人乳头瘤病毒疫苗防治宫颈癌研究的新进展

宫颈癌的发病率在女性恶性肿瘤居第二位,人乳头状瘤病毒(HPV)感染已被证实为宫颈癌发生的主要因素,采用HPV疫苗防治HPV感染和宫颈癌是最根本的病因治疗方法,其中HPV疫苗分为预防性疫苗和治疗性疫苗两大类,本文综述了近几年关于HPV疫苗的研究成果.     

Human papillomavirus vaccine as a new way of preventing cervical cancer: a dream or the future?

Cervical cancer is the major cause of death in women of reproductive age in parts of the developing world. Thanks to the effectiveness of national screening programs, the incidence and mortality rates for cervical cancer have declined dramatically in developed countries. According to many researchers, human papillomavirus (HPV) infection has an important role in the development of cervical neoplasm. The effects of HPV infection on the oncogenesis of cervical carcinoma can be explained to a large degree by the regulation and function of the two viral oncogenes, E6 and E7. About 25 of >80 types infect the genital tract. HPV types are stratified into low, intermediate- and high-risk categories. Today, vaccines are available against many serious human pathogens. It is accepted worldwide that cervical carcinoma is a consequence of infection with HPV viruses. Therefore it is reasonable to assume that vaccine that prevents infection will reduce the incidence of cervical cancer. Virus-like particles are empty viral capsids, and are the leading candidate vaccines for the treatment or prevention of cervical cancer in humans. The HPV type 16 (HPV16) L1 virus-like particle vaccines have been shown to be generally well tolerated and they generate high levels of antibodies against HPV16. Since approximately 50% of cervical cancers are associated with HPV16 infection, the administration of this type of vaccine to young women could reduce the incidence of HPV16 infection, which is related to cervical dysplasia and cervical neoplasm. Vaccination against HPV infection could reduce the risk of infection and, most importantly, decrease the incidence of cervical cancer. A vaccine for cervical cancer is not a dream in the far future, it is happening today.     

Cervical Cancer Prevention Through HPV Vaccination in Low- and Middle-Income Countries in Asia

Cervical cancer is ranked the first or second most common cancer in women of low- and middle-income countries (LMICs) in Asia. Cervical cancer is almost exclusively caused by human papillomavirus (HPV), and majority of the cases can be prevented with the use of HPV vaccines. The HPV vaccines have demonstrated high vaccine efficacies against HPV infection and cervical cancer precursors in clinical and post-marketing studies, and are in use in most high-income countries. However, their use in LMICs are limited mainly due to the high costs and logistics in delivering multiple doses of the vaccine. Other issues such as the safety of the vaccines, social and cultural factors, as well as poor knowledge and awareness of the virus have also contributed to the low uptake of the vaccine. This mini-review focuses on the need for HPV vaccine implementation in Asia given the substantial disease burden and underuse of HPV vaccines in LMICs in this region. In addition, the progress towards HPV vaccine introduction, and barriers preventing further rollout of these essential, life-saving vaccines are also discussed in this article.     

Human papillomavirus vaccines in HIV-positive men and women

PURPOSE OF REVIEW: Individuals with HIV are at greater risk of human papillomavirus-related cancers. This report will assess the potential and limitations of vaccines against human papillomavirus in HIV-positive individuals. RECENT FINDINGS: A worldwide meta-analysis of published data established the under-representation of HPV16, and increased prevalence of multiple-type human papillomavirus infections in HIV-positive women. Associations between HIV-related immunodepression, the progression of human papillomavirus infection to cervical lesions, and an increased risk of cervical cancer in women with HIV have also been shown. An increased incidence of human papillomavirus infection in anal and vulvar/vaginal neoplasia has been reported in individuals with HIV. A prophylactic vaccine against HPV6, 11, 16 and 18 has been licensed, and one against HPV16 and 18 is under evaluation. Both have shown efficacy against persistent infection, as well as related human papillomavirus cervical lesions for up to 5 years. Preliminary results have also been reported on therapeutic vaccines, notably for the treatment of cervical intraepithelial neoplasia grades 2 and 3. SUMMARY: The safety and efficacy of human papillomavirus vaccines in individuals with HIV need to be assessed to prevent cervical cancer in current and future generations. Screening for human papillomavirus-related cancer among HIV patients should be undertaken.     

