vaccines. If a preservativewere to be added, the effect on antigenicity and immunogenicity must beassessed and known not to have an negative impact as has been observed withthiomersal (6).With respect to the nonclinical studies it is critical that such studies demonstrateimmunogenicity and the production of neutralizing antibodies.With respect to clinical assessment of HPV VLP vaccines there are several critical considerations:WHO/BS/06.2050 - FinPage 71)Since 90% of HPV related cancers are cervical cancers, the efficacy of thevaccines developed so far has been studied in sexually active women;2)In order to obtain maximal benefit from these vaccines, the primary targetpopulation for immunization should consist of young adolescents prior toonset of sexual activity. Although the attack rate for HPV is high in the 5 to 10years following sexual debut, most women remain naïve to vaccine HPVtypes during this time, and few have been infected with all vaccine HPV types;3)Licensure of first generation vaccines requires a definitive demonstration ofprophylactic efficacy with respect to cervical intraepithelial neoplasm (CIN)2/3 and adenocarcinoma in situ (AIS) caused by vaccine HPV types;5)Persistent infection (e.g. detection of the DNA of the same virion incervicovaginal specimens collected on consecutive visits over a period of atleast 12 months) may be an appropriate endpoint for second generationvaccines, including those with additional HPV types. At the time of preparingthese Guidelines, however, there was no international consensus on adefinition for HPV persistence based on detection of HPV DNA by restrictedPCR; and6)Once licensed, long term effectiveness evaluation of these vaccines should beintegrated with current screening programs for cervical cancer.Part A. Guidelines on manufacturingA.1 DefinitionsA.1.1 International name and proper nameThe international name should be “Recombinant human papillomavirus virus-like particle vaccine” followed in parenthesis by the genotype specificity and the name of recombinant protein (e.g. genotype 16 and 18 L1 proteins). The proper nameshould be equivalent to the international name in the language of the country oforigin.The use of the international name should be limited to vaccines that satisfy thespecifications elaborated below.A.1.2 Descriptive definitionThe recombinant HPV VLP vaccine is a sterile liquid vaccine preparation whichcontains purified VLPs composed of the recombinant major capsid proteins ofone or more HPV genotypes (further referred to as "types"). The VLPs may beformulated with a suitable adjuvant. Such vaccines are for prophylactic use.A.1.3 International reference preparationsWHO/BS/06.2050 - FinPage 8International reference preparations based on recombinant HPV VLPs were notavailable when this Guidelines were prepared. However, reference reagents foruse in the laboratory evaluation of the biological effects following vaccineadministration to humans, such as antibody titers and viral DNA detection, areunder development for HPV types 16 and 18. Some information can be found inthe literature (7-10).A.1.4 TerminologyThe definitions given below apply to this document only.HPV L1 protein: The major structural protein of human papillomavirus, of which 360 molecules are found in the native virion associated in 72 pentamericcapsomers.L1 virus-like particle: A non-infectious, non-enveloped, icosahedral capsidparticle which does not contain viral DNA and which is composed of regulararrays of L1 pentameric capsomers.Parental yeast cell: Yeast host cell to be manipulated for the expression ofprotein(s) to give rise to a recombinant yeast production strain.Recombinant baculovirus master seed lot: A quantity of recombinant baculovirus of uniform composition derived from an original baculovirus construct, processed at one time and passaged for a documented number of times.Recombinant baculovirus working seed lot: A quantity of recombinantbaculovirus of uniform composition, derived from the master seed lot by a limited number of passages. The recombinant baculovirus virus working seed lot may be used to prepare inoculum intermediates or alternatively to initiate the productionof recombinant L1 proteins.Inoculum intermediate: A quantity of recombinant baculovirus of uniformcomposition, derived from the working seed lot. The inoculum intermediate has a defined shelf-life. It is intended to be used to initiate the production ofrecombinant L1 proteins.Cell bank: A collection of ampoules containing aliquots of a suspension of cellsfrom a single pool of cells of uniform composition, stored frozen under definedconditions (typically <−60 °C for yeast, and in liquid nitrogen for insect ormammalian cell lines).Master cell bank (MCB): A collection of containers containing aliquots of asuspension of cells