Human Papillomavirus Vaccine Trials Research Articles

Monitoring of human papillomavirus vaccination

Persistent infection with oncogenic human papillomavirus (HPV) is a necessary causal factor in the development of cervical cancer. Moreover, HPV, predominately type 16 and to a lesser degree type 18, is linked causally to varying proportions of other anogenital cancers (vulva, vagina, penis, anus) as well as cancers elsewhere in the body (oropharynx, larynx, conjunctiva). HPV types 6 and 11 cause most of genital warts and recurrent respiratory papillomatosis. Effective prophylactic vaccines have been developed. In this review, we address briefly the immunological aspects of HPV infection and the results of HPV vaccination trials. Internationally standardized monitoring and evaluation of prophylactic HPV vaccination programmes will be essential for arriving at the most cost-effective strategies for cancer control.

Re: Impact of Human Papillomavirus (HPV)-6/11/16/18 Vaccine on All HPV-Associated Genital Diseases in Young Women

As we contemplate the astonishing successes of human papillomavirus (HPV) vaccines, it is worthwhile to consider whether randomized controlled trials of the sort recently published in the Journal can ever show reductions in cervical cancer rates (1). In their excellent article, Munoz et al. (1) reported nearly complete efficacy of quadrivalent HPV vaccine against vulvar and cervical intraepithelial neoplasia, adenocarcinoma in situ, and genital warts that contained viral types in the vaccine. Of course, this study did not show differences in cervical cancer because that was never its intent. However, the hope that one day randomized controlled trials like these will finally show that HPV vaccines prevent cervical cancer is nicely summarized by the conclusion of a recent systematic review (2) of HPV vaccine trials, “To evaluate cervical cancer incidence and mortality, a longer follow-up is necessary.” But is this really true? Assessing clinical trial outcomes related to cervical disease typically requires regular Papanicolaou test screenings, and ethics require that women with abnormal screening results receive follow-up and treatment, as appropriate. This combination of screening and treatment should prevent all but the most aggressive interval cervical cancers (3). Indeed, one of the most interesting findings reported by Munoz et al. was that none of the women in the trial developed cervical cancer during the approximately 63 000 women-years reported. Because their study participants had at least annual screening for cervical abnormalities to assess the main outcomes, clinicians treated abnormalities identified during the tests with procedures known to be effective in preventing cervical cancer and thus vastly reduced the chances the women would get cervical cancer. We can think of this risk reduction as reflecting a “cervical cancer Heisenberg principle,” according to which studying intermediate outcomes obliterates more severe ones. One way that researchers have devised to get around this Heisenbergian challenge is to design studies that continue past the duration of most efficacy trials (ie, beyond 4–6 years) (3). Women remain randomly assigned to condition, but they no longer receive regular testing as part of the trial. Instead, the researchers follow the women over the next decades by linking their identities to national cancer registries. The ethical justification is that routine screening and medical treatment outside the trial are the standard of care. In contrast, HPV vaccine provision to older women is not the standard of care, and the majority of HPV infections will have already occurred during the ages in which women were enrolled in the trial. The other alternative to get around this Heisenbergian challenge is to evaluate HPV vaccine impact at the population level by use of one of the many alternatives that we have previously reviewed elsewhere (4). These evaluations have to rely on prospective cohort studies and other nonexperimental study designs that yield weaker evidence than randomized controlled trials. One such study (5) recently reported decreases in the incidence of genital warts after implementation of a national HPV vaccination program in Australia. It is highly likely that additional studies, many of which are under way, will provide similar correlational evidence for the population-level impact of HPV vaccine on cervical cancer. While we wait for further evidence to accumulate, it is important to remember that most randomized controlled trials cannot and will not tell us whether HPV vaccines prevent cervical cancer.

Prophylactic HPV vaccines: the Finnish perspective

Finland is a country with a dual role in the human papillomavirus (HPV) field. Finnish scientists have pioneered in HPV research and participated in international HPV vaccine trials, but officially Finland is reluctant to implement HPV vaccines into its national vaccination program owing to the reasons discussed in this article. In contrast to other European countries, Finnish authorities were reluctant to initiate the evaluation process for HPV vaccines after licensure. Instead of prompt implementation, it was decided that a long-term prospective (Phase IV effectiveness) study to evaluate the bivalent HPV vaccine in a randomized community trial should be started. In addition, the Finnish authorities refuse to accept the compelling scientific evidence on the efficacy and safety of HPV vaccines. They report that cervical cancer (CC) is effectively controlled by the national screening program, despite the fact that CC in Finland has increased very rapidly since 1992. The Finnish perspective on HPV vaccines appears to postpone all critical decisions until the second half of the 2010s. This will have two direct consequences: 1) every year of delay means that an entire birth cohort (>60,000 girls and boys) will lose the opportunity of being offered the state-of-art cancer prevention provided by prophylactic HPV vaccines; and 2) given the declining trends of CC elsewhere, within a few years Finland will fall among the countries with a high incidence of CC. It is the personal conviction of this author that there are no sustainable arguments remaining that advocate continuing this Finnish perspective on HPV vaccines any further.