预防性 HPV 疫苗的临床应用进展及思考

宫颈癌是女性生殖系统最常见的恶性肿瘤,并且高危型人乳头瘤病毒（human papillomavirus, HPV）持续感染与宫颈癌的密切关系已经得到流行病学及临床研究证实。因此,HPV 疫苗在预防 HPV 持续感染及宫颈相关病变等方面备受瞩目。本文对目前美国 FDA 批准上市的3种预防性疫苗的临床应用进展进行综述,同时列举出一些尚存在争议的问题,旨在引起人们的重视及共同思考。     

Human papillomavirus,it's genes...and cancer vaccines

Genital human papillomavirus (HPV) infection is causally linked to the development of cervical cancer, a leading cause of cancer-related mortality in women worldwide. Recent studies demonstrate the effectiveness of virus-like particle-based vaccines to induce neutralizing antibodies against HPV and prevent cervical intraepithelial neoplasia.     

HPV vaccination and the effects on rates of HPV-related cancers

Globally, human papillomavirus (HPV) infection is one of the most common sexually transmitted infection. HPV is linked to at least five malignancies including vulvar, vaginal, anal penile, oropharyngeal, and cervical cancer. Three HPV vaccines are currently available: bivalent (HPV 16,18), quadrivalent (HPV 6,11,16,18), and nonavalent (6,11,16,18,31,33,45,52,58) targeting between 2 and 7 oncogenic HPV serotypes. This review highlights the currently epidemiologic burden of HPV-related cancers, efficacy of current HPV vaccines, and speculates about the benefits of widespread HPV vaccination. At present, all three vaccines are effective in reducing cervical disease and anogenital dysplasia in industry sponsored clinical trials and in limited study of clinical effectiveness. Models predict elimination of HPV infection with global vaccination rates of 80% and benefits in reducing malignancy at 20% global coverage. Large population-based clinical efficacy studies of these vaccines will be necessary to assess the true impact of vaccination. HPV vaccines provide a promising primary approach to preventing malignancy and barriers to vaccine access must be addressed to meet vaccination goals.     

Strategies for the introduction of human papillomavirus vaccination: modelling the optimum age- and sex-specific pattern of vaccination in Finland

Phase III trials have demonstrated the efficacy of human papillomavirus (HPV) vaccines in preventing transient and persistent high-risk (hr) HPV infection and precancerous lesions. A mathematical model of HPV type 16 infection and progression to cervical cancer, parameterised to represent the infection in Finland, was used to explore the optimal age at vaccination and pattern of vaccine introduction. In the long term, the annual proportion of cervical cancer cases prevented is much higher when early adolescents are targeted. Vaccinating against hr HPV generates greater long-term benefits if vaccine is delivered before the age at first sexual intercourse. However, vaccinating 12 year olds delays the predicted decrease in cervical cancer, compared to vaccinating older adolescents or young adults. Vaccinating males as well as females has more impact on the proportion of cases prevented when vaccinating at younger ages. Implementing catch-up vaccination at the start of a vaccination programme would increase the speed with which a decrease in HPV and cervical cancer incidence is observed.     

Prophylactic HPV vaccines: prospects for eliminating ano-genital cancer

Virtually all cases of cervical cancer and its precursor intra-epithelial lesions are a result of infection with one or other of a subset of genital human papillomaviruses (HPVs), suggesting that prevention of HPV infection by prophylactic vaccination would be a highly effective anticancer strategy. Two HPV L1 virus-like particle vaccines have been developed, a quadrivalent HPV16/18/6/11 product and a bivalent HPV16/18 product; both have been shown to be highly immunogenic with a good safety profile and 100% efficacy against HPV16/18-related high-grade cervical intra-epithelial neoplasia (CIN2/3), implying that they will be effective at preventing HPV16/18-related cervical cancer.     

