WHO对HPV疫苗质量、安全性及有效性指导原则
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).。
宫颈癌病毒疫苗管理制度
宫颈癌病毒疫苗管理制度宫颈癌病毒疫苗是一种用于预防宫颈癌和相关疾病的疫苗。
该疫苗可以预防人类乳头瘤病毒（HPV）感染，从而降低患宫颈癌和其他相关癌症的风险。
宫颈癌病毒疫苗通常在青春期开始接种，因此对于青少年的疫苗管理极为重要。
在接种过程中，需要建立一个严格的管理制度，以确保疫苗的安全性和有效性。
本文将探讨宫颈癌病毒疫苗管理制度的各个方面。
一、疫苗接种对象宫颈癌病毒疫苗通常适用于11至12岁的女孩和男孩。
此外，也可以考虑对15至26岁的未接种者进行疫苗接种。
在制定疫苗管理制度时，需要明确接种对象的范围，并确保相关人员能够及时获得疫苗接种的信息和服务。
二、疫苗供应与储存为了保证疫苗接种的顺利进行，必须建立完善的疫苗供应和储存系统。
疫苗的供应必须能够满足接种对象的需求，并且要确保疫苗的质量和安全。
此外，对于疫苗的储存，需要严格控制温度和湿度，以保证疫苗的稳定性和有效性。
三、接种计划与管理建立完善的宫颈癌病毒疫苗接种计划非常重要。
接种计划需要明确接种对象的范围和时间，同时也要充分考虑疫苗的安全性和有效性。
在接种过程中，还需要对接种的人员进行管理和监测，以确保接种的顺利进行。
四、接种点管理为了方便接种对象的接种，需要建立多个接种点，并确保这些接种点能够提供疫苗接种服务。
在接种点的选择和管理上，需要考虑各种因素，包括场地、设施、人员等。
此外，还需要建立完善的信息管理系统，以方便对接种情况进行监测和跟踪。
五、接种安全与监测在建立宫颈癌病毒疫苗管理制度时，一定要重视接种的安全性和监测。
需要建立健全的接种安全监测系统，及时发现和处理接种意外事件。
同时，也要加强对接种对象的监测和跟踪，以确保接种的安全和有效性。
六、宣传与教育宣传和教育是疫苗管理制度中至关重要的环节。
需要通过各种方式向社会大众宣传宫颈癌病毒疫苗的重要性和安全性，提高接种意识和参与度。
同时也要向接种对象和其家长提供详尽的疫苗知识和接种信息，促进疫苗接种的顺利进行。
2020年宫颈癌进展盘点—实施三级预防策略,《加速消除宫颈癌全球战略》
2020年宫颈癌进展盘点—实施三级预防策略，《加速消除宫颈癌全球战略》宫颈癌进展盘点2020年是不平凡的一年，尽管面临全球新冠肺炎疫情的挑战，宫颈癌领域的防控也在不断推进。
由于宫颈癌病因明确，人乳头瘤病毒（HPV）疫苗，即宫颈癌预防性疫苗已经上市多年，宫颈癌筛查和癌前病变诊断有多年的成功经验，宫颈癌的治疗有成熟的规范，可以说宫颈癌是当代唯一具有完整的肿瘤防治策略的癌种。
2018年5月19日，WHO总干事谭德塞提出全球消除宫颈癌的目标。
2019年2月，WHO宣布加速消除宫颈癌的威胁。
2020年11月17日，世界卫生大会上发布了《加速消除宫颈癌全球战略》[1]。
这是一个具有历史意义的里程碑，194个国家根据这项决议首次承诺消除宫颈癌。
其实现主要通过三个关键措施（即实施三级预防策略：疫苗接种-宫颈癌筛查-宫颈癌治疗），达到宫颈癌发病率小于4例/10万女性的指标；而要达到这一指标，需在2030年实现“90-70-90”目标（即，90：90%女孩在15岁之前全程接种宫颈癌疫苗；70：70%女性在35-45岁，接受至少1次高质量的筛查；90：90%已罹患宫颈癌的女性得到治疗和关怀）。
实现这个目标将使全世界所有国家走上消除宫颈癌的道路，到2050年减少40%以上宫颈癌新发病例和500万相关死亡病例。
我国宫颈癌的发病形势不容乐观，尽管多年来我国加强了宫颈癌的防治工作，但宫颈癌仍在严重威胁我国女性的健康，并有发病率增高和逐渐年轻化的趋势。
根据国家癌症中心《2020年全国癌症中心年度工作报告》，在我国，宫颈癌仍为女性癌症的第六大高发肿瘤，死亡率仍位于女性恶性肿瘤的第八位。
2018年，中国宫颈癌新发病例106 430例，死亡病例47 739例[2]。
实现消除宫颈癌的战略目标依然任重而道远。
01一级预防——推进HPV疫苗的接种中国健康女性HPV感染情况。
2019年，一项纳入了198项研究的中国系统性综述显示，中国25~45岁女性高危型HPV的感染率达19.9%[3]。
WHO对HPV疫苗质量、安全性及有效性指导原则
欢迎阅读GUIDELINESTOASSURETHEQUALITY,SAFETYANDEFFICACYOFREC OMBINANTHUMANPAPILLOMA VIRUSVIRUS?LIKEPARTICLEV ACCIN ESHPV二、Specialconsiderationsection:在生产、非临床及临床中过程中的考虑因素：1、 VLP 1) 2)3) 4) L1VLP 。
5) 纯化后的L1VLP 要进行生化及免疫上的鉴定，并测定L1的浓度、纯度及组聚情况。
6) 如加入了防腐剂，应对其免疫性进行验证，并确认不会有负作用2、 非临床方面：关键就是要证明其免疫原性，并能否产生免疫中和抗体。
