Historical pearls of HPV research: from condyloma to cervical cancer.

The oldest discovered human papilloma virus (HPV) infection in an ancient Egyptian mummy testifies that there is still much to unearth in its history. The Graeco-Roman world recognized venereal infections, and its nomenclature is still valid concerning HPV lesions. Western Europeans, eons later, created various theories for HPV evolution. Animal experiments during the 19th century had a profound impact for the understanding of HPV. In the late 20th century the arcinogenic properties of the virus had been clarified. This historical review presents the most important figures and discoveries in HPV research.

On the contextual nature of vaccine safety monitoring: Adverse events reporting after HPV-vaccination in Denmark, 2015.

BACKGROUND: In 2013-15, Denmark experienced an increase in reported suspected adverse events following vaccination (AEFI) against human papilloma virus (HPV). Dedicated centres ("One Access") were established in order to standardize management of patients who experienced medically unexplained physical symptoms after HPV vaccination. Since One Access was targeted patients with suspected AEFI after HPV vaccination, we used this opportunity to estimate completeness in AEFI reporting to the Danish Medicines Agency (DMA), and explore the topic of AEFI reporting from the perspective of physicians working at the centres to better understand health professionals' reporting behaviour. METHODS: The study consisted of a quantitative and a qualitative part. In the quantitative analysis, we used the Danish civil registry number to merge a line-list of all One Access patients referred in 2015 with total number of patients who had reported suspected serious AEFI following HPV vaccination to the DMA in the years 2009-2015. We conducted four semi-structured interviews with doctors representing three out of five regions. The Theoretical Domains Framework together with empirical data from two clinical fieldtrips guided the formation of the qualitative study. RESULTS: Among 1577 One Access patients, only 404 (26%) were reported to the DMA. We found significant regional differences in reporting completeness (p < 0.001) and differences between regions when looking at reporters' backgrounds (healthcare professionals vs non-professionals; p = 0.004). We identified several factors of importance for reporting behaviour amongst physicians, mainly under the domains of Knowledge, Motivation & Goals, and Environmental Context. CONCLUSIONS: Despite an official aim of homogenous case management, reporting of suspected AEFI was incomplete with large regional differences. The qualitative study corroborated that reporting behaviour was contextual. This observation represents an important caveat in interpreting data from AEFI reporting, in particular when these data are used for research or policymaking.

Seroprevalence of Human Papillomavirus 6/11/16/18 Among Self-identified Gay/Bisexual Men Who Have Sex With Men, Men Who Have Sex With Women, and Females, United States, 2003-2010.

BACKGROUND: Differences in human papillomavirus (HPV) seroprevalence by sex have been observed, likely due to differences in the anatomic site of HPV exposure. Seroconversion may be more likely after exposure at nonkeratinized (mucosal) compared to keratinized epithelium. We compared seroprevalence among self-identified gay/bisexual men who have sex with men (MSM) and females, 2 groups more likely exposed at mucosal epithelium, and men who only have sex with women (MSW), a group likely exposed primarily at keratinized epithelium, using data from the National Health and Nutrition Examination Survey from 2003 to 2010. METHODS: HPV 6/11/16/18 serum antibody was detected using a multiplexed, competitive luminex immunoassay. Weighted seroprevalence was estimated among unvaccinated, sexually experienced 18-59 year-old MSM, MSW, and females, overall and by demographic and sexual behavior characteristics. Seroprevalences were compared using prevalence ratios adjusted for sexual behavior (aPRs). RESULTS: Overall, seroprevalence in MSM, MSW, and females was 42.6%, 13.2%, and 37.1%, respectively. Seroprevalence in MSM was comparable to females (aPR: 0.85, 95% confidence interval [CI]: 0.68-1.08) and higher than MSW (aPR: 2.72, 95% CI: 2.19-3.38). MSW had a significantly lower seroprevalence than females (aPR: 0.31, 95% CI: 0.28-0.34). Similar associations were seen in all sociodemographic subgroups. Seroprevalence increased with number of lifetime sex partners in all groups. CONCLUSIONS: In this population-based survey, HPV seroprevalence among groups likely exposed at mucosal epithelium (MSM, females) was comparable; seroprevalence in both groups was higher than in MSW. Future research could explore whether differences in seropositivity following infection result in differential protection from future infection.