from a single pool of cells of uniform composition, storedfrozen under defined conditions (typically <−60 °C for yeast, and in liquidWHO/BS/06.2050 - FinPage 9 nitrogen for insect or mammalian cell lines). The MCB is used to derive all working cell banks for the anticipated lifetime of the vaccine product.Working cell bank (WCB): A collection of containers containing aliquots of a suspension of cells from a single pool of cells of uniform composition, derived from the MCB, stored frozen under defined conditions (typically <−60 °C for yeast, and in liquid nitrogen for insect or mammalian cell lines). One or more aliquots of the WCB are used for routine production of the vaccine. Multiple WCBs are made and used during the lifetime of vaccine productProduction cell culture: A cell culture derived from one or more containers of the WCB used for the production of vaccines.End of production cells: A cell suspension containing the cells harvested at the end of culture/fermentation.Adventitious agents: Contaminating microorganisms of the virus, or cell substrate or materials used in their cultures, that may include bacteria, fungi, mycoplasmas, and endogenous and exogenous viruses that have been unintentionally introduced. Fermentation cell paste: A suspension of cells harvested at the end of the yeast fermentation stored frozen (<-60°C).Single antigen harvest: A cell-suspension containing the intended HPV antigens of one virus type harvested from cell cultures prepared from a single production runSingle harvest pool: A homogenous pool of multiple single harvests of the intended HPV antigens of one virus type, collected into a single vessel before clarification.Purified monovalent antigen bulk: A batch of purified antigen of the same HPV type. Different batches of purified monovalent antigen bulks may be pooled before collection into a single vessel.Adsorbed monovalent antigen bulk: A batch of purified monovalent antigen bulk adsorbed on an aluminium containing adjuvant. Different batches of adsorbed monovalent antigen bulks may be pooled before collection into a single vessel. Adjuvant: A vaccine adjuvant is a component that potentiates the immune response to an antigen and/or modulates it towards the desired immune responses.Final vaccine bulk: The formulated bulk present in the container from which the final containers are filled. The final bulk may be prepared from one or more adsorbed monovalent antigen bulks and may contain VLP antigens from one or multiple HPV virus types.WHO/BS/06.2050 - FinPage 10Filling lot (final vaccine lot): A collection of sealed final containers of vaccinethat is homogeneous with respect to the risk of contamination during the fillingprocess. A filling lot must therefore have been filled or prepared in one workingsession.A.2 General manufacturing recommendationsThe general manufacturing requirements contained in Good manufacturingpractices for biological products (11) should apply to the establishment ofmanufacturing facilities for recombinant HPV VLP vaccines, with the addition of the following:•Production steps involving manipulations of recombinant HPV L1 VLP types should be conducted at a biosafety level consistent with the recombinantproduction microorganism;•Quality control procedures should be in place to ensure segregation of different HPV L1 VLP types during bulk manufacturing steps.Sufficientcleaning validation and product changeover data should be available; and•The antigen manufacturing process should be validated to demonstrate production consistency. Typically, three consecutive lots per HPV type arerequired. However, if one or more HPV types use the same manufacturingprocess, validation of all processes with at least one type may be acceptable.The assessment of manufacturing consistency should include evaluation ofcritical quality parameters and their corresponding attributes. Examples ofprocess quality attributes are nucleic acid and host cell protein clearance orcumulated population doubling level and examples or process key operatingparameters is column loading. The process validation antigen batches shouldshow compliance with the pre-established antigen quality controlspecifications for the HPV antigen such as antigen identity and antigen purity(see section A.5).A.2.1 Characterization of the antigenCharacterization of HPV antigen is performed on lots produced during vaccinedevelopment, including the process validation batches.The protein composition should be established by techniques such as sodiumdodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) under reducing conditions or mass spectrometry. The bands should be identified by sensitivestaining techniques and where possible by specific antibodies or massspectrometry to confirm the presence of the expected products of the L1 protein.The