Assessment of the knowledge and attitude of female students towards cervical cancer prevention at an international university in Japan

Cervical cancer resulting from prior infection with human papillomavirus (HPV) is a significant public health threat against young Japanese women. A national immunization plan to vaccinate 13~16 year old female students against HPV infection has been started in Japan since 2010, and may reach almost full coverage by the end of 2012. Older age females who may already be sexually active are not targeted by this plan but should follow safer sex practices as well as periodic screening of the cervix cytology to reduce their risk of developing cervical cancer. HPV vaccination alone does not offer full protection either, because only some HPV types are covered by the vaccines and the long-term efficacy of the vaccines has not been determined yet. Therefore, we did a survey at an international university in Japan to study the knowledge and attitude of female college students towards prevention of cervical cancer, to examine the age when they start sexual activity and other related attributes that may influence the risk of cervical cancer. We discuss the results of our survey and what they imply for the possible impact of an HPV immunization plan on the risk of cervical cancer in Japan, and conclude by an emphasis on the need to increase awareness among Japanese female adolescents and to enhance the cervical screening rates among older females who are already sexually active.     

Advances in primary and secondary interventions for cervical cancer: human papillomavirus prophylactic vaccines and testing

Cytologic screening has greatly reduced the incidence of invasive cervical cancer in many industrialized nations. State-of-the-art cervical cancer prevention is costly, however, and includes cytologic screening at repeat intervals, confirmation of abnormalities by colposcopic biopsy, and treatment of precancerous lesions. In resource-limited settings, accessibility to prevention programs for cervical cancer is often poor, or such programs are simply unavailable or inadequately supported. This disease, therefore, remains a leading form of cancer among women living in low-resource regions, and over 250,000 women worldwide die from cervical cancer each year. Persistent cervical infection with one of approximately 15 carcinogenic human papillomavirus (HPV) types causes virtually all invasive cervical cancer and its precursor abnormalities, which can be detected by cytologic screening. Genital HPV infections are primarily transmitted via sexual intercourse. One promising prophylactic HPV vaccine is available and others continue in development as primary cervical cancer prevention strategies in younger women. As secondary interventions, HPV tests are simultaneously evolving for use in cervical cancer screening programs, including routine screening of older women. HPV testing is more sensitive and reproducible than cytology with colposcopy for the detection of cervical precancer and cancer. This article presents current advances and perspectives on HPV vaccines and HPV testing.     

人乳头瘤病毒治疗性疫苗的研究进展

人乳头瘤病毒(HPV)持续感染是宫颈上皮内瘤变和宫颈癌发生的必要因素.以治疗HPV感染为出发点研制有效的治疗性疫苗是防治宫颈癌的新策略.近年来,治疗性HPV疫苗的研制与试验已取得了巨大的进步,载体的选择、佐剂的使用、融合和嵌合蛋白的合成被广泛应用于研究中,以增强疫苗免疫原性、加强接种安全性、减少不良反应等.临床试验结果令人鼓舞,各类疫苗能诱导特异性免疫应答,且具有良好的耐受性;但如何取得进一步的成功依然需要大量的研究.此外,HPV病毒种类繁多,如何扩大疫苗的作用范围及减少免疫逃逸也是研究的重点.     

How will HPV vaccines affect cervical cancer?

Cancer of the uterine cervix is the second largest cause of cancer deaths in women, and its toll is greatest in populations that lack screening programmes to detect precursor lesions. Persistent infection with 'high risk' genotypes of human papillomavirus (HPV) is necessary, although not sufficient, to cause cervical carcinoma. Therefore, HPV vaccination provides an opportunity to profoundly affect cervical cancer incidence worldwide. A recently licensed HPV subunit vaccine protects women from a high proportion of precursor lesions of cervical carcinoma and most genital warts. Here we examine the ramifications and remaining questions that surround preventive HPV vaccines.     