Three factor eating questionnaire-R18 as a measure of cognitive restraint, uncontrolled eating and emotional eating in a sample of young Finnish females

BackgroundThe aim of the study was to examine the construct validity of the Three-Factor Eating Questionnaire -R18 (TFEQ-R18), a measure of eating behaviour, and to evaluate cognitive restraint, uncontrolled eating and emotional eating in a sample of adolescent and young adult females of different weights.MethodsSubjects were 2 997 females, aged 17 to 20 years, who participated in a phase III human papillomavirus vaccination trial in Finland in 2004 – 2009.Self-administered questionnaires and weight and height measurements were used. The factor structure of the TFEQ-R18 was verified by factor analysis. Connections between measured eating behaviour and Body Mass Index (BMI) were tested using analysis of variance.ResultsThe original factor structure of the TFEQ-R18 was replicated: six of the eighteen items measured cognitive restraint, nine measured uncontrolled eating, and three measured emotional eating. On average, higher BMI was associated with higher levels of cognitive restraint (p < 0.001) and emotional eating (p < 0.001), but not with uncontrolled eating.ConclusionStructural validity of the TFEQ-R18 was good in this sample of young Finnish females with a varying range of body weights. Use of the instrument as a measure of eating behaviour was thus corroborated. Connections of restrained and emotional eating with BMI were in accordance with previous findings from young females.

Genotyping of Human Papillomaviruses by a Novel One-Step Typing Method with Multiplex PCR and Clinical Applications

We describe here a rapid, high-throughput genotyping procedure that allows the simultaneous detection of 16 high- and low-risk genital human papillomavirus (HPV) types by multiplex PCR in a single reaction tube. Multiplex PCR is based on the amplification of HPV DNA by sets of HPV genotype-specific primers, and the genotypes of HPV are visually identified by the sizes of amplicons after they are separated by capillary electrophoresis. The procedure does not include a hybridization step with HPV-specific probes and is rapid and labor-saving. We detected all 16 HPV genotypes (types 16, 58, 52, 51, 56, 31, 18, 39, 66, 59, 6, 33, 30, 35, 45, and 11) with a high sensitivity and a high degree of reproducibility. By using this newly developed method, we conducted a pilot study to examine the correlation between the prevalence and genotype distributions of HPV and the cytological group classifications for 547 cervical samples. Compared with the group of samples considered normal (14.7%), there was a significant increase in the prevalence of HPV in women with atypical squamous cells of unknown significance (61.3%), low-grade intraepithelial lesions (75.8%), and high-grade intraepithelial lesions (HSILs) (82.2%). The prevalence and distribution of type 58 were correlated with cytological malignancies, with the highest prevalence in women with HSILs. In conclusion, the novel multiplex PCR method described appears to be highly suitable not only for the screening of cervical cancer precursor lesions but also for the characterization of genotype distributions in large-scale epidemiological studies and HPV vaccination trials.

Human papillomavirus vaccine and cervical cancer prevention: Practice and policy implications for pharmacists

To review the epidemiology and natural history of human papillomavirus (HPV), summarize relevant clinical trials of the prophylactic HPV vaccines, and describe the practice and policy implications that HPV vaccine represents for pharmacists. Search of Medline through June 2007 using keywords human papillomavirus vaccine, Gardasil, and Cervarix; meeting abstracts; bibliographies from selected articles; and National Institutes of Health clinical trials registry. English language review articles, clinical trials, and published abstracts were considered for inclusion. HPV is a sexually transmitted infection that is necessary for the development of cervical cancer, and types 16 and 18 are associated with 70% of cases of invasive cervical cancer worldwide. A quadrivalent prophylactic vaccine against HPV-6, -11, -16, and -18 is currently available, and a bivalent vaccine targeting HPV-16 and -18 is under review by the Food and Drug Administration. Both are highly effective at preventing persistent HPV infection and precancerous lesions caused by vaccine-specific HPV. HPV vaccine is currently indicated for girls aged 9 to 26 years, but ongoing trials are evaluating the efficacy in other populations. Implementation of a vaccine administration program is an area of opportunity for new policies to include pharmacists in the administration of prophylactic HPV vaccines. Pharmacists are allowed to administer vaccinations in 46 states and can potentially play a role in HPV vaccine administration. For this to happen, however, multiple legal and regulatory changes must occur. Prophylactic HPV vaccines safely and effectively prevent HPV infection and precancerous lesions in the cervix. The availability of these vaccines also create new clinical opportunities for community pharmacists, provided needed legal, regulatory, and policy changes are made.