identity of the protein should be established by peptide mapping and/orterminal amino acid sequence analysis.Page 11 Since it is known that conformational epitopes are essential for efficacy, it isessential that the morphological characteristics of the VLPs and degree ofaggregation should be determined. In addition, the protein, lipid, nucleic acid andcarbohydrate content should be measured when applicable. VLP characterizationmay be done by atomic force and transmission electron microscopy, dynamiclight scattering, epitope mapping and reactivity with neutralizing monoclonalantibodies.The level of residual host cell protein derived from insect cells and/or a novel cellsubstrate should meet acceptable safety in nonclinical and clinical studies (seeParts B and C).A.3 Control of source materialsA.3.1 Cell cultures for antigen productionThe use of any cell line should be based on a cell bank system. Only cells thathave been approved and registered with the national regulatory authority shouldbe used to produce HPV L1 protein. The national regulatory authority should beresponsible for approving the cell bank. Appropriate history of the cell bankshould be provided.A.3.1.1 Yeast cellsThe characteristics of the recombinant production strain (host cell in combinationwith the expression vector system) should be fully described and informationgiven on the absence of adventitious agents and on gene homogeneity for themaster and working cell banks. A full description of the biological characteristicsof the host cell and expression vectors should be given. The physiologicalmeasures used to promote and control the expression of the cloned gene in thehost cell should be described in detail. This should include genetic markers of the host cell, the construction, genetics and structure of the expression vector and theorigin and identification of the gene that is being cloned.The nucleotide sequence of the gene insert and of adjacent segments of the vectorand restriction-enzyme mapping of the vector containing the gene insert should beprovided as required by the national control authority.A.3.1.2 Insect cellsIf insect cells are used for production of recombinant HPV L1 VLP vaccines, theuse of insect cell substrate should be based on a cell bank system. The cellsubstrates and cell banks should conform with Requirements for use of animalcells as in vitro substrates for the production of biologicals (12,13), as appropriateto insect cells, and should be approved by the national regulatory authority.Page 12The maximum number of passages (or population doublings) allowable betweenthe MCB, the WCB and the production cells should be approved by the nationalregulatory authority. Additionally, the MCB or WCB cells should be propagatedto or beyond the maximum production level and be examined for tumorigenicityin an animal test system and for the presence of retroviruses and arthropod-borne viruses.The MCB is made in sufficient quantities and stored in a secure environment and is used as the source material to make manufacturers WCB. In normal practice aMCB is expanded by serial subculture up to a passage number (or populationdoubling, as appropriate) selected by the manufacturer and approved by thenational regulatory authority, at which point the cells are combined to give asingle pool distributed into ampoules and preserved cryogenically to form theWCB.The manufacturers working cell bank is used for the preparation of productioncell culture, and thus for production of HPV L1 antigen batches.A.3.1.3 Other Cell SubstratesIf other host cells are used, the cell substrates and cell banks should conform with Requirements for use of animal cells as in vitro substrates for the production ofbiologicals (12,13) where appropriate, and should be approved by the nationalregulatory authority.A.3.2 Cell culture mediumIf serum is used for the propagation of cells, it should be tested to demonstratefreedom from bacteria, fungi and mycoplasmas, according to the requirementsgiven in Part A, sections 5.2 (14) and 5.3 (15)of Requirements for biologicalsubstances no. 6 and from infectious viruses. Suitable tests for detecting viruses in bovine serum are given in Appendix 1 of Recommendations for production andcontrol of poliomyelitis vaccine (oral) (16).Validated molecular tests for bovine viruses may replace the cell culture tests ofbovine sera. As an additional monitor of quality, sera may be examined forfreedom from phage and endotoxin. Gamma-irradiation may be used to inactivate potential contaminant viruses.The acceptability of the source(s) of any components of bovine, porcine, sheep or goat origin used should be approved by the national regulatory authority. Thesecomponents should comply with current WHO guidelines in relation to animaltransmissible spongiform encephalopathies (17).。

