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.     

Human papillomavirus (including vaccination)

Human papillomavirus (HPV) is responsible for 99.7% of cervical cancer. Worldwide, cervical cancer causes more deaths than any other cancer, almost two per minute. Over 200 types of HPV have been identified. HPV is transmitted by skin-to-skin contact. Most HPV infections are cleared by the immune system; persisting infections can cause intra-epithelial neoplasia and invasive disease. Prophylactic HPV vaccines have been developed and prevent disease caused by the included HPV types. Current vaccines could prevent 70–75% cases of cervical cancer. The UK, in 2008 added HPV vaccination to the national immunization programme. The vaccines are safe and well tolerated. It is likely that the benefits will be seen over a 15–20 year period. Tests for HPV have been developed and are being evaluated as to their possible role in clinical practice. Research is ongoing regarding therapeutic HPV vaccination and improving prophylactic vaccines to prevent more cases of cancer.     

Human papillomavirus update (including vaccination)

Human papillomavirus (HPV) is responsible for 99.7% of cervical cancer. Worldwide, cervical cancer causes more deaths than any other cancer, around one every two minutes. In the not so distant future cervical cancer may cause more deaths globally per year, (275,000 in 2008), than maternal deaths, (358,000 in 2008). Over 200 types of HPV have been identified. HPV is transmitted by skin-to-skin contact. Most HPV infections are cleared by the immune system; persistent infection may cause intraepithelial neoplasia and invasive disease.Prophylactic HPV vaccines prevent disease caused by the included HPV types and potentially prevent 70–75% cases of cervical cancer. The UK added HPV vaccination to the national immunization programme in 2008. The vaccines are safe and well tolerated. It is likely that the benefits will be seen over a 15–20 year period.Tests for HPV have been developed and are being evaluated as to their possible role in clinical practice.Research is ongoing regarding therapeutic HPV vaccination and second generation prophylactic vaccines to prevent more cases of cancer.     

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.     

Prevalence of human papillomavirus genotypes in women with cervical cancer in Papua New Guinea

ObjectiveProphylactic human papillomavirus (HPV) vaccines are currently not available in Papua New Guinea. Prior to introducing these vaccines, knowledge about the HPV genotypes present in cervical cancer in this region is necessary to determine whether the types covered by the 2 commercially licensed vaccines are the same as those in other regions of the world.MethodsFresh, frozen cervical biopsies from 70 women with cervical cancer in Papua New Guinea were collected over a 3-year period from 2006–2009. HPV genotypes were detected using the Genera PapType assay.ResultsOverall, 100% of the specimens were HPV DNA positive, with HPV types 16 and 18 being the most prevalent at 57.1% and 25.7% (95% CI, 0.45–0.68 and 0.17–0.37) respectively, followed by HPV 33 (10%; 95% CI, 0.05–0.19) and HPV 31 (4.3%; 95% CI, 0.01–0.12). Multiple genotypes were identified in 6 women (8.6%), with all biopsies containing HPV 16 and 1 other high-risk type.ConclusionThe 2 most prevalent HPV types identified in women with cervical cancer in Papua New Guinea correspond to global data. This suggests that the currently available HPV vaccines could potentially reduce the burden of HPV-related cervical cancer in Papua New Guinea significantly.     

Prophylactic human papillomavirus vaccines: the beginning of the end of cervical cancer

Persistent infection with one of the oncogenic human papillomavirus (HPV) types is a necessity for the development of cervical cancer. By HPV vaccination, cervical cancer could become a very rare disease. Two types of HPV vaccines can be distinguished: (i) therapeutic vaccines which induce cellular immunity targeted against epithelial cells infected with HPV and (ii) prophylactic vaccines inducing virus-neutralizing antibodies protecting against new but not against established infections. At present, several vaccines have been developed and tested in clinical trials. The vaccines are generally well tolerated and highly immunogenic. The current clinical data indicate that prophylactic vaccines are very effective against new persistent infections and the development of cervical intraepithelial lesions. The protection is type specific. However, the follow-up of the vaccination trials is still short. The effect of HPV vaccines on future cancer incidence will only be known after decades of follow-up. This article will address the status of recently terminated phase II and currently running phase III trials with prophylactic HPV vaccines.     