Human Papillomavirus (HPV) Genotyping Using Paired Exfoliated Cervicovaginal Cells and Paraffin-Embedded Tissues To Highlight Difficulties in Attributing HPV Types to Specific Lesions

Defining type-specific human papillomavirus (HPV) infections within cervical tissues is important for understanding the pathogenesis of cervical neoplasia and assessing the effectiveness of prophylactic vaccines with limited type-specific spectra. We compared HPV DNA-testing results from 146 matched exfoliated-cell and formalin-fixed-tissue specimens collected by cervicovaginal lavage (CVL) within 90 days of each other from women with histologically confirmed cervical intraepithelial lesions (CIN). The CVL specimens were HPV typed using a MY09/11 L1 consensus primer PCR method followed by dot blot hybridization. The tissue specimens were HPV typed using an SPF(10) line probe assay HPV detection system. Of the 146 specimen pairs with evidence of CIN in the tissue, 91.8% were positive for one or more HPV types in both the tissue and cellular specimens. Tissue sections were more likely to be HPV negative (P < 0.01). Typing directly from tissue sections resolved multiple infections detected in exfoliated cells to a single HPV type in only 46.9% of cases. Combined use of both specimen types to attribute lesions to HPV type 16 (HPV-16) and/or -18 led to 43.1% attributed to HPV-16 and/or -18 by both specimen types and 19.9% attributed to HPV-16 and/or -18 by one, but not both, specimen types. Unambiguous attribution of cervical lesions to a single, specific HPV type remains a difficult proposition. Use of multiple specimen types or the development of highly sensitive and robust in situ hybridization HPV-testing methods to evaluate the certainty of attribution of lesions to HPV types might provide insights in future efforts, including HPV vaccine trials.

Economic evaluations of human papillomavirus vaccines

Vaccines to prevent infection with the human papillomavirus (HPV) have recently been approved for use in preventing cervical precancer and cancer. This paper reviews the HPV vaccine effectiveness and cost–effectiveness studies published to date. In order to fully appreciate the strengths and limitations of the different studies, a short background is provided on the natural history of HPV and cervical cancer, current prevention strategies and HPV vaccine trial results to date. Each study is then summarized in terms of model structure, parameter estimates for the natural history of HPV and cervical cancer, assumptions regarding screening and vaccination, and key findings. The review concludes with recommendations for additional research and a five-year perspective.

Translational Mini-Review Series on Vaccines:&amp;#x2028;Monitoring of human papillomavirus vaccination

Persistent infection with oncogenic human papillomavirus (HPV) is a necessary cause of cervical cancer. Moreover, HPV type 16 (and to a lesser degree HPV type 18) is linked with more rare cancers, namely cancer of the vulva, vagina, penis, anus, oropharynx and larynx. Effective prophylactic vaccines have been developed. In this review, we briefly address immunological aspects of HPV infection and the results of HPV vaccination trials. Internationally standardized monitoring and evaluation of prophylactic HPV vaccination programmes will be essential for arriving at the most (cost-)effective strategies for cancer control.

Emerging Infections: Genital Human Papillomavirus Infection

Over the past few decades, epidemiology and natural history studies have led to improved understanding of human papillomavirus (HPV) infection and to promising prevention strategies. HPV infection is the cause of anogenital warts and cervical cancer, as well as a proportion of other anogenital and head and neck cancers. Data from clinical trials have resulted in recommendations that support the use of an HPV test in the context of cervical cancer screening and management. Prophylactic HPV vaccine trials have demonstrated high efficacy, and an HPV vaccine that prevents cervical cancer precursors, cervical cancer, and anogenital warts caused by HPV types 6, 11, 16, and 18 was licensed for use in girls and women aged 9-26 years by the US Food and Drug Administration (FDA) in June 2006. In this article, we review genital HPV for the clinician, with a primary focus on the prevalence of HPV infection in the United States.

