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 vaccines for cervical cancer.

Cervical cancer is one of the most common causes of cancer-related death in women. As a result of several recent advances in molecular biology, the association between human papillomavirus (HPV) infection and cervical cancer has been firmly established, and the oncogenic potential of certain HPV types has been clearly demonstrated. Several lines of evidence suggest the importance of the host's immune response, especially cellular immune response, in the pathogenesis of HPV-associated cervical lesions. These observations form a compelling rationale for the development of vaccine therapy to combat HPV infection. Both prophylactic and therapeutic HPV vaccine strategies are being developed. Prophylactic strategies currently under investigation focus on the induction of effective humoral immune responses against subsequent HPV infection. In this respect, impressive immunoprophylactic effects have been demonstrated in animals using papillomavirus-like particles (VLPs). VLPs are antigenic and protective, but are devoid of any viral DNA that may be carcinogenic to the host. For treatment of existing HPV infection, techniques to improve cellular immunity by enhancing viral antigen recognition are being studied. For this purpose, the oncogenic proteins E6 and E7 of HPV-16 and -18 are the focus of current clinical trials for cervical cancer patients. The development of successful HPV-specific vaccines may offer an attractive alternative to existing screening and treatment programs for cervical cancer.     

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.     

Human papillomavirus vaccines: Understanding the benefit–risk

Fish and fish oils are known to counteract coronary heart disease risk factors. We have previously showed that eating moderate amounts of freshwater fish modifies lipid and prostanoid metabolism in healthy students. In this study, the dose response relationship was clarified. One hundred male students took part and were randomly divided into control and four fish diet groups with different fish diets. Hematological, serum lipid and vitamin E and A analyses were performed. Already 1.5 fish containing meals per week increased n-3 to n-6 ratio of fatty acids in erythrocyte ghost phosphatidylethanolamine. The serum triglyceride and apolipoprotein B concentrations fell significantly in the group eating 3.8 fish containing meals a week for 12 weeks. At two lower doses (1.5 and 2.3 meals/week) the tendency to lower values was already seen. No significant changes were observed in the serum cholesterol, apolipoprotein A1 and vitamin E and A concentrations. The hematological variables also remained unchanged. The results show that moderate amounts of fish as a constituent of normal diet have benefical effects on lipid metabolism.     

Prophylactic human papillomavirus vaccines

Human papillomavirus (HPV) infection causes virtually all cases of cervical cancer, the second most common cause of death from cancer among women worldwide. This Review examines prophylactic HPV subunit vaccines based on the ability of the viral L1 capsid protein to form virus-like particles (VLPs) that induce high levels of neutralizing antibodies. Following preclinical research by laboratories in the nonprofit sector, Merck and GlaxoSmithKline are developing commercial versions of the vaccine. Both vaccines target HPV16 and HPV18, which account for approximately 70% of cervical cancer. The Merck vaccine also targets HPV6 and HPV11, which account for approximately 90% of external genital warts. The vaccines have an excellent safety profile, are highly immunogenic, and have conferred complete type-specific protection against persistent infection and associated lesions in fully vaccinated women. Unresolved issues include the most critical groups to vaccinate and when the vaccine's cost may be low enough for widespread implementation in the developing world, where 80% of cervical cancer occurs.     

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 oncogenesis

HPVs have evolved to accomplish the task of controlling host cell proliferation and differentiation to the end of producing more infectious virions. Coincident with the viral life cycle, however, is the risk that the viral genome will be disrupted and its DNA integrated into the host cell chromosomes. Integration of the viral genome is potentiated by host factors and extracellular effectors that alone may increase genetic instability. But it is consequent to viral integration that most HPV-associated malignancies develop. Investigations of the potential for HPV to immortalize primary cells or transform immortalized cells in vitro demonstrate two distinct classes of genital viral types: (1) oncogenic, exemplified by HPV 16 and 18; and (2) the nononcogenic types 6 and 11. Subsequently, localization of the HPV oncogene implicated that E6 and E7 act by uncoupling the checkpoint controls of the cell cycle principally by inhibiting the normal functioning of p53 and pRb, respectively. By in large, the nononcogenic viruses do not effect irreversible growth properties through these same viral genes and the same cellular counterparts.     

Human papillomavirus and vaccination

Human papillomavirus (HPV) infection is the most common sexually transmitted infection in the United States. Modeling estimates suggest that more than 80% of sexually active women will have acquired genital HPV by age 50 years. Although most infections are transient and asymptomatic, persistent infection with high-risk types of HPV can lead to precancerous lesions and progress to cancer. In June 2006, the US Food and Drug Administration licensed the first vaccine to prevent cervical cancers and other diseases in women. This quadrivalent vaccine protects against HPV-6, HPV-11, HPV-16, and HPV-18, which are responsible for 70% of cervical cancers and 90% of genital warts. Several studies have been published examining the vaccine's efficacy, duration, immunogenicity, and safety. Questions and controversy remain regarding mandatory vaccination, need for booster doses, and cost-effectiveness.     

Human papillomavirus vaccine and pregnancy

Question A patient of mine who recently learned she was 6 weeks pregnant had received the recombinant human papillomavirus (HPV) quadrivalent vaccine at 4 weeks of gestation. She is quite worried about how this will affect her baby. What is known about the safety of the HPV vaccine during pregnancy?Answer The HPV vaccine is generally not recommended for use in pregnant women. However, theoretically, because it is not a live vaccine, it is not expected to be associated with an increased risk. Also, information from the manufacturer’s pregnancy registry and phase 3 clinical trials does not indicate an increased risk of fetal malformations or other adverse effects due to the vaccine.     