3、临床方面：（略）三、生产指导（PartA.Guidelinesonmanufacturing）3.1定义definitions3.1.1国际名称和专有名称3.1.2重组基因型3.1.33.2术语hichdoesnotcontainviralDNAandwhichiscomposedofregulararraysofL1pentamericcaps omers.Parentalyeastc ell:Yeasthostcelltobemanipulatedfortheexpressionofprotein(s)togiv erisetoarecombinantyeastproductionstrain.Inoculumintermediate:Aquantityofrecombinantbaculovirusofuniformcomposition, derivedfromtheworkingseedlot.Theinoculumintermediatehasadefinedshelf?life.Itisinten dedtobeusedtoinitiatetheproductionofrecombinantL1proteins.Cellbank:Acollectionofampoulescontainingaliquotsofasuspensionofcellsfromasin glepoolofcellsofuniformcomposition,storedfrozenunderdefinedconditions(typically<?6 0°Cforyeast,andinliquidnitrogenforinsectormammaliancelllines).Mastercellbank(MCB):Acollectionofcontainerscontainingaliquotsofasuspension ofcellsfromasinglepoolofcellsofuniformcomposition,storedfrozenunderdefinedconditioaterialsusedintheircultures,thatmayincludebacteria,fungi,mycoplasmas,andendogenous andexogenousvirusesthathavebeenunintentionallyintroduced.Fermentationcellpaste:Asuspensionofcellsharvestedattheendoftheyeastfermentat ionstoredfrozen(<?60°C).Singleantigenharvest:Acell?suspensioncontainingtheintendedHPVantigensofonevi rustypeharvestedfromcellculturespreparedfromasingleproductionrunSingleharvestpool:AhomogenouspoolofmultiplesingleharvestsoftheintendedHPVa ntigensofonevirustype,collectedintoasinglevesselbeforeclarification.Purifiedmonovalentantigenbulk:AbatchofpurifiedantigenofthesameHPVtype.Di fferentbatchesofpurifiedmonovalentantigenbulksmaybepooledbeforecollectionintoasin glevessel.3.3应分别生产，同时，还要有充分的清洁验证。
WHO对HPV疫苗质量安全性及有效性指导原则
WHO对HPV疫苗质量安全性及有效性指导原则世界卫生组织（WHO）对人乳头瘤病毒（Human Papillomavirus，简称HPV）疫苗的质量、安全性及有效性制定了一系列指导原则。
首先，WHO建议疫苗研发商在研发和生产过程中遵循国际标准和规范，确保疫苗的质量。
这包括对病毒株的选择、制备疫苗的工艺、生产设备和环境的控制等方面。
同时，疫苗研发商需要进行严格的质量控制，确保每一批疫苗都符合质量标准。
其次，WHO强调疫苗的安全性是至关重要的。
疫苗研发商需要在临床试验阶段进行全面的安全性评估，并依据国际规范进行监测和报告。
在疫苗上市后，监管机构和疫苗研发商需要持续监测疫苗的安全性，及时报告任何可能的不良反应，并采取必要的措施进行风险管理。
第三，WHO指导疫苗研发商进行有效性评估。
疫苗的有效性评估需要包括原始病毒株类型的选择、免疫原性和保护机制的研究、动物模型和临床试验等方面。
通过这些研究，可以评估疫苗的免疫原性和保护效果，从而确定疫苗是否能有效预防HPV感染和相关疾病。
此外，WHO还倡导疫苗研发商进行全球合作，共同推动HPV疫苗研发和应用，以降低世界各地HPV感染和相关疾病的发病率和死亡率。
为此，WHO提供技术支持和合作机会，促进疫苗研发商在全球范围内进行合作，共同提高HPV疫苗的质量、安全性和有效性。
最后，WHO强调对HPV疫苗的监管和监测工作的重要性。
国家和地区的监管机构需要确保疫苗研发商遵守相关法规和规范，对疫苗进行审查和批准，并对疫苗市场进行监管。
同时，监管机构需要与疫苗研发商、卫生机构和公众开展沟通和合作，共同推动HPV疫苗的安全性和有效性监测工作。
总结起来，世界卫生组织对HPV疫苗的质量、安全性及有效性制定了一系列指导原则，包括遵循国际标准和规范、进行严格的质量控制、全面评估疫苗的安全性和有效性、倡导全球合作和加强监管和监测工作等。
这些指导原则对于保证HPV疫苗的质量、安全性和有效性，进一步预防和控制HPV感染和相关疾病具有重要意义。
WHO对HPV疫苗质量、安全性及有效性指导原则
