Vaccines against cervical cancer

Cervical cancer and precancerous lesions of the genital tract are a major threat to women’s health worldwide. Although the introduction of screening tests to detect cervical cancer and its precursor lesions has reduced overall cervical cancer rates in the developed world, the approach was largely unsuccessful for developing countries, primarily due to a lack of appropriate infrastructures and high costs. Annually, 470,000 cervical cancer cases are diagnosed worldwide, of which 80% occur in developing countries. Despite advances in treatment of cervical cancer, approximately half of the women afflicted with the disease will die. Over 20 years of dedicated research has provided conclusive evidence that a subset of human papillomaviruses are the aetiological agents for cervical cancer. Finding a viral origin for this disease provided the basis to fight cervical cancer using prophylactic or therapeutic vaccination. Both vaccine approaches are reviewed here, with an emphasis on recent clinical data.     

人乳头状瘤病毒核酸检测试剂盒用于宫颈癌及癌前病变筛查的临床价值

目的分析人乳头状瘤病毒(HPV)杂交捕获-化学发光法核酸检测试剂盒(DH3)用于宫颈癌及癌前病变筛查的临床价值。方法收集480例妇科门诊妇女宫颈脱落细胞样本,分别采用DH3、TCT和HPV-PCR检测,对TCT≥ASC-US者行阴道镜下病理检测,以病理学结果为金标准,分析DH3诊断价值。结果病理学结果显示,正常者370例(77.08%),良性病变者(≤CINⅠ)59例(12.29%),高危者(≥CINⅡ)51例(10.63%);TCT、HPV-PCR和DH3诊断阳性率分别为26.04%、32.08%和27.08%;DH3与TCT检测一致率为94.79%(P0.01),与HPV-PCR检测一致率为93.13%(P0.01);DH3灵敏度98.18%,特异度87.57%,阳性预测值70.13%,阴性预测值99.39%,准确率为90%,检出高危型(≥CINⅡ)的ROC曲线面积Z=0.887(95%CI为0.785~0.918,P0.01)。结论 DH3试剂盒与TCT、HPV-PCR在检出HPV宫颈癌及癌前病变具有高度一致性,灵敏度、特异度和准确率高,操作便捷,临床筛查意义显著。     

Sequence analysis and expression of a virus-like particle protein,VLP2, from the parasitic wasp Venturia canescens

Endoparasitoid wasps produce maternal protein secretions, which are transported into the body of insect hosts at oviposition to regulate host physiology for successful development of their offspring. Venturia canescens calyx fluid contains so-called virus-like particles (VLPs) that are essential for immune evasion of the developing parasitoid inside the host. VLPs consist of four major proteins. In this paper, we describe the isolation and molecular cloning of a gene (vlp2) that is a constituent of VLPs and discuss its possible role in VLP structure and function.     

高危型人乳头瘤病毒检测对宫颈病变的临床价值

目的探讨高危型人乳头瘤病毒(high-risk human papillom avirus,HR-HPV)检测在宫颈病变诊断中的应用价值。方法用二代杂交捕获法(hybird captureⅡ,HC-Ⅱ)对宫颈涂片结果异常的3426例患者进行HR-HPV DNA、阴道镜和宫颈多点活检组织病理学检查,对结果进行回顾性分析。结果检出宫颈浸润癌45例,宫颈上皮内瘤变(cervical intraepithelial neoplasia,CIN)2/3级670例,CIN1级、宫颈湿疣及宫颈炎2711例。高级别病变(CIN2/3 )及宫颈癌患者HPV DNA阳性率高于低级别宫颈病变和宫颈炎患者,宫颈病变组比宫颈炎组的病毒载量明显升高。结论单次HR-HPV DNA载量与CIN2/3 有一定相关性,HR-HPV检测多次阳性的患者有发生CIN2/3 的风险,检测HR-HPV并对其感染者密切随访对检出CIN2/3 有重要意义。     