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（hrHPV）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。     

Prophylactic and therapeutic vaccine therapy in papillomavirus infections

HPV types are carcinogenic in cervical cancer. This view is supported by epidemiological and biological evidence. Knowledges of HPV gene expression, of natural history of cervical HPV infection and neoplasia and of tumoral antigenic expression have lead to develop two strategies for vaccine development: 1-Prophylactic vaccines of HPV infections. 2-Therapeutic vaccines aimed to control the tumor growth and even to cure the patient. After an update of natural history of cervical HPV infection, the different target of vaccine strategies. The first published trials will be presented.     

Epidemiology and Burden of Disease Associated with HPV Infection

Infection with certain types of human papillomavirus is associated with approximately 660,000 cancers and over 350 million cases of genital warts annually. This ubiquitous virus is transmitted by skin-to-skin contact, including through sexual contact. Of the 40 types infecting the anogenital tract, approximately 15 are considered carcinogenic, particularly types 16 and 18 which are the commonest types found in women diagnosed with invasive cervical cancer. HPV has oncogenic potential at the cervix, vagina, vulva, penis, anus, and certain head and neck cancers. Benign disease is expressed as genital warts and the very rare condition of laryngeal papillomatosis. Infection with oncogenic types of HPV is considered essential in nearly all invasive cervical cancers and a varying percentage of the other HPV-related cancers. Recently, two HPV vaccines, the bivalent and quadrivalent vaccines, have become commercially available and both have shown high immunogenicity and efficacy. The vaccine is prophylactic, and current recommendations are to administer the vaccines to girls 9–12 years of old and, in settings with increasing resources, to extend the target group to boys and to older girls up to 26 years. The combination of vaccine and screening has the potential to significantly reduce the burden of HPV-related disease.     

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.     

ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists. Number 61, April 2005. Human papillomavirus

More than 15 years ago, a relationship between human papillomavirus (HPV) infection and cervical cancer was recognized. Since then, important strides in understanding the virus have been made, particularly in the following areas: modes of transmission and risk factors associated with transmission; the oncogenic potential of specific viral types and the mechanism by which they cause cancer; and the spectrum of infection, ranging from asymptomatic carrier states to overt warts, preneoplastic lesions, and invasive cancer. Sophisticated new tests for the detection of HPV that hold great promise for improved screening for cervical cancer precursors and invasive cancer and for the triage of abnormal cervical cytology also have been developed. Understanding the immunology of HPV has allowed the development of new and more effective treatment modalities for HPV infection and the preliminary development of primary prevention modalities, including HPV vaccines.     

Prophylactic HPV vaccines

Infection with human papillomavirus (HPV), in particular HPV 16 and HPV 18, is the main cause of cervical cancer. Two prophylactic vaccines against types 6, 11, 16 and 18 have shown great promise in clinical trials, with recent results demonstrating 100% efficacy against persistent HPV infection and development of CIN up to five years of follow-up. One of these (Gardasil, recently licensed) contains all four HPV types, offering protection against genital warts (types 6 and 11) as well as cervical cancer. The other (Cervarix) contains types 16 and 18, targeting cervical cancer alone. Recent data suggest a degree of cross-protection, against types 31 and 45; this could significantly increase the level of protection afforded by the vaccines. It is envisaged that girls between 11 and 12 will be the target, and this is what has been recommended in the United States. There is still debate about the issue of vaccinating boys. A fundamental issue is the lack of education of both the public and health professionals about HPV. In theory, an HPV vaccine could prevent almost all cervical cancer, eventually removing the need for cervical smears. However, there is at least one whole generation of women for whom the vaccine will come too late, and who will continue to require screening.     

