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.     

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.     

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.     

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.     

Human papillomavirus infection: an old disease, a new vaccine

Human papillomavirus (HPV) infection is common and causes a wide spectrum of disease. With recent advances in the development of prophylactic HPV vaccines, it is likely that these will be licensed for use in the near future. This review focuses on the science behind HPV vaccines, published clinical trial results for both prophylactic and therapeutic HPV vaccines, important issues relevant to implementation and cost-effectiveness models of HPV vaccination programs. It may be that an HPV vaccine that protects against the complications of HPV infection such as cervical cancer will be one of the most significant public health initiatives of this decade.     

Benefits, cost requirements and cost-effectiveness of the HPV16,18 vaccine for cervical cancer prevention in developing countries: policy implications

Approximately 70% of cases of cervical cancer worldwide are caused by genotypes 16 and 18 of human papillomavirus (HPV), which is sexually transmitted. With the availability of an effective vaccine against these HPV types, there is real hope for reducing the global burden of cervical cancer in developing countries. Stakeholders faced with decisions about where to invest money to improve health must consider the burden of disease caused by cervical cancer relative to other priorities and the comparative benefits of different interventions. We conducted a series of analyses to obtain information for agencies drafting immunisation policy recommendations, financing coordination mechanisms, and country decision-makers on the benefits, cost requirements and cost-effectiveness of the HPV16,18 vaccine. We found that making an HPV16,18 vaccine accessible to 70% of young adolescent girls in 72 of the poorest countries, China, Thailand, and all of Latin America and the Caribbean, could prevent the future deaths of more than four million women vaccinated over the next decade. Provided the cost per vaccinated girl is less than $10-$25, adolescent HPV16,18 vaccination would be cost-effective even in relatively poor countries. Concerns about financial costs and affordability highlight the need for lowering vaccine prices, cost-efficient mechanisms for delivery of vaccinations to adolescents, and creative sources of financing.     

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。     

History of human papillomavirus, warts and cancer: what do we know today?

Human papillomavirus has been a cause of infection in humans for thousands of years. The history of papillomaviruses, knowledge of their causative role in benign and malignant disease, and their structural characteristics have led to the development of vaccines to prevent cervical and anogenital cancers. Many questions remain unanswered before HPV vaccines can be optimised; however, the concept of virtual eradication of cervical cancer is not impossible, and remains a realistic aspiration.     

The use of vaccines in treating cervical cancer: present status and future prospects

Abstract. Onon TS, Kitchener HC. The use of vaccines in treating cervical cancer: Present status and future prospects.
HPV types are carcinogenic agents in cervical cancer. This view is supported by epidemiological and biological evidence. The oncogenic products and capsid proteins of high risk HPV types are potential targets against which effective immunity may be generated by vaccination. Both therapeutic and prophlylactic immunisation are potential strategies to deal with the widespread problem of HPV infection and possibly established cervical neoplasia. Clinical trials are now underway to evaluate candidate vaccines.     

Human papillomavirus

Human papillomaviruses are ancient small DNA viruses and represent the most common sexually transmitted infection in the world. In the majority, HPV infection is cleared by an incompletely understood immune response. HPV is a necessary but not sufficient cause of cervical cancer, and responsible for a proportion of other anogenital cancers including vulval, vaginal, anal and oropharyngeal. Oncogenesis is likely mediated through viral proteins which hijack host-cell machinery in epithelial keratinocytes and disrupt host tumour-suppressor proteins. Much work has been undertaken to further characterise the natural history of HPV infection and cervical disease. Such efforts have been translated to important public health interventions like the introduction of HPV tests in cervical screening. HPV vaccination programmes are expected to further reduce the incidence of high-risk HPV infections and resultantly HPV-related disease.     

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.     

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.     

At what age should we be vaccinating for human papillomavirus?

