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.     

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。     

Human Papillomavirus (HPV), HPV-Related Disease, and the HPV Vaccine

Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States, and persistent HPV infection is strongly associated with risk of cervical cancer and genital warts. The recently approved quadrivalent HPV vaccine targets the HPV strains responsible for approximately 70% of cervical cancers and 90% of genital warts. It is also effective in reducing the incidence of HPV-related conditions, especially when given prior to exposure to HPV. The vaccine is recommended for all girls aged 11 to 12 with catch-up vaccination for women up to age 26, and most insurance plans cover the vaccine. A second bivalent HPV vaccine is currently pending approval by the US Food and Drug Administration (FDA). HPV vaccination reduces the incidence of HPV-related cancers and precancerous lesions in the United States and abroad, though decisions regarding implementation of vaccination remain.     

Cervical cancer prevention in the era of prophylactic vaccines: a preview for gynecologic oncologists

OBJECTIVE: The recent approval of a vaccine to prevent HPV infection is an important advance in cervical cancer prevention. This article is intended to provide gynecologic oncologists with a comprehensive background in modern cervical cancer prevention strategies. METHODS: We describe and contrast the quadrivalent and bivalent vaccines. More established cervical cancer prevention strategies are reviewed, with comments on the impact of HPV vaccination. Clinical guidance is provided for use of the approved quadrivalent vaccine. Safety and side effects of both vaccines are reviewed and future questions and challenges are explored. RESULTS: It is vitally important that both vaccinated and unvaccinated women continue to fully engage in cervical cancer prevention, including cervical cancer screening, follow-up of abnormal screens, and treatment of premalignant lesions. A quadrivalent virus-like particle vaccine has now been approved for use in girls and women ages 9 to 26. A bivalent vaccine may be available soon. Vaccine efficacy in clinical trials has been outstanding, with 100% protection against HPV-type-specific cervical intraepithelial neoplasia (CIN) II and III. CONCLUSIONS: Comprehensive cervical cancer protection now includes prophylactic vaccination for girls and young women in addition to screening and treatment of premalignant changes. Gynecologic oncologists will continue to play an important role in promoting optimal prevention practices.     

四价HPV疫苗预防宫颈癌、HPV感染相关疾病Meta分析

目的：评价四价人乳头瘤病毒（HPV）疫苗预防宫颈癌及HPV相关感染与疾病的有效性与安全性。方法：计算机检索Cochrane图书馆、MEDLINE,EMBASE,NGC和CBM,纳入所有关于四价HPV疫苗的随机对照试验（RCT）,2名研究者独立提取数据并进行方法学质量评估。试验数据的统计分析采用Cochrane协作网提供的RevMan4．2软件。结果：共纳入5项RCT,包括23617例女性。Meta分析结果显示：与安慰剂相比,预防性四价疫苗明显降低与HPV6,11,16和18型相关的Ⅱ,Ⅲ级宫颈上皮内瘤样变、原位癌及Ⅱ／Ⅲ级外阴、阴道上皮内瘤样变和外生殖器疣的发病率。主要不良反应较轻微。严重不良反应在疫苗组和安慰剂组保持均衡。结论：四价HPV疫苗对预防相关类型HPV所致宫颈癌及外生殖器病变安全有效。     

四价HPV疫苗预防宫颈癌、HPV感染相关疾病Meta分析

目的：评价四价人乳头瘤病毒（HPV）疫苗预防宫颈癌及HPV相关感染与疾病的有效性与安全性。方法：计算机检索Cochrane图书馆、MEDLINE,EMBASE,NGC和CBM,纳入所有关于四价HPV疫苗的随机对照试验（RCT）,2名研究者独立提取数据并进行方法学质量评估。试验数据的统计分析采用Cochrane协作网提供的RevMan 4.2软件。结果：共纳入5项RCT,包括23 617例女性,Meta分析结果显示：与安慰剂相比,预防性四价疫苗明显降低与HPV6,11,16和18型相关的Ⅱ/Ⅲ级宫颈上皮内瘤样变、原位癌及Ⅱ/Ⅲ级外阴、阴道上皮内瘤样变和外生殖器疣的发病率。主要不良反应较轻微,严重不良反应在疫苗组和安慰剂组保持均衡。结论：四价HPV疫苗对预防相关类型HPV所致宫颈癌及外生殖器病变安全有效。     