Cervical cancer vaccines: progress and prospects

Cervical cancer remains a leading cause of cancer-related mortality in women, particularly in developing countries. The causal association between genital human papillomavirus (HPV) infection and cervical cancer has been firmly established and the oncogenic potential of certain HPV types has been clearly demonstrated. In recognition of the causal association of cervical cancer with this sexually transmitted viral infection, substantial interest has arisen to develop effective prophylactic and therapeutic vaccines. Prophylactic strategies currently under investigation focus on the induction of effective humoral and cellular immune responses that are potentially protective against subsequent HPV infection. Papillomavirus-like particles have been synthesized to induce neutralizing antibody responses, and impressive immunoprophylactic effects have been demonstrated in both animals and humans. For the treatment of existing HPV infection, techniques to augment cellular immunity by enhancing viral antigen recognition are under investigation. Vaccines targeting the oncogenic proteins E6 and E7 of HPV-16 and -18 are the focus of current clinical trials for cervical cancer patients. It is hoped that the development of successful HPV-specific vaccines will diminish the costs of existing cervical cancer screening programs and reduce the morbidity and mortality associated with the treatment of cervical neoplasias.     

Population-based HPV vaccination programmes are safe and effective: 2017 update and the impetus for achieving better global coverage

Persistent oncogenic human papillomavirus (HPV) is the cause of cervical cancer, as well as cancers of the anus, penis, vulva, vagina and oropharynx. There is good evidence that prophylactic HPV vaccines are immunogenic and effective against targeted-type HPV infections and type-specific genital lesions, including high-grade cervical intraepithelial neoplasia (CIN), when administered prior to HPV infection. There is good evidence that HPV vaccines are safe in population usage, with the most frequent adverse event being injection-site reactions. There is evidence to support some cross-protection against non-targeted types occurring following the administration of HPV vaccines. There is limited evidence suggesting that HPV vaccines may be beneficial in preventing future disease in women treated for high-grade CIN. This chapter focuses on the accumulated evidence regarding the global use of the three licensed HPV vaccines including safety, immunogenicity, duration of protection, effectiveness, coverage to date and barriers to higher coverage.     

Strategies for the prevention of cervical cancer by human papillomavirus vaccination

As cervical cancer is causally associated with 14 high-risk types of human papillomavirus (HPV), a successful HPV vaccine will have a major impact on this disease. Although some persistent HPV infections progress to cervical cancer, host immunity is generally able to clear most HPV infections. Both cell-mediated and antibody responses have been implicated in influencing the susceptibility, persistence or clearance of genital HPV infection. There have been two clinical trials that show that vaccines based on virus-like particles (VLPs) made from the major capsid protein, L1, are able to type specifically protect against cervical intra-epithelial neoplasia and infection. However, there is no evidence that even a mixed VLP vaccine will protect against types not included in the vaccine, and a major challenge that remains is how to engineer protection across a broader spectrum of viruses. Strategies for production of HPV vaccines using different vaccine vectors and different production systems are also reviewed.     

人乳头瘤病毒疫苗的研究与临床应用

人乳头瘤病毒(HPV)感染是宫颈癌发生的必要原因之一,而全世界近70%的宫颈癌是由HPV16和18亚型导致,针对HPV16,18的预防性疫苗已经上市,针对HPV感染及宫颈癌的治疗性疫苗正在研究中。     

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。     

HPV infection and cervical carcinoma--epidemiology, detection and immunology

Certain molecularly defined types of human papillomaviruses (HPV) induce, by interaction with additional cofactors, cervical cancer. In comparison to infection with HPV, all risk factors identified to date are less important. In addition to HPV a not yet classified genetic predisposition is important. Identification of HPV in cervical smears is done by detection of viral DNA. PCR based methods have the highest specificity. Currently, first vaccination studies with therapeutic vaccines are performed and phase I/II trials for prophylactic vaccination show promising results.     

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 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.