Introducing human papillomavirus vaccines - questions remain

Genital human papillomavirus (HPV) infection and HPV-associated cervical and other anogenital cancers are significant public health problems. HPV 16 and HPV 18 are responsible for approximately 70% of all invasive cervical cancers worldwide. The first prophylactic HPV virus-like particle (VLP) vaccine against HPV types 6/11/16/18 was licensed in 2006 for girls and women aged 9-26 years. The second prophylactic HPV vaccine against HPV types 16 and 18 has been licensed this year. These vaccines are almost 100% effective in preventing infection and high-grade precancer associated with the HPV types included in the vaccine. The vaccines are well tolerated, safe, and highly immunogenic when given in three doses within 6 months. Efficacy of the vaccine against external vulvar and HPV-related vaginal lesions is also high. Even though the vaccine is highly effective against high-grade cervical, vaginal, or vulvar precancers, this only applies to women unexposed to these HPV types and only to high-grade intraepithelial lesions caused by these HPV types. Therefore, it is important to understand that the population impact of the vaccines will be much lower than vaccinating naive populations. Implementing HPV vaccine is a great opportunity but also a great challenge. However, mandatory HPV vaccination may raise many questions, and more answers are needed.     

Human papillomavirus, cervical cancer, and the vaccines

How are human papillomavirus (HPV), cervical cancer, and the recently developed HPV vaccines associated with each other? Human papillomavirus is a highly prevalent infection that is easily and unknowingly transmitted because of its asymptomatic nature and long incubation period. Infection requires skin-to-skin contact and is typically sexually transmitted. More than one-half of sexually active women acquire HPV, making it the most prevalent sexually transmitted disease. Cervical cancer ranks second in deaths from cancer among women in developing countries and kills nearly 4000 women in the United States annually. Several types of HPV have been strongly linked to causing cervical cancer and genital warts. Those causing cervical cancer are considered high-risk types and those causing genital warts are considered low-risk types. Until recently, prevention strategies included abstinence, condom usage, and early detection with a Papanicolaou test (Pap smear). New developments have led to 2 vaccines aimed at preventing the viral infection. One is a quadrivalent vaccine preventing infection from 4 HPV types (HPV types 6, 11, 16, and 18) (Gardasil). It is approved in the United States and Europe for the prevention of HPV-associated cervical cancers and genital warts in females between the ages of 9 and 26 years old. The second is a bivalent vaccine preventing infection from 2 high-risk oncogenic HPV types (HPV types 16 and 18) (Cervarix). It is currently under study and not yet available in the United States. Both vaccines have proven highly effective at preventing infection from their corresponding HPV types. Of importance, neither vaccine is to be used for treatment. Vaccination does not replace routine cervical cancer screening with Pap smears, as the vaccines do not protect against all HPV types.     

HPV vaccination with Gardasil: a breakthrough in women's health

Human papillomavirus (HPV) represents one of the most common sexually transmitted infections. Although infection is often self-limited, a percentage of women with HPV infection will go on to develop cervical precancerous or cancerous lesions. It is estimated that HPV16 is responsible for approximately half of all cervical cancers worldwide. Several studies have tested vaccines directed against specific HPV types, namely types 6, 11, 16 and 18. This paper reviews these studies, particularly focusing on a quadrivalent (type 6, 11, 16 and 18) HPV L1 virus-like particle vaccine under investigation in Phase III trials at present. Data indicate that this vaccine, referred to as Gardasil, can prevent precancerous cervical lesions and early in situ cervical cancers with few adverse effects, and the vaccine has been approved by the FDA for this indication. Another vaccine, HPV16 L1, directed solely against HPV16, has also been demonstrated to be effective (at present, follow-up has been for up to 48 months) in providing protection against persistent infection with this viral strain and preventing HPV16-related cervical intraepithelial neoplasia 2/3, while producing minimal adverse effects in recipients. Given the lack of a pharmacological intervention that can eradicate HPV in infected individuals and the prevalence of cervical cancer secondary to HPV infection across the world, the HPV vaccine represents a significant breakthrough in women's health.     