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 prophylactic vaccines: stakes and perspectives

Human Papillomavirus (HPV) infection is established as the necessary cause of cervical precancers and cancers. To date, more than 120 genotypes are known, but only high risk oncogen genotypes could induce a cancer. HPV 16 and 18 are implied in nearly 70% of cervical cancer around the world. Although some persistent HPV infections progress to cervical cancer, host immunity is generally able to clear most HPV infections providing an opportunity for cervical cancer prevention through vaccination. Candidate prophylactic vaccines based on papillomavirus L1 virus-like particles (VLPs) are currently on human clinical trials: one targeting cervical cancer with a bivalent VLP L1 vaccine containing the two genotypes most frequently involved in cervical cancer (type 16 and 18) and the other, protecting against warts as well as cervical cancer, with a quadrivalent HPV VLP L1 vaccine containing genotypes 6, 11, 16 and 18. The first clinical trials revealed the satisfactory tolerance and excellent immunogenicity of these vaccines inducing high serum antibody titers with minimal side effects. After more than three years, both clinical trials on women 15 to 25 years old have shown that vaccines are able to type specifically protect against nearly 90% of infection and all cervical intra-epithelial neoplasia. The vaccinal strategy defined to date targets preadolescents and adolescent young females (11-13 years) before the first sexual course but some questions are still not resolved concerning the prescriber, the actors of the vaccination and the duration of the protection. Nevertheless cervical cancer screening should be carried on for many years, even if a large vaccinal strategy is decided. Such a vaccine would save lives and reduce the need for costly medical procedures and the psychological stress induced by this cancer.     

The HPV vaccine mandate controversy

In this editorial we address the controversies surrounding human papillomavirus (HPV) vaccine school-entry mandate legislation, but differentiate between the mandate debate and issues specific to the vaccine itself. Our goal is not to take a stand in favor of or opposed to mandates, but rather to critically examine the issues. We discuss the following arguments against HPV vaccine school-entry requirements: 1. The public health benefit of mandated HPV vaccination is not sufficient to warrant the intrusion on parental autonomy; 2. A vaccine that prevents a non-casually transmitted infection should not be mandated; 3. Opt-out provisions are inherently unfair to parents who oppose HPV vaccination; 4. Limited health care dollars should not be directed toward cervical cancer prevention; and 5. The vaccine is expensive and potential problems with supply suggest that mandates should not be implemented until insurance coverage and supply issues are resolved. Next, we critically evaluate the following critiques of HPV vaccination itself: 1. Giving girls HPV vaccine implies tacit consent to engage in sexual activity; 2. Giving girls this vaccine will confer a false sense of protection from sexually transmitted infections and will lead to sexual disinhibition; 3. Children already have too many vaccinations on the immunization schedule; 4. Long-term side effects of HPV vaccine are unknown; 5. The vaccine's enduring effectiveness is unknown and booster shots may be required; and 6. It is wrong to only target girls with HPV vaccine; boys should be vaccinated as well.     

Human papillomavirus vaccines: an update for gynecologists

Human papillomavirus (HPV) infections cause several common gynecologic problems. Oncogenic HPV infections are responsible for abnormal cervical cytology, cervical dysplasia, and cervical cancer. In 2006, a vaccine was introduced to prevent these common problems in women's health. The currently available HPV vaccine is quadrivalent, with HPV types 6, 11, 16, and 18. Recently published clinical trials have consistently shown efficacy approaching 100%. Current clinical recommendations are for universal vaccination of adolescent and young adult women. This review will discuss the natural history and epidemiology of HPV, the diseases associated with these infections and current clinical usage of this vaccine. Future developments in this area will also be discussed.     

Cost-consequences evaluation between bivalent and quadrivalent HPV vaccines in Italy: the potential impact of different cross-protection profiles

Objectives

Two human papillomavirus (HPV) vaccines are currently available: a bivalent HPV-16/18 and a quadrivalent HPV-6/11/16/18 vaccine. The vaccines may have different sustained- and cross-protection levels against non-vaccine oncogenic HPV-types. This study investigated the potential difference in clinical and economic impacts provided by two HPV vaccines in Italy.