WHO对HPV疫苗质量、安全性及有效性指导原则GUIDELINES TO ASSURE THE QUALITY, SAFETY AND EFFICACY OF RECOMBINANT HUMAN PAPILLOMA VIRUS VIRUS¬LIKE PARTICLE V ACCINESHPV二、Special consideration section:在生产、非临床及临床中过程中的考虑因素：1、生产方面：VLP是复杂的生物产物，必须在不同水平下对其进行检测分析。
因而在其生产过程及质量控制上必须考虑以下几个因素：1)新的表达体系如杆状病毒（GSK），新的特殊要求。
但我们用的毕赤酵母，相对比较常见。
2)新佐剂（略）3)天然的L1蛋白是没有被糖基化修饰，目前的两种表达体系，在糖基化修饰上不存大问题,但要对糖基化及其位点进行分析。
4)L1衣壳蛋白亚单位的解聚与再聚，可能有利于纯化，并得到更稳定的VLP。
目前，我们的路线可能是不经解聚，直接纯化获得VLP。
个人感觉，到后期可以兵分两路，一路直接获得VLP，而另一路则将VLP解聚后，再进行纯化与重组。
5)纯化后的L1 VLP要进行生化及免疫上的鉴定，并测定L1的浓度、纯度及组聚情况。
6)如加入了防腐剂，应对其免疫性进行验证，并确认不会有负作用2、非临床方面：关键就是要证明其免疫原性，并能否产生免疫中和抗体。
3、临床方面：（略）三、生产指导（Part A. Guidelines on manufacturing）3.1定义definitions3.1.1国际名称和专有名称国际名称：重组人乳头瘤类病毒颗粒疫苗（基因型16 L1蛋白）3.1.2定义描述重组HPV VLP疫苗为无菌的液态疫苗，里面含纯化后由一种或多种HPV基因型重组的主要的衣壳蛋白，并与相应佐剂混合。
3.1.3国际标准品在此指导原则编写时，市场上暂无国际标准品提供。
但有相应试剂在实验室水平上，在进行注射后进行生物效价方面的评价如抗体滴度和病毒DNA检测。
WHO对HPV疫苗质量安全性及有效性指导原则
GUIDELINES TO ASSURE THE QUALITY, SAFETY AND EFFICACY OF RECOMBINANT HUMAN PAPILLOMA VIRUS VIRUS¬LIKE PARTICLE V ACCINESHPV二、Special consideration section:在生产、非临床及临床中过程中的考虑因素:1、生产方面:VLP就是复杂的生物产物,必须在不同水平下对其进行检测分析。
因而在其生产过程及质量控制上必须考虑以下几个因素:1)新的表达体系如杆状病毒(GSK),新的特殊要求。
但我们用的毕赤酵母,相对比较常见。
2)新佐剂(略)3)天然的L1蛋白就是没有被糖基化修饰,目前的两种表达体系,在糖基化修饰上不存大问题,但要对糖基化及其位点进行分析。
4)L1衣壳蛋白亚单位的解聚与再聚,可能有利于纯化,并得到更稳定的VLP。
目前,我们的路线可能就是不经解聚,直接纯化获得VLP。
个人感觉,到后期可以兵分两路,一路直接获得VLP,而另一路则将VLP解聚后,再进行纯化与重组。
5)纯化后的L1 VLP要进行生化及免疫上的鉴定,并测定L1的浓度、纯度及组聚情况。
6)如加入了防腐剂,应对其免疫性进行验证,并确认不会有负作用2、非临床方面:关键就就是要证明其免疫原性,并能否产生免疫中与抗体。
3、临床方面:(略)三、生产指导(Part A、Guidelines on manufacturing)3、1定义definitions3、1、1国际名称与专有名称国际名称:重组人乳头瘤类病毒颗粒疫苗(基因型16 L1蛋白)3、1、2定义描述重组HPV VLP疫苗为无菌的液态疫苗,里面含纯化后由一种或多种HPV基因型重组的主要的衣壳蛋白,并与相应佐剂混合。
3、1、3国际标准品在此指导原则编写时,市场上暂无国际标准品提供。
但有相应试剂在实验室水平上,在进行注射后进行生物效价方面的评价如抗体滴度与病毒DNA检测。
疫苗临床试验质量管理指导原则
疫苗临床试验质量管理指导原则1.严格遵守伦理原则：疫苗临床试验必须在伦理框架下进行，确保试验过程中人体受试者的权益和福利。
疫苗试验应遵循国家和国际伦理准则，包括通过伦理委员会审查和获得知情同意。
2.设计良好的试验方案：疫苗临床试验方案应具备科学性、合理性和可操作性。
方案应明确试验的目的、假设、研究人群、终点指标、样本量计算、试验时间和进度安排等内容。
3.严格控制试验质量：疫苗临床试验应实施严密的质量控制措施，包括选择合适的试验中心和合格的调查员，编制规范的操作规程、案例报告表和数据收集表，进行试验前培训和现场监管，进行数据监测和核查，确保试验数据的准确性和完整性。
4.客观评估疫苗效果：疫苗临床试验的效果评价应客观、科学和可靠。
在试验设计中应明确主要和次要终点指标，合理选择评价指标和测量方法，并制定分析计划。
评价结果应通过双盲评价、随机化、对照组等方法进行比较分析，确保评估的客观性和可比性。
5.保护受试者安全：疫苗临床试验过程中，保护受试者的安全是最重要的原则。
试验前应详细评估疫苗的安全性，制定安全监测和报告计划。
试验中应密切监测受试者的不良反应和严重不良事件，及时采取适当的安全措施。
6.严格控制试验数据：疫苗临床试验的数据管理应严格按照规范进行，确保数据的准确性和完整性。
试验过程中应建立完善的数据收集、录入和管理系统，确保数据的及时录入和核对。
在数据分析阶段，应采用适当的方法进行统计分析，确保分析结果的有效性和可靠性。
7.保证试验可追溯和重复：疫苗临床试验的原始资料和相关文件应妥善保存，确保试验的可追溯性和重复性。
试验记录和报告应详细完整，包括试验设计、操作规程、数据收集表、药物配方和使用情况等，以便于审计和验证研究结果的真实性和可靠性。