HPV vaccination with Gardasil®: a breakthrough in women’s health

Human papillomavirus (HPV) represents one of the most common sexually transmitted infections. Although infection is often self-limited, a percentage of women with HPV infection will go on to develop cervical precancerous or cancerous lesions. It is estimated that HPV16 is responsible for approximately half of all cervical cancers worldwide. Several studies have tested vaccines directed against specific HPV types, namely types 6, 11, 16 and 18. This paper reviews these studies, particularly focusing on a quadrivalent (type 6, 11, 16 and 18) HPV L1 virus-like particle vaccine under investigation in Phase III trials at present. Data indicate that this vaccine, referred to as Gardasil^®, can prevent precancerous cervical lesions and early in situ cervical cancers with few adverse effects, and the vaccine has been approved by the FDA for this indication. Another vaccine, HPV16 L1, directed solely against HPV16, has also been demonstrated to be effective (at present, follow-up has been for up to 48 months) in providing protection against persistent infection with this viral strain and preventing HPV16-related cervical intraepithelial neoplasia 2/3, while producing minimal adverse effects in recipients. Given the lack of a pharmacological intervention that can eradicate HPV in infected individuals and the prevalence of cervical cancer secondary to HPV infection across the world, the HPV vaccine represents a significant breakthrough in women’s health.     

Issues and challenges in implementing cervical cancer screenings in the emergence of HPV vaccination in Thailand

The discovery of the HPV vaccine has been a major breakthrough in preventing cervical cancer and other HPV-related diseases around the globe. Cervical cancer is a significant public health problem in Thailand. Despite the long-time availability of cervical cancer screening programs in Thailand, the uptake among the target female population remains low. HPV vaccines were approved by the Food and Drug Administration of Thailand in 2007. As of March 2011, due to financial limitations, HPV vaccines have still not been included in the national immunization program under the public health benefit plans although individuals has the option to pay privately for the vaccine. This paper discusses the issues and challenges in implementing cervical cancer screening programs in the era of HPV vaccination in Thailand. Recommendations to increase the uptake of cervical cancer screening and further research to inform a policy regarding the cervical cancer screening measures are proposed.     

Human papillomavirus vaccines

OBJECTIVE: To review the pharmacology, efficacy, safety, tolerability, and pharmacoeconomics of Cervarix and Gardasil, 2 human papillomavirus (HPV) vaccines. DATA SOURCES: English-language articles were obtained by MEDLINE search (1966-February 2006) using the key words human papillomavirus vaccine, Cervarix, and Gardasil. Bibliographies of selected articles were used to identify additional sources. STUDY SELECTION AND DATA EXTRACTION: All available published articles or abstracts reporting the results of human studies of HPV vaccines were reviewed for inclusion in this article. Additional information about ongoing clinical trials was obtained from manufacturers' Web sites. DATA SYNTHESIS: Cervarix and Gardasil are recombinant vaccines against HPV. Cervarix targets HPV-16 and -18, which are responsible for 70% of cervical cancers. Gardasil also targets HPV-16 and -18, plus the HPV-6 and -11 types responsible for more than 80% of genital warts. Both vaccines have been effective in preventing persistent infection with targeted HPV types and in preventing cervical intraepithelial lesions, while Gardasil has also been effective in preventing vulvar and vaginal neoplasia and genital warts. Both vaccines have been well tolerated, with the most common adverse effects occurring at the injection site. Phase III trials are ongoing to further evaluate vaccine efficacy. CONCLUSIONS: Cervarix and Gardasil are effective for prevention of HPV infection and cervical lesions. Issues remaining to be addressed include duration of protection, efficacy for prevention of cervical cancer, optimal age for vaccination, feasibility of application to the developing world, the ideal combination of HPV subtypes, and the most efficient combination of vaccination and cervical cancer screening.     

Human papillomavirus type 16 L1E7 chimeric capsomeres have prophylactic and therapeutic efficacy against papillomavirus in mice