Methods

A prevalence-based model estimated the potential net difference in HPV-related lesions (abnormal pap smear, cervical intraepithelial neoplasia (CIN), cervical cancer (CC) and genital warts (GW)) and associated costs generated by the two vaccines. Incidence and treatment costs were obtained from Italian and European sources. Vaccine efficacy rates were based on published data for each vaccine. Lifetime vaccine efficacy was assumed. Results are reported over one year after reaching a steady state. Sensitivity analyses were performed on the lesion incidence, vaccine effectiveness, treatment costs and sustained protection.

Results

The bivalent vaccine would prevent an additional reduction of 7976 abnormal pap smears; 601 CIN1; 1826 CIN2/3 and 295 CC cases compared to the quadrivalent vaccine while 25,848 genital wart cases would be prevented by the quadrivalent vaccine. The additional cost averted with the bivalent vaccine was estimated at €2,385,354 per year compared to the quadrivalent vaccine. The most influential parameters were CC- and GW-related costs and the difference in sustained protection.

Conclusions

Our model suggests that, in the Italian setting, the bivalent vaccine would prevent more precancerous and CC lesions than the quadrivalent vaccine. This translates into a greater cost averted for the bivalent vaccine, which could completely offset savings in GW-related costs associated with the quadrivalent vaccine.     

Human papillomaviruses in Western Africa: prevalences and risk factors in Burkina Faso

Purpose

Cervical cancer is the most common cancer in women in low income countries. Certain oncogenic types of human papillomaviruses are causally associated with the cervical cancer. To ensure effective primary prevention through the introduction of a national vaccination program in Burkina Faso, information about the disease burden of HPV infection in the country is of great importance.

Methods

In the present work the prevalence of 54 different HPV types and 18 other sexually transmitted infection as well as the predominant risk factors for the development of cervical cancer were investigated in Ouagadougou. A cross-sectional study on two populations without (n=471) and with known cervical dysplasia (n=39) was carried out between October 2013 and March 2014. Retrospectively, data on possible and secured risk factors of the cervical carcinoma were collected. The participants were examined gynecologically and a vaginal lavage was taken, which was molecular genetically examined for 54 different human papillomavirus genotypes and 18 other STIs.

Results

The prevalence of human papillomavirus was 42.3% (188/444) in the first study population and 87.2% (34/39) in the second study population. The immunization coverage would be 24.5% of the HPV types and 33.9% of the high-risk HPV types with quadrivalent vaccine Gardasil®. The nonavalent vaccine Gardasil®9 (9vHPV) would cover 37.3% of all HPV types and 57.1% of high-risk HPV types.

Conclusion

The prevention of infection with human papillomaviruses by vaccination is expected to result in a drastic reduction in the morbidity and mortality of the cervical cancer in Burkina Faso.

     

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.     

Ethnically diverse female university students’ knowledge and attitudes toward human papillomavirus (HPV), HPV vaccination and cervical cancer

Objective

Cervical HPV is the most common sexually transmitted disease among college-age women. This study aimed to assess knowledge and attitudes towards HPV infection, HPV vaccination and cervical cancer among female university students, to provide insight into development of HPV educational information.

Study design

A cross-sectional survey using a convenience sample. A total of 1083 ethnically diverse female students attending a public university were approached and 650 were interviewed.

Results

Knowledge regarding HPV, HPV vaccination, cervical screening and cervical cancer risk factors was remarkably poor. Across the sample, the mean total knowledge score (14-item) was only 3.25 (S.D. ±2.41; 95% CI 3.07–3.44). Only 10.3% had heard of the newly released HPV vaccine. Approximately 48% of participants indicated an intention to receive an HPV vaccine. Intention to receive an HPV vaccine was significantly associated with knowledge of HPV and genital warts (OR 1.53; 95% CI 1.25–1.88), and knowledge of cervical screening and cervical cancer risk factors (OR 1.21; 95% CI 1.11–1.33). Of those who refused HPV vaccination, 50.9% doubted the safety and efficacy of the new vaccine, and 41.5% perceived themselves as not at risk of HPV infection.

Conclusion

The findings suggest that providing education about the etiology of cervical cancer and the HPV link is an essential component to enhance HPV vaccine uptake.     