Human papillomavirus and cervical cancer

Human papillomaviruses (HPVs) are double stranded DNA viruses. To date, over 100 genotypes have been identified. Oncogenic types of HPV, including types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68, are commonly associated with cervical cancer, with HPV16 being the most frequently detected genotype in women with cervical cancer worldwide. Genital HPV infections are common among young sexually active women and usually transient. Only a small fraction of infected women develop cervical cancer, implying the involvement of environmental and genetic cofactors in cervical carcinogenesis. The epidemiology of HPV infections and current advances on HPV vaccines will be reviewed here.     

Human papillomavirus vaccination for boys

Question

In Canada, generally provincial human papillomavirus (HPV) vaccination programs exist for only the female population. What should I recommend when parents and teenage boys ask about male HPV vaccination?

Answer

The quadrivalent HPV vaccine is effective and will reduce the incidence of disease in boys and girls. The quadrivalent HPV vaccination is approved and recommended for both boys and girls in Canada. Public funding for male vaccination is available in Prince Edward Island and Alberta. The remaining provinces and territories will need to consider cost-effectiveness analyses before expanding their female-only vaccination programs to include the male population.     

Human papillomavirus infections in primary care

Cervical cancer continues to be a leading cause of mortality worldwide. The incidence and mortality associated with invasive cervical cancer have declined significantly in developed countries due to widespread availability of screening with the Papanicolaou (Pap) test. However, the incidence and prevalence of non-invasive cervical intraepithelial neoplasms and genital warts related to oncogenic and nononcogenic strains of human papilloma viruses (HPV) have remained relatively stable. Recent advances in molecular diagnostics have resulted in improved characterization of various HPV types and have led to changes in terminology of Pap test findings. Changes in nomenclature may lead to confusion among primary care providers regarding how best to further evaluate abnormal cytological results. This article provides a concise overview of the approach to the treatment of genital warts and management of abnormal cervical cytology based on guidelines from the American Society of Colposcopy and Cervical Pathology. It also reviews advances in HPV vaccine development and the new recombinant vaccine recently approved for use in the United States.     

New approaches to prophylactic human papillomavirus vaccines for cervical cancer prevention

The currently licensed human papillomavirus (HPV) vaccines are safe and highly effective at preventing HPV infection for a select number of papillomavirus types, thus decreasing the incidence of precursors to cervical cancer. It is expected that vaccination will also ultimately reduce the incidence of this cancer. The licensed HPV vaccines are, however, type restricted and expensive, and also require refrigeration, multiple doses and intramuscular injection. Second-generation vaccines are currently being developed to address these shortcomings. New expression systems, viral and bacterial vectors for HPV L1 capsid protein delivery, and use of the HPV L2 capsid protein will hopefully aid in decreasing cost and increasing ease of use and breadth of protection. These second-generation vaccines could also allow affordable immunization of women in developing countries, where the incidence of cervical cancer is high.     

Therapeutic human papillomavirus vaccines: current clinical trials and future directions

Background: Cervical cancer is the second largest cause of cancer deaths in women worldwide. It is now evident that persistent infection with high-risk human papillomavirus (HPV) is necessary for the development and maintenance of cervical cancer. Thus, effective vaccination against HPV represents an opportunity to restrain cervical cancer and other important cancers. The FDA recently approved the HPV vaccine Gardasil for the preventive control of HPV, using HPV virus-like particles (VLP) to generate neutralizing antibodies against major capsid protein, L1. However, prophylactic HPV vaccines do not have therapeutic effects against pre-existing HPV infections and HPV-associated lesions. Furthermore, due to the considerable burden of HPV infections worldwide, it would take decades for preventive vaccines to affect the prevalence of cervical cancer. Thus, in order to speed up the control of cervical cancer and treat current infections, the continued development of therapeutic vaccines against HPV is critical. Therapeutic HPV vaccines can potentially eliminate pre-existing lesions and malignant tumors by generating cellular immunity against HPV-infected cells that express early viral proteins such as E6 and E7. Objective: This review discusses the future directions of therapeutic HPV vaccine approaches for the treatment of established HPV-associated malignancies, with emphasis on current progress of HPV vaccine clinical trials. Methods: Relevant literature is discussed. Results/conclusion: Though their development has been challenging, many therapeutic HPV vaccines have been shown to induce HPV-specific antitumor immune responses in preclinical animal models and several promising strategies have been applied in clinical trials. With continued progress in the field of vaccine development, HPV therapeutic vaccines may provide a potentially promising approach for the control of lethal HPV-associated malignancies.     

Human papillomavirus: clinical manifestations and prevention

Human papillomaviruses cause the most common sexually transmitted infection in the world and are responsible for nearly all cases of cervical cancer. Genital human papillomavirus infection can be divided into low-risk infections (causing genital warts) and high-risk infections (causing cervical intraepithelial neoplasia, and cervical and other cancers). Exposure to human papilloma- virus typically produces a sexually transmitted infection that may progress to a clinically apparent process, such as genital warts and cervical intraepithelial neoplasia lesions of the lower genital tract. Although most human papillomavirus infections resolve spontaneously within two years, some high-risk infections persist and are considered cancer precursors. Risk factors for persistent infection include multiple sex partners, sex at an early age, history of sexually transmitted infections, and smoking. Condom use is only partially protective against human papillomavirus infection. The two human papillomavirus vaccines are most effective if given to girls before the onset of sexual activity.