总之，疫苗临床试验质量管理是确保疫苗安全性和有效性的重要环节，需要遵循伦理原则，设计良好的试验方案，严格控制试验质量，保护受试者安全，严格控制试验数据，保证试验可追溯和重复。
hpv疫苗管理制度
hpv疫苗管理制度引言人类乳头瘤病毒（HPV）是一种常见的性传播疾病，其感染可能导致宫颈癌和其他相关癌症。
为了预防这些癌症，HPV疫苗的关注度日益增加。
然而，疫苗的使用需要一套完善的管理制度来确保其安全和有效性。
本文将探讨HPV疫苗管理制度的建立和实施，以及其中涉及的关键要素和挑战。
一、政策和法规首先，建立HPV疫苗管理制度需要清晰的政策和法规指导。
政府部门应明确规定关于HPV疫苗的使用、分发、监管和报告的法律框架。
这包括规定疫苗接种的目标群体、接种程序和时间表，以及对不同年龄段和风险群体的建议。
此外，政策还需要规定疫苗的采购渠道、存储条件、疫苗事件监测和报告体系，以及疫苗接种后的随访和追踪。
二、疫苗供应链管理疫苗供应链管理是HPV疫苗管理制度的关键组成部分。
它涉及从疫苗生产商到最终接种点的整个分发和物流过程。
确保疫苗的可及性和质量是至关重要的。
因此，建立一个高效的供应链管理系统是必不可少的。
这包括对疫苗的采购、储存、运输和分发的规范和标准操作程序（SOPs）。
同时，还需要建立监测和评估机制，以确保疫苗的安全和有效性。
三、疫苗接种计划和推广HPV疫苗的接种计划和推广策略是保障人群得到疫苗的关键环节。
在建立接种计划时，需要考虑到疫苗供应、接种场所和人员、接种流程、接种对象等因素。
同时，对不同群体的接种推广策略也是必不可少的，包括对农村地区、社区服务机构、学校等地方的定向推广，以确保更多的人群能够接种疫苗。
四、疫苗接种服务管理疫苗接种服务管理涉及到疫苗接种点的管理和监督。
这包括对接种人员的培训和认证、接种场所的设施和设备、接种程序的监管和审核，以及疫苗事件的管理和报告。
此外，还需要建立疫苗接种记录系统和信息管理系统，以便进行疫苗接种率的监测和评估。
五、监测和评估建立HPV疫苗管理制度需要一个完善的监测和评估体系。
这包括对疫苗接种率、安全性、有效性和覆盖范围的定期监测。
同时，还需要进行疫苗接种后的效果监测和评估，以评估疫苗在预防HPV感染和相关疾病方面的效果。
hpv疫苗 安全评估
hpv疫苗安全评估
HPV疫苗已经通过多个安全评估，并被证明是安全有效的。
首先，在HPV疫苗上市前，临床试验已经进行了大规模的研究。
这些试验涉及数以千计的参与者，评估其安全性和有效性。
试验结果显示，HPV疫苗在预防HPV相关疾病方面具有高度
的保护作用。
其次，疫苗上市后，监测系统对HPV疫苗进行了长期的安全
监测。
这些监测系统包括疫苗不良事件报告系统、美国疾病控制与预防中心疫苗安全监测系统以及其他国家和地区的自主监测系统。
这些系统记录和调查可能与疫苗接种相关的不良反应。
根据这些监测数据，HPV疫苗在大多数情况下被认为是安全的。
最后，世界卫生组织（WHO）和其他专业机构也对HPV疫苗
进行了评估并提出了相关的推荐意见。
这些机构确认了HPV
疫苗的安全性和有效性，并鼓励适龄人群接种。
总体而言，HPV疫苗已经通过多个安全评估，并广泛被认为
是安全可靠的疫苗。
然而，像任何其他疫苗一样，个体的反应可能有所不同。
因此，如果有任何疑虑或担忧，应咨询医生或专业医疗机构的意见。
疫苗临床前研究指导原则
06
研究结果总结与建议
研究结果总结
疫苗有效性
在临床前研究中，疫苗的有效性通常是通过评估疫苗对实验模型中病原体的中和 抗体滴度和细胞免疫反应来确定的。这些研究结果表明，疫苗可以诱导产生针对 病原体的中和抗体和细胞免疫反应，从而有效地预防疾病。
疫苗安全性
疫苗的安全性也是临床前研究的重要内容之一。在研究中，疫苗的成分和剂量通 常被严格控制，以避免不良反应和副作用。此外，研究人员还会对疫苗对实验动 物的免疫原性和安全性进行评估，以确保疫苗的安全性和有效性。
疫苗稳定性研究
对疫苗在储存、运输和使用过程中 的稳定性进行深入研究，确保疫苗 在有效期内保持其效价和质量。
疫苗评价
动物模型研究
在疫苗研制初期，需进行动物 模型研究，评估疫苗在动物体 内的免疫应答、保护效果和安
全性。
临床试验
根据国家药品监管部门的相关 法规和伦理原则，进行多期临 床试验，评估疫苗在人体内的
免疫剂量与效果关系
研究疫苗剂量与免疫效果的关系，以确定最佳的免疫剂量。
保护效果评价
01
ቤተ መጻሕፍቲ ባይዱ
02
03
动物模型保护试验
在动物模型中评估疫苗对 特定病原体的保护效果。
交叉保护
评估疫苗对其他相关病原 体的交叉保护效果。
疫苗安全性
在临床前研究中，对疫苗 的安全性进行严格评估。
临床试验设计
试验设计
遵循随机、对照、双盲等原则设计 临床试验。
检测疫苗刺激机体产生免疫反应的能力，包括抗体产生水平、免疫细胞活性等。 评估疫苗接种后抗体持续时间及免疫记忆反应。
检测疫苗对免疫系统的刺激是否引发过度免疫反应或免疫抑制。
04
疫苗有效性评价
预防用疫苗临床可比性研究技术指导原则
附件1预防用疫苗临床可比性研究技术指导原则一、前言为进一步规范预防用疫苗（以下简称疫苗）临床试验和提高临床研发水平，保证同类疫苗注册上市时具有相似的安全有效性，指导非创新性疫苗的临床研发和评价，特制定本指导原则。
本指导原则所述非创新性疫苗是指已有同类疫苗在中国境内上市，其在质量、安全性和有效性方面与已上市同类疫苗具有可比性的疫苗。
本指导原则适用于采用免疫原性替代终点进行有效性评价的非创新性疫苗。
对涉及处方和生产工艺等变更的疫苗，如需要通过临床可比性研究进一步评价其变更可行性的，也可参考本指导原则。