对37种HPV亚型感染的风险评估及预防建议

对37种HPV亚型感染的风险评估及预防建议感谢您提供的任务名称，我将为您撰写关于对37种HPV亚型感染的风险评估及预防建议的内容。

HPV（人乳头瘤病毒）是一类常见的性传播病毒，根据其基因组的序列差异，可以将HPV病毒分为不同的亚型。

据统计，目前已经发现了37种与人类疾病相关的HPV亚型。

不同的HPV亚型具有不同的感染和致病风险，下面是对这些亚型感染风险的评估及预防建议：1. 高风险亚型（包括HPV16和HPV18）：高风险亚型是最常见的致癌型HPV亚型，它们与宫颈癌以及其他相关癌症（如肛门、阴道和喉咙癌）的发生密切相关。

为了预防这些癌症，推荐进行以下预防措施：- 接种HPV疫苗： HPV疫苗可以预防高风险HPV亚型的感染，建议女性在9-26岁接种疫苗，男性在9-21岁接种。

- 定期进行宫颈癌筛查：尽早发现宫颈异常细胞变化，建议女性每年进行宫颈细胞学检查（Pap试验）或HPV-DNA检测。

- 保持健康生活方式：均衡饮食、定期锻炼、戒烟限酒等健康生活方式有助于提高免疫力，减少感染风险。

2. 中风险亚型（包括HPV31、HPV33和HPV45）：中风险亚型与宫颈癌的发生也存在一定的风险，预防措施与高风险亚型类似：- 定期进行宫颈癌筛查：尽早发现宫颈异常细胞变化，建议女性每年进行宫颈细胞学检查（Pap试验）或HPV-DNA检测。

- 保持健康生活方式：均衡饮食、定期锻炼、戒烟限酒等健康生活方式有助于提高免疫力，减少感染风险。

3. 低风险亚型（如HPV6和HPV11）：低风险亚型通常引起生殖器疣（尖锐湿疣）的发生，尖锐湿疣是一种常见的性传播疾病。

预防措施如下：- 接种HPV疫苗： HPV疫苗也可以预防低风险HPV亚型的感染，接种疫苗可以减少尖锐湿疣的发生。

- 定期进行性病筛查：保持性伴侣间的互信，如果出现尖锐湿疣症状，及时就医治疗。

需要注意的是，无论感染的是高、中、低风险亚型，及时就医非常重要。

如果出现不适或症状，建议立即向专业医生咨询和就诊。

男性接种HPV_疫苗预防效果的研究进展

783综述新医学2023年11月第54卷第11期男性接种HPV 疫苗预防效果的研究进展刘松惠刘珂珂付连国刘志荣【摘要】男性感染人乳头瘤病毒（HPV ）会严重影响其身体健康，HPV 与尖锐湿疣、阴茎癌、肛门癌、口腔和口咽疾病密切相关。

已有研究表明，HPV 疫苗对男性HPV 感染性疾病具有较好的预防效果，尤其是针对特殊人群。

然而，男性接种HPV 疫苗的认知程度低和HPV 疫苗供应短缺，导致男性HPV 疫苗接种率不理想。

该文对男性HPV 感染情况、接种HPV 疫苗对男性HPV 感染相关疾病的预防效果、男性接种HPV 疫苗的可能障碍进行综述，并提出推广男性接种HPV 疫苗的建议。

笔者认为，应加强HPV 疫苗接种相关知识健康教育，提供相关医疗咨询服务和疫苗开发，以提高男性HPV 疫苗接种率。

【关键词】人乳头瘤病毒；疫苗；男性；尖锐湿疣；阴茎癌；肛门癌A systematic review of research progress in preventive effect of HPV vaccine in men Liu Songhui △， Liu Keke ， Fu Lianguo ， Liu Zhirong.△Bengbu Medical College ， Bengbu 233000， China Corresponding author ， Liu Zhirong ， E -mail:*************【Abstract 】 Human papillomavirus （HPV ） infection in men can severely affect male health. HPV is closely associated withcondyloma acuminatum ， penile cancer ， anal cancer ， oral cavity and oropharyngeal diseases ， etc. Studies have shown that HPV vaccine exerts favorable preventive effect on male infectious diseases ， especially for special populations. However ， low awareness of HPV vaccination among men and the shortage of HPV vaccine supply have led to unsatisfactory HPV vaccination rates among men. In this article ， HPV infection in men ， preventive effect of HPV vaccination on HPV infection -related diseases and potential barriers of HPV vaccination in men were reviewed. Suggestions were given to promote HPV vaccination in men. Health education about HPV vaccination ， related medical counseling services and vaccine development should be strengthened to increase the HPV vaccination rate among men.【Key words 】 Human papillomavirus ； Vaccine ； Male ； Condyloma acuminatum ； Penile cancer ； Anal cancer人乳头瘤病毒（HPV ）属于乳多空泡病毒科、乳头瘤病毒属，是一类无包膜、小的双链DNA 病毒，病毒颗粒半径20~50 µm ，具有二十面体立体对称的核衣壳结构，表面有72个壳微粒［1］。

2021年HPV感染诊治专家共识(全文)

