宫颈癌HPV预防性疫苗的研究进展

人乳头瘤病毒(HPV)感染是常见的性传播疾病之一。高危人乳头瘤病毒(hr HPV)持续感染是宫颈癌前病变及宫颈癌的主要危险因素。HPV16和HPV18型导致全球大约70%的宫颈癌。宫颈癌普查可减少宫颈癌发生的危险,但不能阻止HPV的感染。很多报道表明,有效的HPV疫苗可以减少HPV相关的宫颈癌、生殖道疣状物的发病率和死亡率。因此,为了有效预防这类疾病,全世界开展了HPV预防性疫苗的研究。目前临床应用的HPV疫苗有HPV 2价疫苗、4价疫苗及9价疫苗,它们可以有效预防相应HPV类型的感染,从而大量减少与此相关的宫颈病变及宫颈癌的发病率和死亡率。本文就HPV、宫颈癌及这3类HPV疫苗的免疫原性、接种剂量的数量和临床应用进行综述。     

人乳头瘤病毒16疫苗预防宫颈上皮内瘤样病变的效果

常见人乳头瘤病毒（HPV）型（包括HPV16）的预防性疫苗的出现给有效预防宫颈癌带来了希望。HPV病毒样颗粒（virus-like particle，VLP）疫苗预防持续性HPV感染的功效已被证实，但其预防作用是否能超过18个月以及对宫颈上皮内瘤样病变（CIN）Ⅱ～Ⅲ的影响尚不明确。     

宫颈癌HPV预防性疫苗的研究进展

宫颈癌是导致全球妇女死亡的主要肿瘤之一。一定型别的人乳头瘤病毒（HPV）感染是宫颈癌发生的必备条件，预防性HPV疫苗可大量减少与此相关的宫颈病变及宫颈癌发病率和死亡率。而由L1自我组装成的病毒样颗粒（VLPs）是预防性疫苗的最佳侯选者之一，肌肉注射VLP后可以产生很强的B细胞、T细胞介导的适应性免疫和中和抗体的天然免疫。VLP的Ⅱ期临床实验均取得可喜成果，Ⅲ期临床实验也在逐步进行。     

HPV持续感染与子宫颈上皮内瘤变2级及更严重病变的相关性

宫颈癌严重危害人类的健康,许多研究已充分证明其是由人乳头瘤病毒（HPV）感染引起[1]。由于从HPV感染发展到宫颈癌的进程长达10-20年,其中宫颈上皮内瘤变2级（CIN2）及更严重病变是发展为宫颈癌所经历的癌前阶段。出于伦理,目前已经上市的预防HPV感染的宫颈癌疫苗（二价和四价HPV疫苗）,     

人乳头瘤病毒疫苗预防宫颈癌的应用

宫颈癌严重危害女性健康,现已明确人乳头瘤病毒(HPV)感染是其主要致病因素。HPV通过机体的细微损伤入侵,HPV E6和E7癌蛋白中的1种或2种持续表达是高危型HPV感染致瘤的关键所在,检测高危型HPV感染及病毒癌蛋白仍不能有效预防宫颈癌。研究者们正着手研制针对HPV的病毒疫苗,从源头预防HPV感染,以期实现宫颈癌的一级预防。目前已有针对HPV16/18型的二价疫苗Cervarix和针对HPV16/18/11/6型的四价疫苗Gardasil的认证上市,预防性HPV疫苗已在全球范围内推广使用并取得显著效果。新一代预防性HPV疫苗在解决疫苗的成本、持久性和广谱免疫问题上取得突破性进展,宫颈癌有望成为人类抗肿瘤史上第一个可以预防的癌症。综述近年HPV的生物学特性、致病机制及预防性HPV疫苗的应用研究与现状。     

宫颈癌HPV预防性疫苗的研究进展

宫颈癌是导致全球妇女死亡的主要肿瘤之一.一定型别的人乳头瘤病毒(HPV)感染是宫颈癌发生的必备条件,预防性HPV疫苗可大量减少与此相关的宫颈病变及宫颈癌发病率和死亡率.而由L1自我组装成的病毒样颗粒(VLPs)是预防性疫苗的最佳侯选者之一,肌肉注射VLP后可以产生很强的B细胞、T细胞介导的适应性免疫和中和抗体的天然免疫.VLP的Ⅱ期临床实验均取得可喜成果,Ⅲ期临床实验也在逐步进行.     