人乳头瘤病毒、人巨细胞病毒和单纯疱疹病毒感染与宫颈癌的关系

目的　本研究旨在探讨宫颈癌前病变和宫颈癌的发生发展与人乳头状瘤病毒及HSV、CMV的关系。方法　对81例不同宫颈病变组织进行HPV16 /18和HPV6 /11原位杂交,同时对98例不同宫颈病变组织用DNA扩增法检测HPV、HSV和CMV。结果　病毒DNA原位杂交信号的分布与HE染色中挖空细胞的分布一致。HPV16 /18与不同宫颈病变组织原位杂交阳性率平均为5 1 .1% ,HPV6 /11的则为6 4 .7%。HPV16 /18、HPV6 /11、HSV、CMV在不同宫颈病变组织中的阳性率分别为2 1%、4 %、2 3%、0 %。结论　HPV感染具有特定的组织学部位,HSV可协同HPV16 /18恶性转化宫颈上皮细胞。     

Immune responses against human papillomavirus (HPV) infection and evasion of host defense in cervical cancer

Human papillomavirus (HPV) is the most important etiological factor for cervical cancer. A recent study demonstrated that more than 20 HPV types were thought to be oncogenic for uterine cervical cancer. Notably, more than one-half of women show cervical HPV infections soon after their sexual debut, and about 90 % of such infections are cleared within 3 years. Immunity against HPV might be important for elimination of the virus. The innate immune responses involving macrophages, natural killer cells, and natural killer T cells may play a role in the first line of defense against HPV infection. In the second line of defense, adaptive immunity via cytotoxic T lymphocytes (CTLs) targeting HPV16 E2 and E6 proteins appears to eliminate cells infected with HPV16. However, HPV can evade host immune responses. First, HPV does not kill host cells during viral replication and therefore neither presents viral antigen nor induces inflammation. HPV16 E6 and E7 proteins downregulate the expression of type-1 interferons (IFNs) in host cells. The lack of co-stimulatory signals by inflammatory cytokines including IFNs during antigen recognition may induce immune tolerance rather than the appropriate responses. Moreover, HPV16 E5 protein downregulates the expression of HLA-class 1, and it facilitates evasion of CTL attack. These mechanisms of immune evasion may eventually support the establishment of persistent HPV infection, leading to the induction of cervical cancer. Considering such immunological events, prophylactic HPV16 and 18 vaccine appears to be the best way to prevent cervical cancer in women who are immunized in adolescence.     

高危型人乳头瘤病毒检测及TCT检测在宫颈病变筛查中的应用

目的：探讨高危型人乳头瘤病毒（HPV）检测及液基超薄层细胞检测技术（TCT）在宫颈病变筛查中的诊断价值。方法：对782例妇女进行TCT检测并采用二代杂交捕获技术进行HPV检测,其中TCT结果≥非明确意义不典型鳞状细胞（ASCUS）或HPV（＋）者行阴道镜下活组织检查187例以及同期因子宫良性病变行子宫全切术的妇女107例术前全部做HPV及TCT检测,病理结果为金标准。结果：若将TCT结果≥ASCUS,病理结果≥宫颈上皮内瘤变I级（CINI）确定为阳性,应用HPV检测的阴性预测值高于TCT,差异有统计学意义（P〈O．05）。若将TCT结果≥低度鳞状上皮内病变（LSIL）确定为阳性,病理结果≥CINⅡ确定为阳性,HPV检测灵敏度及阴性预测值高于TCT检测,特异度、阳性预测值低于TCT检测,差异有统计学意义（P〈0．05）;TCT≥LSIL,病理≥CINⅡ为阳性与TCT≥ASCUS,病理≥CINI为阳性的评价指标分析,HPV检测的灵敏度、两种检测方法的阴性预测值均有明显提高,差异有统计学意义（P〈O．05）。结论：可将HPV检测作为宫颈病变筛查的第一步,它是可靠的阴性预测值,具有临床推广意义。     

Therapeutic human papillomavirus vaccines: current clinical trials and future directions

Background: Cervical cancer is the second largest cause of cancer deaths in women worldwide. It is now evident that persistent infection with high-risk human papillomavirus (HPV) is necessary for the development and maintenance of cervical cancer. Thus, effective vaccination against HPV represents an opportunity to restrain cervical cancer and other important cancers. The FDA recently approved the HPV vaccine Gardasil for the preventive control of HPV, using HPV virus-like particles (VLP) to generate neutralizing antibodies against major capsid protein, L1. However, prophylactic HPV vaccines do not have therapeutic effects against pre-existing HPV infections and HPV-associated lesions. Furthermore, due to the considerable burden of HPV infections worldwide, it would take decades for preventive vaccines to affect the prevalence of cervical cancer. Thus, in order to speed up the control of cervical cancer and treat current infections, the continued development of therapeutic vaccines against HPV is critical. Therapeutic HPV vaccines can potentially eliminate pre-existing lesions and malignant tumors by generating cellular immunity against HPV-infected cells that express early viral proteins such as E6 and E7. Objective: This review discusses the future directions of therapeutic HPV vaccine approaches for the treatment of established HPV-associated malignancies, with emphasis on current progress of HPV vaccine clinical trials. Methods: Relevant literature is discussed. Results/conclusion: Though their development has been challenging, many therapeutic HPV vaccines have been shown to induce HPV-specific antitumor immune responses in preclinical animal models and several promising strategies have been applied in clinical trials. With continued progress in the field of vaccine development, HPV therapeutic vaccines may provide a potentially promising approach for the control of lethal HPV-associated malignancies.     