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

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. 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. 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. 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. 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.

Genotyping of human papillomavirus in cervical lesions by L1 consensus PCR and the Luminex xMAP system

Infection with human papillomavirus (HPV) is the main cause of cervical cancer, the principal cancer in women in most developing countries. Molecular epidemiologic evidence clearly indicates that certain types of HPV are the principal cause of invasive cervical cancer and cervical intraepithelial neoplasia. Comprehensive, high-throughput typing assays for HPV, however, are not currently available. By combining L1 consensus PCR and multiplex hybridization using a Luminex xMAP system-based suspension array, the authors developed a rapid high-throughput assay, the HPV DNA suspension array (HPV-SA), capable of simultaneously typing 26 HPVs, including 18 high-risk HPV genotypes and eight low-risk HPV genotypes. The performance of the HPV-SA applied to 26 synthetic oligonucleotide targets was evaluated. The HPV-SA system perfectly discriminated 18 high-risk HPV targets from eight low-risk HPV targets. To assess the clinical applicability of the assay, the HPV-SA was performed with 133 MY09/MY11 primer set-mediated PCR (MY-PCR)-positive clinical specimens; of the 133 samples, 121 were positive by HPV-SA. Both single and multiple types were easily identified. The authors believe that improvement of the assay may be useful for epidemiological studies, cancer-screening programmes, the monitoring of therapeutic interventions, and the evaluation of the efficacy of HPV vaccine trials.

Assessment of Knowledge and Attitudes of Young Uninsured Women toward Human Papillomavirus Vaccination and Clinical Trials

Study Objective To assess knowledge and attitudes of young uninsured women toward human papillomavirus (HPV) vaccination and clinical trials. Design Cross-sectional study. Setting Clinic-based sample in Brazil. Participants A consecutive sample of 204 women aged 16 to 23 years, attending a public outpatient gynecological clinic. Interventions A questionnaire administered by in-person interview. Main Outcome Measures Data on knowledge and attitudes towards HPV vaccination. Results Overall, 72% of the respondents would enroll in a HPV vaccine trial, despite the fact that 69% of women were ignorant of what HPV may cause, and only 10% acknowledged that HPV might lead to cervical cancer. The need of a placebo arm (31%) and three vaccinations injections (26%) were the trial design characteristics most cited for deterring participation. Factors promoting participation were “careful/detailed consultations by the same physician” (92%), “access to more information on women's health” (84%), and “office visits on time” (79%); whereas “clinic too far from home” (36%), “fear of adverse events” (29%), and “gynecologic examination discomfort” (25%) were the most commonly reported reasons for not enrolling in a trial. Being sexually active, more than three lifetime sexual partners and perception of high risk for cervical cancer were predictors of participation in a HPV vaccine trial. Conclusions Knowledge of HPV infection and cervical cancer is low in this urban, young population. Thus, when planning HPV vaccine trials, it is important to consider implementing educational programs to provide knowledge of the benefits of a preventive vaccine and information on the etiology of and risk factors for cervical cancer.

Population-based enrolment of adolescents in a long-term follow-up trial of human papillomavirus vaccine efficacy

We evaluated a study setting for assessment of the long-term vaccine efficacy (VE) of human papillomavirus (HPV) virus-like-particle (VLP) vaccine against cervical carcinoma. A total of 22,412 16- to 17-year old adolescent women from seven cities in Finland were invited by letter to participate in a phase III study of a quadrivalent HPV (types 6, 11, 16, 18) VLP vaccine, between September 2002 and March 2003. A total of 30,947 18-year old women were invited to participate as unvaccinated controls. These women were asked about their willingness to participate in an HPV vaccination trial and to fill a health questionnaire. These three population-based cohorts of adolescent women, including women vaccinated with HPV vaccine or placebo vaccine and unvaccinated control women, are systematically followed over time. The study cohort database will be linked with the Finnish Cancer Registry using cervical carcinoma in situ (CIS) and invasive cervical carcinoma (ICC) as endpoints. Assuming that the cumulative incidence of CIS and ICC over 15 years is 0.45%, and that there is no loss to follow-up, and power of 80%, the determination of 70% total VE will require 3357 HPV vaccine recipients, 3357 placebo vaccine recipients, and 6714 unvaccinated controls. At the baseline, 2632 (12%) of the invited adolescents volunteered to the phase III vaccination trial, and 6790 (22%) responded to the questionnaire study. During a recruitment period of 10 months, 874 HPV vaccine recipients, 875 placebo recipients and 1919 unvaccinated controls were enrolled. Population-based enrollment of large cohorts of vaccinated and unvaccinated adolescents for passive registry-based follow-up with cervical carcinoma as the end-point is feasible and currently going on in Finland.