Genital human papillomavirus (HPV) infection is the primary cause of cervical cancer in women. Although the HPV recombinant L1 protein was recently licensed as an available vaccine, it has numerous shortcomings. New vaccination strategies should be considered. To enable the design of a prophylactic and therapeutic low-cost vaccine candidate, chimeric HPV16 L1DeltaC34E7N1-60 capsomeres were produced in Escherichia coli. The immune characteristics and potential prophylactic and therapeutic effects of these capsomeres were examined in C57BL/6 mice. Following protein purification and renaturation, the majority of the recombinant chimeric proteins (L1DeltaC34E7N1-60) assembled into capsomeres. These capsomeres were able to induce conformational and neutralizing antibodies against HPV virus-like particles and trigger cell-mediated specific immune responses against the L1 and E7 peptides. In vivo tumor challenge assays showed that mice immunized with the capsomeres were protected against a challenge with both C3 and TC-1 tumor cells. Furthermore, in vivo tumor rejection assays showed that capsomeres have therapeutic efficacy in mice following inoculation with C3 and TC-1 tumor cells. Chimeric capsomeres are capable of preventing and eliminating HPV16 infection. Therefore, our study has provided an economical vaccine candidate.     

889例基于PCR反向点杂交技术的HPV检测回顾性分析

目的分析该院妇产科及泌尿外科就诊的患者HPV感染者比例,HPV高危及低危各亚型的分布及各年龄组高危型HPV优势亚型的分布特点,了解该地区HPV感染情况,为该地区宫颈癌的预防和针对该地区的疫苗研制提供参考依据。方法采用PCR反向点杂交技术检测2014-2015年来该院就诊的889例女性患者宫颈脱落细胞,共检测26种HPV亚型,其中高危型17种,低危型9种。结果 889例细胞样本中,检出HPV阳性者168例,阳性率为18.9%,以单一感染为主,高危亚型检测出142例,占总阳性例数的84.5%。共检出了24种HPV亚型,仅高危亚型HPV45及低危亚型HPV57未检出。检出率排名前三的HPV高危亚型分别为HPV52、HPV16、HPV58,中青年妇女以HPV16和HPV52为优势感染亚型,60岁的妇女主要感染HPV58。结论可据此针对不同年龄研发和采用不同亚型疫苗,防治宫颈癌,提高本地区女性健康水平。     

HPV Vaccination: Does It Have a Role in Preventing Penile Cancer and Other Preneoplastic Lesions?

ObjectivesHuman papillomavirus (HPV) is the most common sexually transmitted infection globally, which causes nearly all cervix carcinomas and contributes to oropharyngeal, penile, vulva, vagina, and anal cancers. Despite the role of HPV in several preneoplastic and cancerous lesions in men, male vaccine coverage is low. This article aims to provide insights into the pathophysiology of HPV-related penile cancer and penile intraepithelial neoplasia (PeIN). Moreover, this review endeavors to outline the advantages of implementing HPV vaccination in male vaccination programs and the role of health care providers in this mission.Data SourcesThis is a narrative review of relevant literature. A search on PubMed and Cochrane database was conducted. The following search terms were used: HPV vaccination, gender-neutral vaccination, male, genital warts, penile cancer, vaccine recommendations.ConclusionHPV is responsible for 50.8% of penile cancers globally, 79.8% of PeIN, and 90% of genital warts. In 2009 the Food and Drug Administration licensed the quadrivalent HPV vaccine for use in males, with a potential efficacy of 90% and 77.5% to reduce genital warts and anal intraepithelial neoplasia, respectively. However, the uptake of HPV vaccination in men is low, and gender-neutral vaccination is estimated to be implemented only in 42 countries worldwide. Because data in penile cancer are lacking, further research is needed to study the efficacy of incorporation of HPV vaccines in male vaccination programs on preventing penile cancer and PeIN.Implications for Nursing PracticeNurses and other members of the multidisciplinary team should take every opportunity to recommend HPV vaccination in adolescent men. Moreover, they play an important role in raising community awareness about the incidence of HPV and the related range of diseases. A practical approach is needed to incorporate HPV vaccines in vaccination programs and to optimize vaccination coverage.     

Quadrivalent human papillomavirus (HPV) vaccine: a review of safety, efficacy, and pharmacoeconomics