HPV感染对宫颈癌细胞中自噬的影响

自噬是一种高度调节的“自我消化”途径,参与生物的发育、生长等多种过程。细胞自噬的异常导致癌细胞的出现。宫颈癌的主要病因是高危型人乳头瘤病毒(HR-HPV)持续感染,但仅有病毒感染不足以致癌,迫切需要更深入地了解HPV生物学行为及其诱发宫颈癌的机制。自噬在HPV感染及诱发癌症过程中起着基础性的作用,同时HPV感染后也影响了宫颈细胞的自噬作用。HPV与自噬之间的联系促进了旨在抑制HPV感染的新型抗病毒策略的发展。多项研究证明自噬在促进HPV的生命周期和肿瘤进展中起到抑制作用,恢复HPV感染和癌变过程中宫颈细胞自噬反应对于抑制HPV诱发的宫颈疾病具有重要意义。这在构建预防HPV感染和治疗HPV感染的宫颈癌疫苗中也具有临床价值。综述关于致癌的HR-HPV如何影响自噬的最新发现,为今后寻求有效靶向自噬的方法治疗HPV感染导致的宫颈疾病提出新的思路。     

人乳头瘤病毒预防性疫苗现状和问题

宫颈癌在妇女恶性肿瘤中的发病率仅次于乳腺癌。持续性高危型人乳头瘤病毒（HPV）感染导致了几乎所有浸润性宫颈癌的发生。人乳头瘤病毒与宫颈癌之间较为明确的病因学联系使得人乳头瘤病毒预防性疫苗的研发有望从“源头”上遏制宫颈癌。由于病毒型别特异性，人群筛查宫颈癌仍然占有重要地位。目前，第一代人乳头瘤病预防性疫苗的实际推广应用面临许多争议和需要解决的问题。     

宫颈癌的相关免疫治疗及进展

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。     

子宫颈癌疫苗的研究进展

子宫颈癌是妇科常见的恶性肿瘤之一。人乳头状瘤病毒（human papilloma virus,HPV）的持续感染与子宫颈癌的发生密切相关。HPV疫苗在预防和治疗宫颈癌方面备受关注。HPV疫苗能激发机体的细胞和体液免疫应答,有效的预防和控制HPV感染,在预防和治疗宫颈癌方面发挥作用。新型预防性HPV疫苗已在多个国家已经上市;多肽疫苗、蛋白疫苗、病毒载体疫苗、DNA疫苗等治疗性疫苗的研究也有新的进展。现对HPV疫苗在预防和治疗子宫颈癌方面的最新研究进展做一综述。     

Human papillomavirus vaccines and adolescents

PURPOSE OF REVIEW: This review will describe human papillomavirus (HPV) vaccines in development, summarize data regarding safety and efficacy of these vaccines, and discuss key issues related to HPV vaccine implementation. RECENT FINDINGS: Evidence from epidemiologic and genetic studies has confirmed that HPV infection is a necessary cause of cervical cancer and contributes to the development of other cancers. HPV infection also may cause nonmalignant conditions such as external genital warts and recurrent respiratory papillomatosis. Over the past decade, several vaccines that target common HPV types have entered clinical trials. These vaccines are classified as prophylactic or therapeutic. The goal of prophylactic vaccines is to prevent primary or persistent HPV infections, and thus prevent cervical cancer and/or genital warts. Recent evidence indicates that prophylactic vaccines are well tolerated, highly immunogenic and effective in preventing persistent HPV infection and cervical intraepithelial neoplasia (CIN). Questions remain, however, concerning vaccine efficacy against HPV-related diseases other than cervical cancer, the duration of protection, vaccine acceptability and feasibility of vaccine delivery in the developing world. The goal of therapeutic vaccines is to prevent progression of HPV infection, induce regression of CIN or condylomata, or eradicate residual cervical cancer. Although therapeutic vaccines appear to induce both humoral and cell-mediated immunity, they have not consistently demonstrated clinical efficacy. SUMMARY: HPV vaccines in development have the potential to reduce the substantial morbidity and mortality associated with cervical cancer and other HPV-associated diseases. Large-scale efficacy studies that are planned or underway will provide additional information about vaccine tolerance and efficacy.     

The impact of anti HPV vaccination on cervical cancer incidence and HPV induced cervical lesions: consequences for clinical management