Vaccination strategies for the treatment and prevention of cervical cancer

PURPOSE OF REVIEW: Immunotherapy of HPV-induced premalignant anogenital lesions and cervical cancer has made impressive progress. HPV as causative agent is targeted by prophylactic and therapeutic vaccination strategies. Preclinical and clinical studies have shown induction of natural and/or vaccine-induced immune responses. This review will summarize the status of vaccine development and clinical testing published since March 2003. RECENT FINDINGS: For prophylactic vaccines there is first clinical evidence of effectivity (ie, 100% protection from HPV infection and dysplasia by virus-like particle (VLP) vaccine-induced neutralizing antibodies). Also, therapeutic vaccines have entered clinical evaluation. While prophylactic VLP vaccines are immunogenic per se, therapeutic vaccines will need further adjuvants to guide T cell differentiation, expansion, survival, and homing to tumor sites. To enhance clinical outcome of successful T cell induction in patients, the susceptibility of the tumor cells for lysis must be addressed in the future, since tumor immune evasion is a severe problem in cervical cancer. SUMMARY: While successful prophylactic HPV vaccines have entered large clinical trials, therapeutic HPV vaccines, in spite of T cell induction, lack clinical responses due to the problem of tumor immune evasion. Adjuvants for systemic and local immune modulation will be mandatory for effective therapy.     

Integrating novel primary- and secondary-prevention strategies: the next challenge for cervical cancer control

The advent of prophylactic vaccines against human papillomavirus (HPV) infection, the cause of cervical cancer, and of new molecular methods to screen for this disease have become key developments in cancer control in the last 5 years. Although Pap cytology has had a significant history as a key method for cervical cancer screening, not all countries have benefited from this technology or have been able to implement the necessary public health steps to manage and treat the precancerous lesions that are detected by the Pap test. Testing of cervical exfoliated cells for DNA of oncogenic HPV types has been proven to be more accurate than Pap cytology. The latter test's high specificity makes it an ideal technique to triage women who are found to be HPV positive via a primary screen. HPV testing followed by Pap testing only for HPV-positive women is a promising strategy for screening women in the post-vaccination era.     

Knowledge towards HPV infection and HPV vaccines among Syrian mothers

Cervical cancer is caused by HPV infection and can be prevented by early vaccination. Objective: To assess Syrian women’s level of knowledge and determinants of good knowledge of cervical cancer, HPV infection and its vaccines. Methods: A cross sectional survey was undertaken among mothers with daughters in sixth grade classes enrolled in primary schools in Aleppo city, Syria. Samples were selected through cluster sampling and data collected using a self-administered questionnaire. Results: Less than a third of the mothers had heard of HPV infection and vaccines against cervical cancer and levels of knowledge were generally low. Good knowledge was associated with high education level, higher family monthly income, having few - less than four children, positive history of cervical cancer screening, and working or having relatives working in the medical field. The main source of information was television and few reported health care providers as a source of knowledge on HPV infection and vaccine. Conclusion: Since knowledge of HPV infection and its connection with cervical cancer and its vaccine are low, more efforts must be made to educate Syrians prior to introduction of any HPV vaccination programme. Public health efforts must focus on educating mothers, the public as well as health care providers.     