疫苗临床试验应严格遵守《中华人民共和国药品管理法》《中华人民共和国疫苗管理法》，执行《药品注册管理办法》的相关规定，按照《药物临床试验质量管理规范》（GCP）、《疫苗临床试验质量管理指导原则》、《疫苗临床试验技术指导原则》、《预防用疫苗临床试验的不良事件分级标准指导原则》等相关要求进行。
本指导原则仅代表当前的观点和认识，随着研究和认识的深入将不断修订和完善。
二、临床试验前的考虑对于非创新性疫苗，在研发立项时应充分评估已上市同类疫苗临床使用的有效性和安全性。
通常应首先进行候选疫苗（或称试验疫苗）与已上市同类疫苗（或称对照疫苗）在药学和非临床方面的比对研究，其比较数据结合临床试验结果用于评价两种疫苗的可比性。
上市疫苗关键质量标准项目的可接受限度（如抗原含量/效价、病毒滴度、产品及工艺相关杂质等），不仅须根据生产工艺能力、稳定性研究等药学研究数据确定，还需结合非临床研究批次和结果、注册临床试验批次的核定结果及临床试验安全有效性结果分析论证其合理性。
因此，应在充分考虑生产规模的预期放大、生产工艺地址变更、生产参数调整及产品关键质量属性的变异度、产品货架期降解等因素基础上，选取在上述因素方面可代表上市生产的试验疫苗进入注册临床试验。
建议采用商业化规模生产的疫苗用于申请上市许可的关键性注册临床试验（含加强免疫）。
三、临床试验设计的一般考虑对于非创新性疫苗，临床试验的主要目的是评价该疫苗与对照疫苗在安全有效性方面的可比性。
hpv指导原则[精品文档]
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附件3人乳头瘤病毒（HPV）核酸检测及基因分型、试剂技术审查指导原则本指导原则旨在指导注册申请人对人乳头瘤病毒（HPV）核酸检测及基因分型试剂注册申报资料的准备及撰写，同时也为技术审评部门审评注册申报资料提供参考。
本指导原则是针对人乳头瘤病毒（HPV）核酸检测及基因分型试剂的一般要求，申请人应依据产品的具体特性确定其中内容是否适用，若不适用，需具体阐述理由及相应的科学依据，并依据产品的具体特性对注册申报资料的内容进行充实和细化。
本指导原则是供申请人和审查人员使用的指导性文件，不涉及注册审批等行政事项，亦不作为法规强制执行，如有能够满足法规要求的其他方法，也可以采用，但应提供详细的研究资料和验证资料。
应在遵循相关法规的前提下使用本指导原则。
本指导原则是在现行法规、标准体系及当前认知水平下制定的，随着法规、标准的不断完善和科学技术的不断发展，本指导原则相关内容也将适时进行调整。
一、范围人乳头瘤病毒（Human Papillomavirus, HPV）属于乳头瘤病毒科，是一种小分子的、无被膜包被的1、环状双链DNA病毒，基因组长约8000碱基对（bp），分为3个功能区，即早期转录区（E区）、晚期转录区（L区）和非转录区（长控制区，LCR）。
HPV通过直接或间接接触污染物品或性传播感染人类。
该病毒不但具有宿主特异性，而且具有组织特异性，只能感染人的皮肤和粘膜上皮细胞，引起人类皮肤的多种乳头状瘤或疣及生殖道上皮增生性损伤。
对于感染生殖道和肛门的HPV，根据各基因型别致病力大小或致癌危险性大小可分为低危型和高危型两大类。
在有性生活史的女性中生殖道HPV感染具有普遍性，据统计70%～80%的女性在其一生中会有至少一次的HPV感染，但大多数感染为自限性，超过90％的感染的女性会出现一种有效的免疫应答，在没有任何长期的健康干预时在6到24个月之间可以清除感染。
而持续性的高危型HPV感染则是导致宫颈上皮内瘤变及宫颈癌的主要原因。
hpv疫苗产品质量标准
hpv疫苗产品质量标准
宫颈癌九价疫苗的质量有一定要求，否则可能达不到预防宫颈癌的效果。
宫颈癌九价疫苗的主要成分是人乳头瘤病毒非活性蛋白，涵盖高危型人乳头瘤病毒的感染。
目前有二价、四价、九价三种疫苗，而且三种疫苗预防HPV感染的类型不同。
1、二价：针对HPV16、18高危型感染，预防有70%的宫颈癌;
2、四价：针对HPV6、11、16、18高危型感染，预防有90%的宫颈癌;
3、九价：针对HPV6、11、16、18、31、33、45、52、58亚型的感染，预防有85%的宫颈癌，同时还可以预防阴道癌、肛门癌等其他癌症，以及90%的肛门直肠癌。
对于接种二价或四价宫颈癌九价疫苗的人群，需要注意年龄，尽量在9-45岁之间接种。
此外，对于有性生活的女性，在接种前建议进行宫颈癌筛查，如TCT、HPV等检查，排除HPV 感染，以及宫颈癌前病变，甚至宫颈癌的可能。
对于有家族性病史的女性，建议接种九价宫
颈癌九价疫苗，在接种第一针后间隔两个月再进行接种，以达到较好的预防效果。
接种宫颈癌九价疫苗后，也需要定期进行宫颈癌的筛查。
对于接种九价宫颈癌九价疫苗的女性，建议在接种九价宫颈癌九价疫苗半年后再进行备孕，以达到较好的预防效果。
WHO对HPV疫苗质量、安全性及有效性指导原则
GUIDELINES TO ASSURE THE QUALITY, SAFETY AND EFFICACY OF REBINANT HUMAN PAPILLOMAVIRUS VIRUS¬LIKE PARTICLEVACCINES HPV二、Special consideration section:在生产、非临床及临床中过程中的考虑因素：1、生产方面：VLP是复杂的生物产物，必须在不同水平下对其进展检测分析。
因而在其生产过程及质量控制上必须考虑以下几个因素：1)新的表达体系如杆状病毒〔GSK〕，新的特殊要求。
但我们用的毕赤酵母，相比照拟常见。