Human papillomavirus (HPV) infections cause high disease burden. Primary prevention by vaccination is a major breakthrough. HPV vaccines are well tolerated and safe. Vaccines protect unexposed individuals against high-grade CIN and VIN/VaIN caused by the vaccine HPV types. Vaccines also provide protection against related oncogenic HPV types. The primary target population is young adolescents before their sexual debut. Catch-up vaccination policy up to age 26 may facilitate long-term health benefits but should not divert resources from vaccinating the primary target population or from effective cervical cancer screening programmes. Health benefits of vaccinating older age groups beyond age 26 are unknown.     

A study of women's knowledge regarding human papillomavirus infection, cervical cancer and human papillomavirus vaccines

AIMS: Human papillomavirus (HPV) infection is a common sexually transmitted viral infection and is associated with the development of cervical cancer. HPV vaccines are now undergoing phase 3 clinical trials in Australia. It is likely that an HPV vaccine will become licensed for use in the near future. METHODS: Ninety women aged 18-30 years from three different groups (those attending a dysplasia clinic, a local university health service and participants currently involved in a phase 3 HPV vaccine trial) completed a questionnaire assessing their knowledge base regarding HPV infection, cervical cancer, Pap tests and HPV vaccines. RESULTS: Respondents demonstrated good understanding of the Pap test and interpretation of an abnormal result. Most respondents (89%) had heard of HPV and attributed a number of different clinical symptoms to infection. For women who had not heard of an HPV vaccine, 79% of respondents stated that the most common resource they would use to obtain further information is their general practitioner. DISCUSSION: Many women do not understand the risk factors for HPV infection, the clinical problems it may cause and the potential long-term complications of infection. Few women have heard of a HPV vaccine, but most women surveyed would approach their general practitioner for more information if one became available. CONCLUSION: This study highlights the need for further education regarding HPV infection and the potential long-term complications such as cervical cancer. It also demonstrates that education of general practitioners regarding an HPV vaccine is essential, as this is the most likely resource women will use to obtain further information in the future.     

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.     

New Developments in Therapeutic HPV Vaccines

Human papillomavirus (HPV) infection is the central causal factor in cervical cancer. For years efforts were undertaken to control HPV-associated disease by the development of HPV vaccines. While prophylactic HPV vaccination represents a major public health breakthrough, it is limited to new infection by certain HPV types and does not have therapeutic effects or prevent progression of pre-existing HPV infections to malignancy. Thus, there is an urgent need for therapeutic HPV vaccines. Therapeutic vaccines aim to induce cytotoxic T cells, facilitating clearance of HPV high-grade lesions and cancers. HPV E6 and E7 oncogenes represent ideal antigens for therapeutic HPV vaccination because of their constitutive expression in HPV-containing carcinomas and their critical role in the induction and maintenance of HPV-associated disease. This review discusses the most recent advances in HPV therapeutic vaccines and summarizes effects of new basic immunology findings and vaccine delivery technologies.     

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.     

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.     

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.     

Human papillomavirus type 18 and other risk factors for cervical cancer in Jakarta, Indonesia

Infection with human papillomavirus (HPV) has now been established as a necessary cause of cervical cancer. Indonesia is a country with a high cervical cancer incidence and with the world's highest prevalence of HPV 18 in cervical cancer. No information exists about the prevalence of HPV 18 or other HPV types in the Indonesian population. We conducted a hospital-based case-control study in Jakarta, Indonesia. A total of 74 cervical carcinoma cases and 209 control women, recruited from the gynecological outpatient clinic of the same hospital, were included. All women were HPV typed by the line probe assay, and interviews were obtained regarding possible risk factors for cervical cancer. HPV was detected in 95.9% of the cases and in 25.4% of the controls. In the control group, 13.4% was infected with a high-risk HPV type. HPV 16 was detected in 35% of the case group and in 1.9% of the control group and HPV 18 was identified in 28% of the case group and in 2.4% of the control group, suggesting that the oncogenic potentials of HPV 16 and HPV 18 in Indonesia are similar. In addition to HPV infection, young age at first intercourse, having a history of more than one sexual partner, and high parity were significant risk factors for cervical cancer. Within the control group, we did not identify determinants of HPV infection. We hypothesize that the high prevalence of HPV 18 in cervical cancer in Indonesia is caused by the high prevalence of HPV 18 in the Indonesian population.