2021年HPV感染诊治专家共识（全文）一、人乳头瘤病毒感染概述人乳头瘤病毒（HPV）感染是常见的女性下生殖道感染，属于性传播感染。

HPV病毒是小DNA病毒，主要侵犯鳞状上皮的基底层细胞以及位于宫颈转化区的化生细胞，直接的皮肤-皮肤接触是最常见的传播途径。

目前发现，HPV病毒有100多个型别，其中40个以上的型别与生殖道感染有关。

根据其引起宫颈癌的可能性，2012年国际癌症研究机构（InternationalAgency for Research on Cancer，IARC）将其分为高危型、疑似高危型和低危型。

前两者与宫颈癌及高级别外阴、阴道、宫颈鳞状上皮内病变（squamousintraepithelial lesion, SIL）相关，后者与生殖器疣及低级别外阴、阴道、宫颈SIL相关。

常见的高危型有：16、18、31、33、35、39、45、51、52、56、58、59共12个型别；疑似高危型有：26、53、66、67、68、70、73、82共8个型别；低危型有：6、11、40、42、43、44、54、61、72、81、89共11个型别。

下生殖道HPV感染比较常见，国外报道普通人群感染率约10%。

中国关于高危型HPV的人群感染率及型别分布的报道存在差异，尚缺乏多中心大样本的研究。

HPV感染后，机体产生的免疫机制可清除HPV，故绝大多数生殖道HPV 感染是一过性的且无临床症状；约90%的HPV感染在2年内消退。

其消退时间主要由HPV型别决定，低危型HPV需要5~6个月，高危型HPV需要8~24个月；只有极少数HPV感染者发生临床可见的下生殖道尖锐湿疣、鳞状上皮内病变和癌等。

二、HPV检测方法目前临床应用广泛的HPV检测方法主要为病毒基因组的DNA检测，该类检测方法很多，主要分为HPV分型检测及不分型检测。

目前，也有HPV不分型基础上的部分分型检测，主要检测12个高危型及2个疑似高危型66和68，其中16、18型为分型检测，而其他为不分型检测。

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Vaccine24S3(2006)S3/35–S3/41Chapter4:Burdenandmanagementofnon-cancerousHPV-relatedconditions:HPV-6/11disease

CharlesJ.N.Laceya,∗,CatherineM.Lowndesb,KeertiV.ShahcaHullYorkMedicalSchool,UniversityofYork,Heslington,YorkYO105DD,UK

bCentreforInfections,HealthProtectionAgency,London,UK

cDepartmentofMolecularMicrobiology,JohnsHopkinsBloombergSchoolofPublicHealth,Baltimore,MD,USA

Received28March2006;accepted1June2006

AbstractHumanPapillomavirus(HPV)-6and-11arethecausativeagentsofano-genitalwarts(GWs)andrecurrentrespiratorypapillomatosis(RRP).Theyarelow-riskHPVtypesthatareuncommonlyfoundinmalignantlesions.GWsareanextremelyprevalentsexuallytransmitteddisease,whereasRRPisararediseasethatcanbelifethreateningandrequiresmultiplesurgicalprocedures.GWsandRRPcausesubstantialhealthcarecosts.AquadrivalentHPV-6/11/16/18vaccine(Merck/SPMSD)hasshownessentially100%protectionagainstGWsinwomeninearlystudies.Cost-effectivenessanalysesareneededtoassessthebeneﬁtsoftheHPV-6/11virus-likeparticle(VLP)componentsofthequadrivalentvaccineinpopulation-basedvaccinationprogrammes.©2006ElsevierLtd.Allrightsreserved.

Keywords:HPV-6/11;Management;Non-cancerous

1.Low-oncogenic-riskHPVtypesHPV-6and-11wereﬁrstclonedfromgenitalwarts(GWs;alsoknownasano-genitalwartsorcondylomataacuminata)andlaryngealpapillomasin1981and1982,respectively[1].Theuseoftheterms“lowandhighoncogenicrisk”or“low-riskandhigh-risk”(LRandHR)HPVbecamecommonplaceinthelate1980s.AroundthattimetheBethesdasystemforreportingcytologyandhistologywasputforward.Thisproposestheconceptsoflow-grade(low-gradesquamousintraepitheliallesions,LSIL)andhigh-grade(high-gradesquamousintraepitheliallesions,HSIL)pre-cancerlesions,andsuchadualclassiﬁcationsystemencompassingbothHPVvirologyanddiseasewassubsequentlyreinforcedbyphylogeneticanalyses.NewmucosalHPVtypescontinuetobedescribedandtheirphylogeneticclassiﬁcationhascon-tinuedtoevolve[1].Withinthegenusalpha-papillomavirus,ﬁvespeciesareentirelycomposedofLRviruses(andgeno-

∗Correspondingauthor.Tel.:+441904725425;fax:+44190464216.