2)新佐剂〔略〕3)天然的L1蛋白是没有被糖基化修饰，目前的两种表达体系，在糖基化修饰上不存大问题,但要对糖基化及其位点进展分析。
4)L1衣壳蛋白亚单位的解聚与再聚，可能有利于纯化，并得到更稳定的VLP。
目前，我们的路线可能是不经解聚，直接纯化获得VLP。
个人感觉，到后期可以兵分两路，一路直接获得VLP，而另一路则将VLP解聚后，再进展纯化与重组。
5)纯化后的L1 VLP要进展生化及免疫上的鉴定，并测定L1的浓度、纯度及组聚情况。
6)如参加了防腐剂，应对其免疫性进展验证，并确认不会有负作用2、非临床方面：关键就是要证明其免疫原性，并能否产生免疫中和抗体。
3、临床方面：〔略〕三、生产指导〔Part A. Guidelines on manufacturing〕3.1定义 definitions国际名称和专有名称国际名称：重组人乳头瘤类病毒颗粒疫苗〔基因型16 L1蛋白〕定义描述重组HPV VLP疫苗为无菌的液态疫苗，里面含纯化后由一种或多种HPV基因型重组的主要的衣壳蛋白，并与相应佐剂混合。
国际标准品在此指导原则编写时，市场上暂无国际标准品提供。
但有相应试剂在实验室水平上，在进展注射后进展生物效价方面的评价如抗体滴度和病毒DNA检测。
3.2术语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 pentameric capsomers.L1 virus¬like particle: A non¬infectious, non¬enveloped, icosahedral capsid particle which does not contain viral DNA and which is posed of regular arrays of L1 pentameric capsomers.Parental yeast c ell: Yeast host cell to be manipulatedfor the e*pression of protein(s) to give rise to a rebinant yeast production strain.Inoculum intermediate: A quantity of rebinant baculovirus of uniform position, derived from the working seed lot. The inoculum intermediate has a defined shelf¬life. It is intended to be used to initiate the production of rebinant L1 proteins.Cell bank: A collection of ampoules containing aliquots of a suspension of cells from a single pool of cells of uniform position, stored frozen under defined conditions (typically <−60 °C for yeast, and in liquid nitrogen for insect or mammalian cell lines).Master cell bank (MCB): A collection of containers containing aliquots of a suspension of cells from a single pool of cells of uniform position, stored frozen under defined conditions (typically <−60 °C for yeast, and in liquid 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 position, 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 product Production 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 e*ogenous 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 run Single harvest pool: A homogenous pool of multiplesingle 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 ponent 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.Filling lot (final vaccine lot): A collection of sealed final containers of vaccine that is homogeneous with respect to the risk of contamination during the filling process. A filling lot must therefore have been filled or prepared inone working session.3.3生产建议生产必须符合GMP要求，生物平安上要求无菌。
hpv指导原则