What is known and background: The introduction of vaccines has lead to a significant reduction in morbidity and mortality from diseases such as measles, rubella and poliomyelitis, as well as the eradication of smallpox (Ertl HC, Xiang Z (1996) The Journal of Immunology, 156 , 3579–3582). A recent vaccine approved by the Food and Drug Administration (FDA) is the recombinant quadrivalent human papillomavirus (HPV) vaccine (Merck, Gardasil®). Concerns raised with this preventive measure include safety and efficacy issues as well as the financial implications. Furthermore, the use of the vaccine in women outside the currently approved age ranges and in adolescent boys and men has also been a source of debate. Objective: A review of two licensed HPV vaccines (Gardasil, Merck and Cervarix, GalxoSmithKline) in the light of these issues. Methods: Literature searches were conducted using the MEDLINE (1966 – December 2008) and PubMed databases in addition to the Centers for Disease Control and Prevention website. Bibliographies of selected references were also evaluated for relevant articles. Published guidelines and press releases were utilized as were the manufacturer’s package inserts. The collection of information for this review was limited to the most recently available human data. Results and discussion: The HPV quadrivalent vaccine has been effective in the management of HPV by preventing vaccine subtype‐related persistent infection and precancerous lesions as evidenced by numerous clinical trials. It is also regarded as a generally safe and well‐tolerated vaccine, based on an assessment of reported adverse events submitted through governmental databases and analyzed by independent researchers. The majority of adverse events were non‐serious and the vaccine has not been conclusively implicated with serious events. The FDA continues to focus on routine post‐marketing surveillance monitoring of reported adverse events. The bivalent vaccine has also been shown to be effective in reported trials. Its adverse effect profile also appears acceptable. What is new and conclusion: The HPV vaccines appear safe and effective. Additional clinical research on the vaccines on women outside the currently approved age ranges and in males is necessary. Studies on longer‐term outcomes, including cervical cancer and the emergence of new viral genotypes are also necessary.     

Design of a large outcome trial for a multivalent human papillomavirus L1 virus-like particle vaccine

BackgroundThe 9-valent human papillomavirus (HPV) (9vHPV) vaccine targets the four HPV types (6/11/16/18) covered by the licensed quadrivalent HPV (qHPV) vaccine and five additional types (31/33/45/52/58). A large outcome trial of 9vHPV vaccine was conducted.MethodsAn active control (qHPV vaccine) was used because a placebo is not ethically acceptable. Since qHPV vaccine is (and 9vHPV vaccine was anticipated to be) highly efficacious against HPV 6/11/16/18, low incidence of HPV 6/11/16/18-associated disease was expected. Consequently, an efficacy comparison of 9vHPV versus qHPV vaccine for HPV 6/11/16/18 would have been prohibitively large in size. Moreover, no minimum antibody level predicting protection against infection or disease is defined for HPV vaccination. As an alternative approach, the two vaccines were compared using immunogenicity bridging for HPV 6/11/16/18 and clinical efficacy for HPV 31/33/45/52/58.ResultsThe two co-primary objectives were to demonstrate: (1) non-inferior anti-HPV 6/11/16/18 antibody response; and (2) superior efficacy in HPV 31/33/45/52/58-related clinical outcome, for 9vHPV vaccine versus qHPV vaccine. For HPV 6/11/16/18, supportive analyses included a non-inferiority assessment of the percent risk reduction (compared to historical placebo) for 9vHPV versus qHPV vaccine.ConclusionsA Phase III study of 9vHPV vaccine was successfully implemented. Experience from this study design may be applicable when developing a multivalent vaccine covering the same serotypes as an existing vaccine plus additional serotypes and there is no immune correlate of protection. Also, this study established that efficacy of a new HPV vaccine may be demonstrated using immunogenicity endpoints, which may open new options in HPV vaccine development.     

Deconstructing the measure of vaccine efficacy against disease irrespective of HPV in HPV vaccine clinical trials

BackgroundHuman papillomavirus (HPV) vaccines were licensed by demonstrating prevention of anogenital disease caused by specific HPV types in clinical studies. Measuring the impact of HPV vaccination on the overall burden of anogenital disease (irrespective of HPV) is an important public health question which is ideally addressed in post-licensure epidemiological studies. Attempts were made to use clinical trial data for that purpose. However, the interpretation of vaccine efficacy on the endpoint of disease irrespective of HPV is not widely understood.MethodsWe used the 9-valent HPV vaccine clinical program as a case study to determine the value of measuring vaccine efficacy in such endpoint. This assessment was rigorously performed by heuristic reasoning and through probability calculations.ResultsThe measure of vaccine efficacy in the irrespective of HPV endpoint is driven simultaneously in opposite directions by the high estimate of prophylactic efficacy and a numerically negative estimate of risk reduction that is also a reflection of high prophylactic efficacy and no cross-protection.ConclusionsThe vaccine efficacy estimate in the irrespective of HPV endpoint is ambiguous and difficult to interpret. Comparing this estimate across different HPV vaccine studies requires an understanding of the contributions of vaccine HPV type efficacy and the incidence of disease not related to vaccine HPV types for each study. Without such understanding, comparing studies and drawing conclusions from such comparison are highly misleading. Approaches are proposed to divide this endpoint in components that are easier to interpret.     