Cervical cancer is the second most common cause of cancer-related deaths in women worldwide. Screening for cervical cancer is accomplished utilizing a Pap smear and pelvic exam. While this technology is widely available and has reduced cervical cancer incidence in industrialized nations, it is not readily available in third world countries in which cervical cancer incidence and mortality is high. Development of cervical cancer is associated with infection with high risk types of human papillomavirus (HPV) creating a unique opportunity to prevent or treat cervical cancer through anti-viral vaccination strategies. Several strategies have been examined in clinical trials for both the prevention of HPV infection and the treatment of pre-existing HPV-related disease. Clinical trials utilizing prophylactic vaccines containing virus-like particles (VLPs) indicate good vaccine efficacy and it is predicted that a prophylactic vaccine may be available within the next five years. But, preclinical research in this area continues in order to deal with issues such as cost of vaccination in underserved third world populations. A majority of clinical trials using therapeutic agents which aim to prevent the progression of pre-existing HPV associated lesions or cancers have shown limited efficacy in eradicating established tumors in humans possibly due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Future trends in clinical trials with therapeutic agents will examine patients with early stage cancers or pre-invasive lesions in order to prevent invasive cervical cancer. Meanwhile, preclinical studies in this field continue and include the further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. Given that cervical cancers are caused by the human papillomavirus, the prospect of therapeutic vaccination to treat existing lesions and prophylactic vaccination to prevent persistent infection with the virus are high and may be implemented in the near future. The consequences for clinical management may include a significant reduction in the frequency of Pap smear screening in the case of prophylactic vaccines, and the availability of less invasive and disfiguring treatment options for women with pre-existing HPV associated lesions in the case of therapeutic vaccines. Implementation of both prophylactic and therapeutic vaccine regimens could result in a significant reduction of health care costs and reduction of worldwide cervical cancer incidence.     

Harnessing the power of prevention: human papillomavirus vaccines

Human papillomavirus (HPV) infection and HPV-associated diseases pose a considerable health care burden in the United States. The morbidity and mortality associated with HPV infection and HPV-associated diseases, ranging from genital warts to cervical cancer, have prompted both the use of screening measures to monitor HPV infection and the development of numerous treatment modalities to address its clinical sequelae. Although screening programs have dramatically reduced the incidence of cervical cancer through early detection and treatment, this devastating illness, which frequently affects women of reproductive age, remains a major public health concern. Prophylactic vaccines that prevent HPV infection have proved to be safe, well tolerated, highly efficacious, and induce long-lasting immunity to HPV. Multivalent vaccines that protect against the most common disease-causing HPV types should significantly reduce the morbidity and mortality associated with HPV.     

HPV vaccination: principles, results and future perspectives

Human papillomavirus (HPV) are responsible of an important morbidity and mortality. HPV is a significant source of morbidity and mortality. HPV is the most common sexually transmitted infection: adolescents are at high-risk for HPV acquisition. Biologic and epidemiologic studies have demonstrated that HPV infection is a necessary but non-sufficient cause of cervical cancer and genital warts. The vast majority of cervical cancers contain high-risk HPV type and approximately 70% contain HPV types 16 or 18. HPV types 6 or 11 are responsible for approximately 90% of genital warts. Thus, a vaccine that could prevent. Prophylactic vaccines based on the use of virus-like particles (VLPs) obtained by auto-assembly of L1 are under clinical trials. Two vaccines are currently evaluated: Cervarix (GlaxoSmithKline Biologics), a bivalent vaccine against HPV 16 and 18, and Gardasil (Merck & Co) a quadrivalent vaccine against HPV 16, 18, 6, and 11. Phase I, II and III studies have demonstrated that both vaccines are well tolerated and provide an excellent immunogenicity. With approximately 5-year follow-up, both vaccines have been effective in preventing persistent infection with targeted HPV types and in preventing cervical intraepithelial lesions. The optimal target for vaccination is probably 12-year-old girls.     

Update on human papillomavirus vaccination: Where are we now?

Infection with human papillomavirus (HPV) is the major cause of pre-invasive and invasive lesions of the urogenital tract, resulting in morbidity and mortality worldwide. HPV-related infection is responsible for most cases of cervical cancer, a leading cause of cancer death in women worldwide. Developed countries have screening programs in place to detect precancerous lesions at early stages; in resource-limited settings however, HPV related diseases are often identified in advanced stages. This is due to limitations in the availability and roll out of effective screening programs. The relatively recent availability of the HPV vaccine has provided a new public health opportunity to decrease the incidence of HPV-related disease. The high mortality rates seen in developing countries could be reduced through effective implementation of HPV vaccination programs. Large trials have proven the efficacy of bivalent, quadrivalent vaccine and most recently 9-valent vaccine. Uptake in vaccination remains low due to multiple barriers including lack of education, lack of access, and costs. New strategies are being assessed to increase access, increase knowledge and reduce costs that may result in feasible vaccination programs worldwide. The goal of this article is to review the effectiveness and safety of the current HPV vaccines available, vaccine delivery strategies, cost effectiveness, and efforts to improve the acceptability. A literature search was conducted through PubMed using the terms “HPV vaccination, and safety, and males, and acceptability and strategies, and cost effectiveness,”focusing on articles published between 2006 and 2015. The most relevant and larger scale trials were evaluated for discussion.     