附件3人乳头瘤病毒〔HPV〕核酸检测及基因分型、试剂技术审查指导原那么本指导原那么旨在指导注册申请人对人乳头瘤病毒〔HPV〕核酸检测及基因分型试剂注册申报资料的准备及撰写，同时也为技术审评部门审评注册申报资料提供参考。
本指导原那么是针对人乳头瘤病毒〔HPV〕核酸检测及基因分型试剂的一般要求，申请人应依据产品的具体特性确定其中内容是否适用，假设不适用，需具体阐述理由及相应的科学依据，并依据产品的具体特性对注册申报资料的内容进行充实和细化。
本指导原那么是供申请人和审查人员使用的指导性文件，不涉及注册审批等行政事项，亦不作为法规强制执行，如有能够满足法规要求的其他方法，也可以采用，但应提供详细的研究资料和验证资料。
应在遵循相关法规的前提下使用本指导原那么。
本指导原那么是在现行法规、标准体系及当前认知水平下制定的，随着法规、标准的不断完善和科学技术的不断开展，本指导原那么相关内容也将适时进行调整。
一、范围人乳头瘤病毒〔Human Papillomavirus, HPV〕属于乳头瘤病毒科，是一种小分子的、无被膜包被的1、环状双链DNA病毒，基因组长约8000碱基对〔bp〕，分为3个功能区，即早期转录区〔E区〕、晚期转录区〔L区〕和非转录区〔长控制区，LCR〕。
HPV通过直接或间接接触污染物品或性传播感染人类。
该病毒不但具有宿主特异性，而且具有组织特异性，只能感染人的皮肤和粘膜上皮细胞，引起人类皮肤的多种乳头状瘤或疣及生殖道上皮增生性损伤。
对于感染生殖道和肛门的HPV，根据各基因型别致病力大小或致癌危险性大小可分为低危型和高危型两大类。
在有性生活史的女性中生殖道HPV感染具有普遍性，据统计70%～80%的女性在其一生中会有至少一次的HPV感染，但大多数感染为自限性，超过90％的感染的女性会出现一种有效的免疫应答，在没有任何长期的健康干预时在6到24个月之间可以去除感染。
而持续性的高危型HPV感染那么是导致宫颈上皮内瘤变及宫颈癌的主要原因。
hpv疫苗开题报告中研究的保障措施
hpv疫苗开题报告中研究的保障措施
在HPV疫苗研究中，有一些重要的保障措施被采取来确保研究的安全性和有效性。
这些措施包括：
1. 遵循伦理准则：研究必须符合伦理原则和法律法规的要求，并经过相关伦理委员会（Ethics Committee）的审查和批准。
这确保了对参与者的尊重、保护和知情同意，并确保研究是在正当合法的框架内进行的。
2. 监管审查：研究必须接受监管部门的审查和监督，例如中国国家药品监督管理局（NMPA）。
监管机构会对研究方案、数据收集、分析和研究结果进行审查，以确保研究的合规性和可靠性。
3. 临床试验阶段：HPV疫苗研究通常需要进行动物实验和临床试验。
动物实验用于评估疫苗的安全性和免疫原性。
随后，临床试验会在人体上进行，分为多个阶段（I、II、III期），以评估疫苗的安全性、效果和剂量选择。
在每个阶段，都会对试验对象（志愿者）进行审慎的评估和监测。
4. 效果评估：研究人员会评估疫苗对HPV感染和相关疾病的预防效果。
这通常涉及疫苗接种后的免疫反应测定、疫苗接种者的随访观察以及与未接种疫苗的人群进行对比。
评估结果会通过统计分析和科学论证的方式进行解读。
综上所述，HPV疫苗研究的保障措施包括遵守伦理准则、监管审查、临床试验阶段和效果评估，以确保研究的安全性、可靠性和合规性。
9价疫苗注意事项及禁忌
9价疫苗注意事项及禁忌随着科技的发展，疫苗在我们生活中的重要性不断被证明。
最近，由于疫苗的普及，HPV疫苗在许多国家中发挥了很大的作用。
9价疫苗正是一种常见的HPV疫苗，接受该疫苗可以提供长达五年的保护期。
然而，在接受9价疫苗之前，你需要了解更多关于它的知识，特别是它的注意事项和禁忌。
一、注意事项1. 接受9价疫苗的合适人群目前，世界卫生组织（WHO）推荐女性和男性在初次性行为前，最好在9岁至14岁之间接受两剂9价HPV疫苗预防。
如果接种时间比初次性行为晚，建议接种三剂，其中第一剂和第二剂之间应该隔6个月，第二剂和第三剂之间应隔12个月。
而对于16岁至26岁未接种过疫苗的人群，建议采用三针方案接种。
同时，对于27岁至45岁未接种过疫苗的人群，虽然9价HPV疫苗可以预防，但它对于这个年龄段的人来说适用性较差。
2. 不适宜接受9价疫苗的人群需要注意的是，如果你在接种前有以下疾病或情况，不建议接受9价HPV疫苗：- 怀孕或打算怀孕。
如果你已经怀孕，建议等待产后再接种。
- 严重的过敏反应史，特别是对于疫苗成分中的任何一种成分过敏， - 免疫系统严重受损状态，例如接受放疗或化疗等治疗， - 患有未治愈的严重疾病或感染，此外，如果你曾经接受过2价或4价HPV疫苗，可以考虑接种9价HPV疫苗，但建议至少要等待六个月。
3. 疫苗的副作用接种9价HPV疫苗并不会离奇地导致严重的副作用。
然而，你可能会在接种后出现以下轻微不适的症状：- 疼痛或肿胀。
可能出现在接种部位，也可能沿着手臂或大腿伸展。
- 低热或发热。
安抚宝宝或使用退热药控制体温就可以了。
- 头晕或昏倒。
若出现这种情况，应该尽快将宝宝躺下并保持头部低于身体的高度，等待缓解。
- 恶心或呕吐。
这是一种常见的副作用，可以使用药物缓解。
- 肌肉疼痛或关节疼痛。
这种状况在接种后几天可能会持续。
你可以用温水袋敷部位缓解不适。
4. 接种的时间和次数根据医生的建议，如果接种9价HPV疫苗，建议在接受第一针疫苗后延迟其他疫苗的接种，以便确定它是否对你的身体产生不良反应。