宫颈癌及癌前病变患者尿液和宫颈脱落细胞中高危型人乳头瘤病毒比较

目的:探讨尿液标本用于检测子宫颈癌及癌前病变患者高危型人乳头瘤病毒的临床应用价值.方法:30例宫颈癌及癌前病变患者晨尿及宫颈脱落细胞标本,应用凯普核酸分子扩增导流杂交方法分型检测21种人乳头瘤病毒基因,比较2种标本检测高危型人乳头瘤病毒的一致性.结果:尿液和宫颈脱落细胞标本的高危型人乳头瘤病毒阳性检出率分别是56.7%和90.0%,差异有统计学意义(P=0.004).尿液与宫颈脱落细胞检测阳性符合卒为63.0%,阳性阴性符合率为66.7%.结论:尿液标本与宫颈脱落细胞标本检测宫颈癌及癌前病变患者的高危人乳头瘤病毒有一定一致性,但仍无法替代目前常规使用的宫颈脱落细胞检测高危人乳头瘤病毒.     

Production of adenovirus vectors and their use as a delivery system for influenza vaccines

Importance of the field: With the emergence of highly pathogenic avian influenza H5N1 viruses that have crossed species barriers and are responsible for lethal infections in humans in many countries, there is an urgent need for the development of effective vaccines which can be produced in large quantities at a short notice and confer broad protection against these H5N1 variants. In order to meet the potential global vaccine demand in a pandemic scenario, new vaccine-production strategies must be explored in addition to the currently used egg-based technology for seasonal influenza.

Areas covered in this review: Adenovirus (Ad) based influenza vaccines represent an attractive alternative/supplement to the currently licensed egg-based influenza vaccines. Ad-based vaccines are relatively inexpensive to manufacture, and their production process does not require either chicken eggs or labor-intensive and time-consuming processes necessitating enhanced biosafety facilities. Most importantly, in a pandemic situation, this vaccine strategy could offer a stockpiling option to reduce the response time before a strain-matched vaccine could be developed.

What the reader will gain: This review discusses Ad-vector technology and the current progress in the development of Ad-based influenza vaccines.

Take home message: Ad vector-based influenza vaccines for pandemic preparedness are under development to meet global vaccine demand.     

HPV vaccine: Cervarix

Importance of the field: Cervical cancer is a major cause of morbidity and mortality worldwide and is common in relatively young women. Cervical screening programs, while successful if properly carried out, are difficult and expensive to implement, and offer secondary, not primary prevention. Vaccination against the human papillomavirus (HPV), which is the major cause of cervical cancer, is a significant step forward.

Areas covered in this review: The data on Cervarix, the GSK HPV vaccine, are reviewed and placed in the context of HPV vaccination as a whole. A literature review using PubMed listed publications and official product websites has been carried out.

What the reader will gain: The reader will gain an understanding of the issues involved in HPV vaccination and of the data to date.

Take home message: Cervarix has been shown to have high efficacy against disease associated with both HPV-16 and HPV-18. Its antibody response profile allows for optimism regarding the duration of immunity. The fact that it is a virus-like particle, rather than a live-virus vaccine, is reassuring regarding safety, as are the reasonably extensive safety data for the vaccine preparation so far accrued. Cross protection against oncogenic non-vaccine HPV types, in particular HPV-45, may be important in the prevention of cervical adenocarcinoma, which is currently not well served by screening.     

Dendritic cell-based vaccines and therapies for cancer

Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs), and are capable of stimulating naive T cells and driving primary immune responses. Due to this unique property, DCs represent both vectors and targets for immunological intervention in numerous diseases and are optimal candidates for vaccination protocols in cancer. This review provides an overview of DC immunobiology and the integration of these important APCs in immunotherapies for cancer.     