The role of human papillomavirus vaccines in cervical neoplasia

Cervical cancer is the second most common cause of cancer-related death in women, in some developing countries accounting for the highest cancer mortality. The evidence for the association of high-risk human papillomavirus types with the aetiology of cervical neoplasia is firmly established, human papillomavirus being detected in virtually all cervical cancers. The risk of progression of precursor cervical intra-epithelial neoplasia lesions is associated with persistence of human papillomavirus infection. One strategy for the management of cervical neoplasia worldwide could be the development of prophylactic and/or therapeutic human papillomavirus vaccines. This chapter will discuss the natural history of human papillomavirus infection, viral immunity and the clinical course of resultant disease as the background to the effective design and use of human papillomavirus vaccines for protection or therapy. The progress of ongoing phase I and II clinical trials for several different vaccine preparations and the challenges for establishing their future use will be discussed.     

New advances in vaccine technology and improved cervical cancer prevention

Cervical cancer, which is caused by oncogenic types of the human papillomavirus (HPV), is the second most common cancer in women, responsible for 274,000 deaths worldwide in 2002. Approximately 70% of all cervical cancers are caused by the two most common oncogenic HPV types, HPV-16 and HPV-18; another 10% are caused by the next most common types, HPV-45 and HPV-31. Therefore, vaccines designed to prevent infection with oncogenic HPV types have the potential to decrease morbidity and mortality associated with cervical cancer and precancerous lesions. Vaccinology research recently has developed tools that may be used to improve the safety and efficacy of vaccines, and several of these tools have been used in the development of HPV vaccines. These advances include new insight into antigen selection, inclusion of adjuvants designed to enhance the immunogenicity of vaccines, and investigation into alternative routes of administration. Clinical studies of HPV vaccines that take advantage of these technological advances have reported excellent safety, immunogenicity, and efficacy results for prevention of HPV infection and incidence of associated cytopathologic abnormalities.     

Cytology and DNA HPV-testing in the era of HPV-vaccine

Human papillomavirus (HPV) persistent infection is the main factor leading to the cervical cancer carcinogenesis. Wide-spread public vaccination against HPV as primary prevention is expected to reduce cervical cancer incidence and mortality rates. It is essential to bear in mind that screening for precancerous lesions cannot be discontinued because vaccination will not protect the patients against HPV types which have not been included in the first and second generation of vaccines.     

Cervical cancer prevention: the impact of HPV vaccination

Cervical cancer remains a critical public health problem that is second only to breast cancer in overall disease burden for women throughout the world. In spite of the success of cervical cancer screening, Pap cytology screening is yet to be effectively implemented or has failed to reduce cervical cancer rates to an appreciable extent. Screening appears to benefit only a small fraction of women although a much larger percentage endures the inconvenience of the Pap test in order to avoid cervical cancer. The establishment of Human Papillomavirus (HPV) infection as the necessary cause of cervical precancers and cancers provides a tremendous opportunity for cervical cancer prevention through vaccination. HPV 16 and 18 which cause 70% of cervical cancers worldwide. Thus a prophylactic vaccine to prevent HPV related precancerous lesions and cancers would save lives, reduce the need for costly medical procedures and provide both women and communities throughout the world with substantial benefits. Based on the induction of neutralizing antibodies by non infectious Virus Like Particles (VLP) of L1 capside protein, prophylactic HPV vaccines have consistently induced high titter of neutralizing antibodies with minimal side effects and induce more than 90% protection from persistent HPV 16-18 infection and HPV 16 and 18 associated high-grade Cervical Intraepithelial Neoplasia (CIN) in proof of concept efficacy trials. HPV 16-18 vaccination will prevent HPV16-18 incident infection, and subsequently decrease in 90% the frequency of abnormal Pap attributable to these types and in about 50% overall abnormal Pap. HPV vaccination will reduce the number of women who require colposcopy, biopsy and cervical treatment for precancerous cervical lesions. The level of protection from death due to cervical cancer could exceed 95%. Three large phases prophylactic HPV VLP trials are now in progress and will form the basis for licensing of candidate vaccines in 2006. HPV vaccination targeting young female adolescents, aged 11 to 16 years, with a catch-up of those aged 17-25 years, would be a strategy to be addressed. Cervical cancer screening strategies, that will be cost-effective for the proper surveillance of women protected by HPV vaccination, are under analysis.     

The quadrivalent human papillomavirus vaccine: potential factors in effectiveness

Cervical cancer, caused by human papillomavirus (HPV) infection, is the second most common female cancer in the world, causing over a quarter of a million deaths worldwide every year. The quadrivalent HPV vaccine (Gardasil) has the potential to significantly reduce morbidity and mortality associated with cervical disease. However, a variety of factors affect the vaccine's success, including exposure to HPV prior to vaccination, duration of protection provided by the vaccine, the in vivo interaction between HPV serotypes, and variation in HPV serotype prevalence worldwide. This article describes the pathophysiology of HPV infection, efficacy and safety of the quadrivalent HPV vaccine, factors that may influence the vaccine's effectiveness in reducing cervical cancer rates, and recommendations for maximizing this effectiveness.