Human papillomavirus and vaccination in cervical cancer

Cervical cancer is not only the most frequently reported cancer among women, but also the most common female genital tract neoplasm in Taiwan. Early detection is effective, because the development, maintenance and progression of precursor lesions (cervical intraepithelial neoplasia [CIN]) evolve slowly into invasive cancer, typically over a period of more than 10 years. It is now recognized that human papillomavirus (HPV) infection is a necessary cause for over 99% of cervical cancer cases. Advances in the understanding of the causative role of HPV in the etiology of high-grade cervical lesions (CIN 2/3) and cervical cancer have led to the development, evaluation and recommendation of HPV-based technologies for cervical cancer prevention and control. The prevention of HPV infection before the onset of CIN is now possible with recently available prophylactic HPV vaccines, e.g. the quadrivalent Gardasil (Merck & Co., NJ, USA) and bivalent Cervarix (GlaxoSmithKline, London, UK). This review article provides an up-to-date summary of recent studies and available information concerning HPV and vaccination in cervical cancer.     

Anti human papillomavirus vaccine: the checkmate to human papillomavirus?

Cervical cancer is the second most frequently found neoplasia in women worldwide. At least 95% of cervical cancers contain viral DNA which, in 80% of cases, belongs to one of the human papillomavirus (HPV) viral types at high oncogenic risk: 16, 18, 31 and 45. HPV is, at this point, considered the first "necessary cause" of cervical cancer, against which primary prevention with a reduction in the risk of infection can be carried out. Numerous molecular biological studies have been conducted to identify the biological markers of this infection and to refine an effective and well tolerated vaccine capable of preventing HPV infection as well as possibly treating those cases in which the infection has already caused an HPV-related disease of the genital tract. In the near future, the real primary prevention of this disease will be conducted, similar to what occurred for Hepatitis B, using immunoprophylaxis with an anti-cancer vaccine.     

HPV Vaccine: How Far have We Achieved?

Globally, cervical cancer is the second most common cancer, and in India, it is the most common cancer in women. Human Papilloma virus (HPV) is the main cause of it. Although there are several methods for preventing cervical cancer, primary prevention by vaccination is the most effective option. HPV vaccine is safe and effective. It is expensive and is not a replacement for periodic cervical screening procedures. In developing countries, the cost effectiveness of vaccine and that of effective screening program with broader coverage is questionable. Today, HPV vaccine with regular cervical cancer screening program is the best possible tool to prevent cervical cancer.     

Human papillomavirus vaccination in the United Kingdom: what about boys?

In September 2008 the UK Department of Health initiated a human papillomavirus (HPV) immunisation programme for girls aged 12-13 for prevention of cervical cancer, which is most often caused by two HPV types. An important question, yet to be addressed, is whether boys should also be vaccinated. Men also get HPV and transmit it sexually, not just women. Certain HPV types are associated with genital warts, which have significant morbidity, and with difficult to treat non-cervical malignancies, including vulval, penile, anal and oro-pharyngeal cancer, which are best prevented through vaccination. Moreover, increased persistence of HPV infection is associated with HIV infection. A review of the literature and evidence from modelling suggest that vaccinating boys would increase vaccination impact and may be necessary to achieve herd immunity targets. Excluding boys sends the wrong message that girls and women alone are responsible for sexual health. Although protective efficacy of the vaccine in men has not yet been fully established, the rationale for vaccinating boys as well as girls at an early age is strong, assuming efficacy is established. Meanwhile, provision of the quadrivalent vaccine should become UK policy, in order to include protection against genital warts, the argument for which is strengthened if boys are also vaccinated.     

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.     

Prävention des Zervixkarzinoms

Cervical carcinoma is one of the most frequent malignancies in women worldwide. Secondary prevention of cervical carcinoma is traditionally achieved by cytological smears (PAP smear) and colposcopy. Since it became known that infections with human papillomavirus (HPV) were responsible for nearly all cases of cervical cancer, primary prevention through protection against HPV infection of the genital tract has become extremely important. A vaccine against HPV has been available in Germany since 2006. In comparison to other malignancies there are several possibilities to prevent cervical carcinoma. As the cervix is visible by vaginal inspection using high magnification (colposcopy) alterations can be directly visualized. Because the infectious origin is now known a protection against infection can be administered. Finally it is thought that a tumor needs at least 10 years to develop, therefore an intervention long before the development of malignant transformation is possible.