Molecular tests potentially improving HPV screening and genotyping for cervical cancer prevention

Introduction: Human papillomavirus (HPV)-related cancers can be averted by type-specific vaccination (primary prevention) and/or through detection and ablation of precancerous cervical lesions (secondary prevention). This review presents current challenges to cervical cancer screening programs, focusing on recent molecular advances in HPV testing and potential improvements on risk stratification.

Areas covered: High-risk (HR)-HPV DNA detection has been progressively incorporated into cervix cancer prevention programs based on its increased sensitivity. Advances in next-generation sequencing (NGS) are being rapidly applied to HPV typing. However, current HPV DNA tests lack specificity for identification of cervical precancer (CIN3). HPV typing methods were reviewed based on published literature, with a focus on these applications for screening and risk stratification in the emerging complex clinical scenario post-vaccine introduction. In addition, the potential for NGS technologies to increase specificity is discussed in regards to reflex testing of specimens for emerging biomarkers for cervix precancer/cancer.

Expert commentary: Integrative multi-disciplinary molecular tests accurately triaging exfoliated cervical specimens will improve cervical cancer prevention programs while simplifying healthcare procedures in HPV-infected women. Hence, the concept of a ‘liquid-biopsy’ (i.e., ‘molecular’ Pap test) highly specific for early identification of cervical precancerous lesions is of critical importance in the years to come.     

Awareness,knowledge and beliefs about HPV,cervical cancer and HPV vaccines among nurses in Cameroon: An exploratory study

Background

While it is known that sub-Saharan African countries face multiple obstacles such as cost in adopting vaccination against human papillomavirus (HPV), the crucial role nurses can play in implementing such programs has not been adequately examined.

Objectives

To investigate the knowledge and awareness of HPV, primary cause of cervical cancer and HPV vaccine among nurses working at four Cameroon Baptist Convention Health Services facilities, and to explore what factors influence nurses’ willingness to inform and recommend HPV vaccine to adolescents and parents attending clinics.

Design and setting

A structured questionnaire survey was administered to a convenience sample of nursing staff working at the four health facilities.

Results

Of 192 eligible nurses 76 (39.6%) participated in the study. There were moderately low levels of knowledge about HPV infection and prevention of cervical cancer, but a moderately high level of knowledge about HPV vaccine. Although 90.8% acknowledged that cervical cancer is directly linked to HPV infection, nearly 32% failed to identify it as a sexually transmitted infection (STI), while 43.4% believed it is an uncommon infection. Willingness to recommend the HPV vaccine was moderate, with 69.7% intentionally initiating discussions with patients about the subject. The most important factors considered when deciding to recommend the vaccine included effectiveness (56.6%) and side effects/safety (11.8%). Cost was less of a concern (6.6%), likely due to the availability of donated vaccine.

Conclusion

Despite high awareness about HPV, more education about the virus, cervical cancer and the vaccine are required to further increase nurses’ willingness to recommend the vaccine and strengthen strategies for reaching adolescents through nurses in Cameroon.     

采用组织芯片技术研究宫颈癌中HPV与细胞周期调控因子p27表达的关系

目的研究宫颈癌组织中HPV感染与细胞周期调控因子p27表达的关系及意义。方法采用组织芯片技术制作60例宫颈癌组织芯片，同时用S—P免疫组织化学和原位分子杂交方法检测宫颈癌组织芯片中HPV、p27、p27mRNA的表达。结果60例宫颈癌组织中HPV、p27、p27mRNA的阳性率分别为48．3％、38．3％、51．7％。淋巴结转移阳性宫颈癌中p27和p27mRNA阳性率明显低于淋巴结转移阴性宫颈癌（P〈0．01）。淋巴结转移阳性宫颈癌中HPV阳性率明显高于淋巴结转移阴性宫颈癌（P〈0．05）。宫颈癌和CINⅢ级宫颈上皮内瘤变组织中HPV阳性率明显高于CINⅠ级和CINⅡ级（P〈0．05）。而p27和p27mRNA阳性率明显低于CINⅠ级和CINⅡ级宫颈上皮内瘤变组织（P〈0．05）。宫颈癌中HPV与p27及p27mR—NA表达呈明显负相关（r=-0．574，P〈0．05；r=-0．612，P〈0．01）。结论HPV感染和细胞周期调控因子p27低表达与宫颈癌密切相关。HPV感染与p27低表达有关。HPV和p27可作为评估宫颈癌预后的参考指标。应用组织芯片大规模高效检测临床组织样本是可行的，具有快速、方便、经济、准确的特点。     