E-mailaddress:charles.lacey@hyms.ac.uk(C.J.N.Lacey).

typesasyetcategorisedasundetermined;seeChapter1).TheseareSpecies1(HPV-32and-42),Species3(HPV-61,-62,-72,-81,-83,-84,-86,-87and-89),Species4(HPV-2a,-27and-57),Species8(HPV-7,-40,-43and-91)andSpecies10(HPV-6,-11,-13,-44,-55and-74).Nevertheless,anHPVtypethatisclearlyLRbyitspatho-logicassociationsisfoundwithinaspeciesofpredominantlyHRviruses,namelyHPV-70(Species7).Thus,phylogeneticcharacteristicscannotsolelypredictLR/HRstatus,andtheessentialcriterionforsuchclassiﬁcationisthepredominantdiseaseassociationoftheHPVtypeinquestion.IntermsofclinicaldiseasecausedbyLRviruses,HPV-6/11over-whelminglypredominatebyvirtueofthefrequencyofGWsinthepopulation;recognisedclinicallesionscausedbyotherLRtypesareinfrequent.WhereasHPV-6/11arenormallyassociatedwithpurelybenigndisease,theycanmuchmorerarelybeassociatedwithvariousmalignancies,includingBuschke–Lowensteintumours,andoccasionallyanal,vul-valandpenilecarcinoma(causingaround2.5–5%oftheselesions).Recurrentrespiratorypapillomas(RRP)canalsorarelyundergomalignantconversion.

0264-410X/$–seefrontmatter©2006ElsevierLtd.Allrightsreserved.doi:10.1016/j.vaccine.2006.06.015S3/36C.J.N.Laceyetal./Vaccine24S3(2006)S3/35–S3/412.GenitalwartsCondylomatabearingHPV-6or-11haveidenticalclinicalmanifestationsandhistology[2].Recentstudieshaveshownthatabout100%ofGWsarecausedbyeitherHPV-6or-11butthat20–50%oflesionsalsocontainco-infectionswithHRHPVtypes[3,4].GWsdonotusuallyresultinmajormorbid-ityormortality,butcausesigniﬁcantpsychologicalmorbidityandverysubstantialhealthcarecosts.OccasionallyGWsper-sistforlongperiodsoftimeand,rarely,suchlong-standinglesionsmayprogresstomalignancy.GWsarehighlyinfec-tious,withatransmissionrateofabout65%withinsexualpartnershipsfromaninfectedtoasusceptiblesexualpart-ner,andanincubationperiodofbetween3weeksand8months,withthemajoritydevelopingwartsataround2–3months[3].OnceGWshavedeveloped,theymayshowmin-imalchangeovertime,becomemorenumerousorlarger,orregressspontaneously.Themajorityofplacebo-controlledGWtherapytrialsshowlowratesofregression(around5%completeclearance)intheshortterm,althoughinonestudyover16weeks20%ofwomenand5%ofmenusingplacebocompletelyclearedtheirwarts,and38%ofwomenand22%ofmenusingplaceboclearedover50%oftheirbaselinewarts[3].RegressingwartscontainsigniﬁcantlymoreCD4positiveTcells,bothwithinthestromaunderlyingthelesionsandthecondylomatathemselves,andgreaterexpressionofactiva-tionmarkers[3].Thereisnoreportoftherateofspontaneousregressionthatmayoccurinthelongerterm.FollowingGWclearancewiththerapy,recurrenceiscommonandisoftenseenwithin3monthsin25%ofcases,althoughratesofupto67%havebeenobserved[3].Inclinicalpracticerecurrencesareoftenseenatsitesofpreviouslesions,andinthesecasesHPVinfectioninstemcellsorslow-turnovercellsatthesiteofpreviousclearancehaspersistedandthenreactivated.TheproportionofHPV-6/11infectionsthatareeithercompletelyclearedorpersistinalatentformafterclinicalresolutionisunknown,and,indeed,animalmodelssuggestthatbothoutcomescanoccur[3].