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GUIDELINES TO ASSURE THE QUALITY, SAFETY AND EFFICACY OF RECOMBINANT HUMAN PAPILLOMAVIRUS VIRUS¬LIKE PARTICLE VACCINES HPV二、Special consideration section:在生产、非临床及临床中过程中的考虑因素：1、生产方面：VLP是复杂的生物产物，必须在不同水平下对其进行检测分析。
因而在其生产过程及质量控制上必须考虑以下几个因素：1)新的表达体系如杆状病毒（GSK），新的特殊要求。
但我们用的毕赤酵母，相对比较常见。
2)新佐剂（略）3)天然的L1蛋白是没有被糖基化修饰，目前的两种表达体系，在糖基化修饰上不存大问题,但要对糖基化及其位点进行分析。
4)L1衣壳蛋白亚单位的解聚与再聚，可能有利于纯化，并得到更稳定的VLP。
目前，我们的路线可能是不经解聚，直接纯化获得VLP。
个人感觉，到后期可以兵分两路，一路直接获得VLP，而另一路则将VLP解聚后，再进行纯化与重组。
5)纯化后的L1 VLP要进行生化及免疫上的鉴定，并测定L1的浓度、纯度及组聚情况。
6)如加入了防腐剂，应对其免疫性进行验证，并确认不会有负作用2、非临床方面：关键就是要证明其免疫原性，并能否产生免疫中和抗体。
3、临床方面：（略）三、生产指导（Part A. Guidelines on manufacturing）3.1定义definitions3.1.1国际名称和专有名称国际名称：重组人乳头瘤类病毒颗粒疫苗（基因型16 L1蛋白）3.1.2定义描述重组HPV VLP疫苗为无菌的液态疫苗，里面含纯化后由一种或多种HPV基因型重组的主要的衣壳蛋白，并与相应佐剂混合。
3.1.3国际标准品在此指导原则编写时，市场上暂无国际标准品提供。
但有相应试剂在实验室水平上，在进行注射后进行生物效价方面的评价如抗体滴度和病毒DNA检测。
3.2术语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 pentameric capsomers.L1 virus¬like particle: A non¬infectious, non¬enveloped, icosahedral capsid particle which does not contain viral DNA and which is composed of regular arrays of L1 pentameric capsomers.Parental yeast c ell: Yeast host cell to be manipulated for the expression of protein(s) to give rise to a recombinant yeastproduction strain.Inoculum intermediate: A quantity of recombinant baculovirus of uniform composition, derived from the working seed lot. The inoculum intermediate has a defined shelf¬life. It is intended to be used to initiate the production of recombinant L1 proteins.Cell bank: A collection of ampoules containing aliquots of a suspension of cells from a single pool of cells of uniform composition, stored frozen under defined conditions (typically <−60 °C for yeast, and in liquid nitrogen for insect or mammalian cell lines).Master cell bank (MCB): A collection of containers containing aliquots of a suspension of cells from a single pool of cells of uniform composition, stored frozen under defined conditions (typically <−60 °C for yeast, and in liquid 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 purifiedmonovalent 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.Filling lot (final vaccine lot): A collection of sealed final containers of vaccine that is homogeneous with respect to the risk of contamination during the filling process. A filling lot must therefore have been filled or prepared in one working session. 3.3生产建议生产必须符合GMP要求，生物安全上要求无菌。