高危型HPV检查和TCT在宫颈癌及癌前病变的早期诊断临床研究

目的研究高危型人乳头瘤病毒(HPV)检查及薄层液基细胞学技术(TCT)在宫颈癌与癌前病变的早期诊断的临床应用价值。方法回顾性分析高危型HPV检查及TCT对1 248例宫颈癌筛查对象的检查结果。比较两种方法及联合应用的临床诊断价值。结果病理组织学CINⅠ期组、CINⅡ期组、CINⅢ期组、宫颈癌组高危型HPV感染率及TCT阳性率与正常及炎症组比较均有统计学差异(P<0.05);CINⅠ-Ⅲ期及宫颈癌组高危型HPV感染率、TCT阳性率均高于正常及炎症组;高危型HPV检测与TCT两种方法联合检测灵敏度(92.2%),正确诊断指数(0.71)、阴性预测值(99.6%)及阳性预测值(40.2%)均有不同程度的提高。结论高危型HPV检测与TCT联合对宫颈癌早期发现、早期诊断有重要的临床意义。     

组氨酸三联体及肺癌抑制因子1基因表达与宫颈癌发生及人乳头瘤病毒感染的相关性

目的探讨肺癌抑制因子1(TSLC1)及组氨酸三联体(FHIT)在正常宫颈组织、宫颈鳞状上皮内病变及宫颈癌组织中的表达及其与人乳头瘤病毒(HPV)的关系。方法采用细胞免疫组化法测定35例正常子宫组织、40例低度鳞状上皮内病变(LSIL)、38例高度鳞状上皮内病变(HSIL)及35例子宫癌组织中TSLC1及FHIT的表达情况。采用HC2基因杂交捕获仪(HC-Ⅱ)检测各组HPV感染情况。结果 HSIL、宫颈癌组织中FHIT、TSLC1阳性表达率显著低于正常宫颈组织及LSIL,而HPV阳性率则高于正常宫颈组织及LSIL(P0.05)。FHIT表达与病理分级、临床分期及淋巴结转移相关(P0.05)。TSLC1表达与临床分期及淋巴结转移相关(P0.05)。在正常宫颈组织、LSIL、HSIL及宫颈癌组织中,FHIT、TSLC1表达与HPV感染呈负相关(P0.05)。结论 FHIT、TSLC1表达缺失发生在HSIL阶段,FHIT、TSLC1表达缺失与HPV感染参与宫颈鳞状上皮细胞内病变、宫颈癌发生、侵袭及转移具有密切的关系。     

Cobas 4800 HR-HPV 检测系统在宫颈癌筛查中的应用

目的：分析cobas 4800检测女性高危型人乳头瘤病毒（HR-HPV）感染宫颈癌状况。方法对2222例女性宫颈脱落细胞进行cobas 4800 HR-HPV检测宫颈薄层液基细胞（TCT ）检查,计算 HR-HPV感染的阳性率与年龄段关系,及与 TCT阳性率的比较。结果2222例标本中HR-HPV阳性者395例,阳性率17．8％,其中 HPV16感染86例（3．9％）,HPV18感染31例（1．4％）,其他12种高危型感染278例（12．5％）。所有样本在19～29岁、30～39岁、40～49岁、50～59岁、60～69、≥70岁6个年龄段HR-HPV的感染率分别为23．23％（84／361）、21．5％（147／686）、15．0％（92／613）、14．7％（56／380）、6．8％（9／132）、14．0％（7／50）。各年龄组的HR-HPV阳性检出率比较差异具有统计学意义（P＜0．01）。在HR-HPV 阳性例数中,TCT阳性97例,阳性率为24．56％（97／395）,高于阴性组的1．59％（29／1827）,两者比较差异有统计学意义（ P＜0．01）。结论统计数据中 H R-HPV感染高峰在19～29岁,以其他12种 HR-HPV为主,HR-HPV检测可以提高宫颈癌筛查检测的敏感性,若同时联合 TCT检测可早期发现治疗宫颈癌前病变。