On surmounting the barriers to HPV vaccination: we can do better

The major impediment to increased human papillomavirus (HPV) vaccination coverage in young males and females is lack of health care provider recommendation. Despite its efficacy in preventing cervical cancer, HPV vaccination in females (49.5%) and males (37.5%) ages 13 through 17 falls well below the Centers for Disease Control and Prevention’s (CDC) Healthy People 2020 target of 80% coverage. Parents’ willingness to vaccinate their child has been shown to be much higher when physicians share personal vaccination decisions for their own children as well as what other parents have done at that particular clinic. Furthermore, the vaccine must be presented presumptively as a “bundle” along with the rest of the standard adolescent vaccine panel. Multiple exemplars presented including in several European countries, low-income countries and Rwanda, demonstrate that school-based health care systems dramatically increase vaccination coverage. Finally, acceptability for vaccination of males must improve by increasing provider recommendation and by presenting the HPV vaccine as a penile, anal and oropharyngeal cancer prevention therapy in males and not merely a vaccine to prevent cervical cancers in females. Paediatricians, obstetrician/gynaecologists and primary care physicians should consider these data as a call-to-action.

• Key messages

• ??Despite recent efforts in the US, only 49.5% of females and only 37.5% of males ages 13 through 17 have received all recommended HPV vaccine doses. These numbers fall well below the 80% target set forth by the Healthy People 2020 initiative.

• ??According to the CDC, if health care providers increase HPV vaccination rates in eligible recipients to 80%, it is estimated that an additional 53,000 cases of cervical cancer could be prevented during the lifetime of those younger than 12 years. Furthermore, for every year that the vaccination rate does not increase, an additional 4400 women will develop cervical cancer.

• ??First and foremost, healthcare providers (HCPs) must make a strong recommendation to vaccinate patients and these recommendations must become routine, including for males.

• ??It is clear that HPV vaccination rates improve significantly when vaccine administration occurs at designated, well-organized sites such as school-based vaccination programmes. Furthermore, HPV vaccination should be a high school requirement and offered in the standard adolescent vaccine panel as a bundle with Tdap and MenACWY vaccines in order to promote maximum adherence.

• ??Finally, research on immunogenicity and antibody titre longevity needs to be done in newborns. The HPV vaccine may be recommended in the newborn panel of vaccines to avoid any issues of sexualization and misplaced fears of sexual disinhibition, akin to the success of the Hepatitis B vaccine in the 1980s.

• ??The HPV vaccine is a vaccine against cancer and should be aggressively marketed as such. As healthcare providers, we need to make every effort to overcome barriers, real or perceived, to protecting our population from potential morbidity and mortality associated with this virus.

     

Increasing Cervical Cancer and Human Papillomavirus Prevention Knowledge and HPV Vaccine Uptake through Mother/Daughter Education

This evidence-based initiative assessed the impact of language-appropriate cervical cancer and human papillomavirus (HPV) prevention education on knowledge level and HPV vaccine uptake among mothers and their daughters. Forty-one mother/daughter dyads from a low-cost, faith-based clinic for the uninsured in southeastern Texas participated in the nurse practitioner-led cervical cancer prevention educational sessions. Spanish was the primary language for the majority of participating mothers. The project produced appreciable knowledge increase and HPV vaccine uptake intent. Aggregate HPV vaccine uptake numbers for the clinic increased considerably compared to HPV vaccine administration prior to educational intervention.     