Facile, Comprehensive, High-Throughput Genotyping of Human Genital Papillomaviruses Using Spectrally Addressable Liquid Bead Microarrays

Human papillomavirus (HPV) is the worldwide cause of carcinoma of the uterine cervix, a cancer that is the second most common neoplasm in women, resulting in nearly 250,000 deaths a year. The magnitude of the risk of cancer after HPV infection, however, is virus type-specific. Over 40 HPV types can infect the genital tract. Comprehensive, high-throughput typing assays for HPV, however, are not currently available. Blending multiplex PCR and multiplex hybridization using spectrally addressable liquid bead microarrays we have developed a high-throughput, fast, single-tube-typing assay capable of simultaneously typing 45 HPV. The overall incidence of HPV in 429 women tested using this new assay was 72.2% for those with squamous intraepithelial lesions, 51.5% for those with atypical squamous cells of undetermined significance and 15.4% for women with normal cytology, respectively. This compared well with the incidence of HPV detected by a parallel non-typing generic high-risk assay. The new assay detected a wide spectrum of HPV types and a high incidence of mixed infections. We believe our assay may find widespread applications in areas requiring virus type-specific information, such as in epidemiological studies, cancer screening programs, monitoring therapeutic interventions, and evaluating the efficacy of HPV vaccine trials.

Eligibility and willingness of young Icelandic women to participate in a HPV vaccination trial

Cervical cancer is an important health problem worldwide, and the incidence of preinvasive cervical cancer is increasing among young sexually active women. The causal association between human papilloma virus (HPV) and cervical cancer makes it theoretically possible to eradicate the disease through vaccination. The aim of this study was to analyze the eligibility and willingness of 18-23-year-old Icelandic women to participate in a vaccination trial to prevent HPV infection and to assess knowledge of HPV. A questionnaire was formulated with questions on demographics, HPV knowledge, sexual behavior, attitude towards HPV vaccination, and other health-related issues. The questionnaire was tested on a subgroup of women before being mailed to 300 women aged 18-23 years, randomly selected by date of birth from the total population living in the Capital area of Reykjavík. The response rate of the mailed questionnaire was 54%. Of respondents, 96% reported having had sexual debut and 39% were aged 15 years or younger at first intercourse. Knowledge of HPV infections and associated diseases was limited, indicating the need for an educational campaign. Although 60% of the respondents were willing to participate in a HPV vaccination trial, the eligibility rate for the invited women was estimated to be approximately 13% (95% CI: 9-17%) after accounting for various exclusion criteria such as number of sexual partners, abnormal Pap smears, planning a pregnancy, or travelling abroad for more than 6 months. Icelandic women between 18 and 23 years of age have a sexual behavior profile and lifestyle that may decrease their eligibility in future prophylactic HPV vaccine trials. Improved education about HPV infection and its consequences is needed. Future trials may need to include younger women to improve recruitment.

Prerequisites for human papillomavirus vaccine trial: results of feasibility studies.

Oncogenic human papillomaviruses (HPVs) are the major cause of cervical cancer and associated cancers. First generation preventive vaccines against HPVs are entering clinical trials. Therefore, it is time to consider prerequisites of field trials in Finland. Incidence of cervical cancer is increasing in young women which is not unexpected since risk taking behavior among young women has also increased. In the developed countries up to 44% of cervical cancer cases are attributable to HPV16 infection alone. However, high risk HPV types other than HPV16 and HPV18 are emerging in the population based on HPV DNA pilot screening studies. Annual attack rates among young women less than 25 years of age is 2.3% for HPV16 infection, and 0.03% for CIN3 invasive cervic cancer. Thus, sample size estimates for HPV vaccine efficacy trial are approximately 1000 when the endpoint is HPV16 infection, and approximately 15000 when the endpoint is >/=CIN3 or worse assuming that the vaccine efficacy is 70%. Both HPV vaccine trial acceptability and compliance rates at routine visits of the general Finnish female population are going to be high based on a pilot study. Prerequisites for large scale field trials on HPV vaccination are fulfilled in Finland.