Vaccines against human papillomavirus and cervical cancer: promises and challenges

Cervical cancer and precancerous lesions of the genital tract are major threats to the health of women worldwide. The introduction of screening tests to detect cervical cancer precursor lesions has reduced cervical cancer rates in the developed world, but not in developing countries. Human papillomavirus (HPV) is the primary etiologic agent of cervical cancer and dysplasia. Thus, cervical cancer and other HPV-associated malignancies might be prevented or treated by HPV vaccines. Two vaccine strategies have been developed. First, prevention of HPV infection through induction of capsid-specific neutralizing antibodies has been studied in clinical trials. However, because the capsid proteins are not expressed at detectable levels by infected basal keratinocytes or in HPV-transformed cells, a second approach of developing therapeutic vaccines by targeting nonstructural early viral antigens has also been developed. Because two HPV oncogenic proteins, E6 and E7, are critical to the induction and maintenance of cellular transformation and are coexpressed in the majority of HPV-containing carcinomas, most therapeutic vaccines target one or both of these gene products. A variety of approaches is being tested in therapeutic vaccine clinical trials, whereby E6 and/or E7 are administered in live vectors, as peptides or protein, in nucleic acid form, or in cell-based vaccines. The paradigm of preventing HPV infection through vaccination has been tested, and two vaccines are currently in phase III clinical trials. However, current therapeutic vaccine trials are less mature with respect to disease clearance. A number of approaches have shown significant therapeutic benefit in preclinical papillomavirus models and await testing in patient populations to determine the most effective curative strategy.     

Human papillomavirus and vaccination: knowledge, attitudes, and behavioural intention in adolescents and young women in Italy

This study assesses knowledge, attitudes, and behavioural intention towards human papillomavirus (HPV) infection and vaccination in a random sample of 1348 adolescents and young women aged 14-24 years in Italy. A self-administered anonymous questionnaire covered demographics; knowledge about HPV infection, cervical cancer, and HPV vaccine; the perceived risk for contracting HPV infection and/or for developing cervical cancer, the perceived benefits of a vaccination to prevent cervical cancer, and willingness to receive an HPV vaccine. Only 23.3% have heard that HPV is an infection of the genital mucosa and about cervical cancer. Those older, with at least one parent who is a health care professional, with personal, familiar, or friendly history of cervical cancer, and having underwent a health checkup in the last year with information about HPV vaccination were significantly more knowledgeable. Risk perception scores (range: 1-10) of contracting HPV infection and of developing cervical cancer were 5.8 and 6.5. Older age, not having a parent who is a health care professional, having had a personal, familiar, or friendly history of cervical cancer, and need of additional information were predictors of the perceived susceptibility of developing cervical cancer. The vast majority professed intent to receive an HPV vaccine and the significant predictors were having at least one parent who is a health care professional, a high perceived risk of contracting HPV infection and of developing cervical cancer, and a high belief towards the utility of a vaccination for preventing cervical cancer. Knowledge about HPV infection and cervical cancer should be improved with more attention to the benefit of HPV vaccination.     

Chapter 4: Genital tract infections,cervical inflammation,and antioxidant nutrients--assessing their roles as human papillomavirus cofactors

Cervical infections by approximately 15 human papillomavirus (HPV) types are the necessary cause of cervical cancer and its immediate precursor lesions. However, oncogenic HPV infections are usually benign and usually resolve within 1-2 years. A few of these infections persist and progress to cervical precancer and cancer. A number of cervical factors, such as infection by sexually transmitted pathogens other than HPV, cervical inflammation, and antioxidant nutrients, may influence the natural history of HPV infection along the pathways of persistence and progression or resolution. We examine the possible roles of these HPV cofactors in cervical carcinogenesis and discuss new methodologies that may enable researchers to measure relevant markers of the cervical microenvironment in which these cofactors may be active.     

人乳头瘤病毒新型检测及分型方法的研究进展

宫颈癌是最常见的妇科恶性肿瘤,高危型人乳头瘤病毒持续感染与宫颈癌的发生密切相关.随着人乳头瘤病毒(human papillomavirus,HPV)检测的不断发展,对宫颈癌筛查管理的更新和完善发挥了重要作用,全球指南的更新将HPV检测及基因分型置于宫颈癌筛查及异常管理的重要前提,但受筛查普及程度和方法学的限制,宫颈癌的...