New adjuvants in evolving vaccine strategies

Adjuvants are becoming the key players of vaccine formulations to enhance the immunogenicity of subunit (peptides, proteins, virus-like particles (VLPs)) and DNA vaccines, as well as to reach the current new goals of preventing and/or treating chronic infectious diseases and cancers. Induction of humoral response, in particular neutralizing antibodies able to inhibit the binding of pathogens to their cellular receptors, remains a major goal of vaccines targeted to prevent acute lytic infections; induction/modulation of cellular immunity is, however, critical to fight latently/chronically infected cells as well as cancer cells. The new adjuvants, included in vaccine preparations, are currently able to modify the presentation of epitopes to the immune system with a specific T_H1 versus T_H2 polarization efficacy. A paradigm of the relevance of these new adjuvants is the immunological result obtained with the inclusion of monophosphoryl lipid A in the formulation of L1-based human papillomavirus (HPV)-naked VLPs. In the May issue of this journal, Garcon and colleagues describe the highly enhanced humoral and memory B cellular immunity of the AS04-adjuvanted HPV vaccine, which results in a long-lasting and broad spectrum immunity.     

Exploring the Need of HPV Education Programs in Korean American Communities

Given the significantly higher cervical cancer risks faced by Korea Americans (KA), the aim of this study was to explore cultural influences and barriers affecting human papillomavirus (HPV) vaccination decisions and preferred educational methods to effectively deliver HPV information. Focus groups included 20 KA parents. This study found a lack of knowledge about HPV and the vaccine, along with negative perceptions about the vaccine, affects HPV vaccination decision-making. Ineffective conversations and a lack of HPV vaccine recommendations by health care providers influenced by cultural beliefs were found to be another major barrier. These findings reveal new insights to guide the development of HPV education programs.     

Intervention to Increase Human Papillomavirus Vaccine Initiation Rates in Adolescent Males

The objective of this quality improvement project was to increase human papillomavirus (HPV) vaccine initiation rates among males aged 11 to 21 years old. A multipronged strategy was implemented at a pediatric practice, including an electronic medical record prompt, educational presentation, and monthly e-mail updates to providers. Deidentified HPV vaccine initiation rate data were collected, and a paired 2-sample t test evaluated differences in prepost vaccine initiation rates. HPV vaccine initiation rates increased by 6.5% during the project period. The medical record prompt was identified as most effective by 75% of participating providers. Small gains can be made to improve HPV vaccine initiation rates among adolescent males.     

Increasing Knowledge of Human Papillomavirus Among Young Adults

HPV is the most common sexually transmitted infection, affecting more than 43 million Americans. HPV is a public health concern because it is the leading cause of cervical, oropharyngeal, vulvar, vaginal, and anal cancer. Despite a highly effective vaccine, the rate of HPV vaccine completion among young adults falls below the Healthy People goal. In efforts to combat this public health concern, an educational brochure was distributed as a quality improvement project in an urban primary care office. After this educational intervention was implemented, there was a significant increase in young adults who received the HPV vaccine from their primary care provider.     

Awareness,knowledge and beliefs about HPV,cervical cancer and HPV vaccines among nurses in Cameroon: An exploratory study

Background

While it is known that sub-Saharan African countries face multiple obstacles such as cost in adopting vaccination against human papillomavirus (HPV), the crucial role nurses can play in implementing such programs has not been adequately examined.

Objectives

To investigate the knowledge and awareness of HPV, primary cause of cervical cancer and HPV vaccine among nurses working at four Cameroon Baptist Convention Health Services facilities, and to explore what factors influence nurses’ willingness to inform and recommend HPV vaccine to adolescents and parents attending clinics.

Design and setting

A structured questionnaire survey was administered to a convenience sample of nursing staff working at the four health facilities.

Results

Of 192 eligible nurses 76 (39.6%) participated in the study. There were moderately low levels of knowledge about HPV infection and prevention of cervical cancer, but a moderately high level of knowledge about HPV vaccine. Although 90.8% acknowledged that cervical cancer is directly linked to HPV infection, nearly 32% failed to identify it as a sexually transmitted infection (STI), while 43.4% believed it is an uncommon infection. Willingness to recommend the HPV vaccine was moderate, with 69.7% intentionally initiating discussions with patients about the subject. The most important factors considered when deciding to recommend the vaccine included effectiveness (56.6%) and side effects/safety (11.8%). Cost was less of a concern (6.6%), likely due to the availability of donated vaccine.

Conclusion

Despite high awareness about HPV, more education about the virus, cervical cancer and the vaccine are required to further increase nurses’ willingness to recommend the vaccine and strengthen strategies for reaching adolescents through nurses in Cameroon.