[History of the development of screening tests for cervical cancer]. / Historia de la evolución de las pruebas de tamizaje en el cáncer cervicouterino.

Cervical cancer (CC) is one of the best known malignancies. Currently, it is accepted that the etiological factor is persistent infection with high-risk human papillomavirus (HPV). Even before the identification of its etiological factors, methods such as Pap cytology and colposcopy were developed as tools for early diagnosis on CC and its precursor lesions. At the time when such tests were being developed, they were not fully accepted by the scientific community of the time; however, as time went by, the dissemination of knowledge, and more extensive application, these tests were finally included within the international guidelines. The implementation of programs with adequate coverage and quality allowed a significant reduction in the incidence and mortality of CC. However this did not occur widely, and CC is still a public health problem in developing countries. From the epidemiological and molecular viewpoint, knowledge on HPVs laid the foundations for the development of new prevention strategies based on vaccination and molecular detection of the causal agent, currently accepted as strategies for primary and secondary prevention. It is expected that the implementation of these strategies will have a greater impact on the control on CC and other malignancies associated with HPV infection.

El cáncer cervicouterino (CaCU) es una de las neoplasias mejor conocidas; actualmente es aceptado que el factor etiológico es la infección persistente por virus de papiloma humano (VPH) de alto riesgo. Sin embargo, aun antes de que se hubiera identificado el agente etiológico, se desarrollaron métodos, como la prueba citológica de Papanicolaou y la colposcopia, como herramientas para el diagnóstico temprano del CaCU y sus lesiones precursoras. En los inicios del desarrollo de ambas pruebas, estas no fueron del todo aceptadas por la comunidad científica de la época. Con el paso del tiempo, la divulgación del conocimiento y la aplicación más extensiva, se logró la aceptación y la inclusión de dichas pruebas en un gran número de guías a nivel internacional. La implementación de programas con cobertura adecuada y de calidad dio como resultado una reducción significativa en la incidencia y mortalidad por CaCU. Sin embargo, esto no se dio de manera generalizada y en países en vías de desarrollo es aún un problema de salud pública. El conocimiento sobre los VPH, desde el punto de vista epidemiológico y molecular, sentó las bases para el desarrollo de nuevas estrategias de prevención, basadas en la vacunación y en la detección molecular del agente causal, actualmente aceptadas como estrategias para prevención primaria y secundaria. Se espera que la aplicación de dichas estrategias tenga un impacto mayor en el control del CaCU y de otras neoplasias asociadas a la infección por VPH.

The estimated impact of natural immunity on the effectiveness of human papillomavirus vaccination.

BACKGROUND: Mathematical modelling is used to estimate the effectiveness of HPV vaccination. These estimates depend strongly on herd immunity and thus on naturally acquired immunity, a mechanism of which little is known. We estimated the impact of different vaccination strategies on HPV-16 and HPV-18 transmission and cervical cancer incidence in the Netherlands, considering different acquired immunity mechanisms. METHODS: We used the STDSIM microsimulation model, and considered two mechanisms for acquired immunity after infection: (I) full immunity with variable duration; (II) cumulatively decreasing susceptibility to reinfection. Girls aged 13-16 years received vaccination (94.7% efficacy for HPV-16 and 92.3% for HPV-18) during a once-off catch-up campaign with 50% coverage, followed by annual vaccination of 12-year-old girls (60% coverage). Alternative vaccination scenarios included increased coverage, including boys, and lower vaccine efficacy. RESULTS: HPV-16 incidence reduced by 64% under mechanism I and 75% under mechanism II; HPV-18 incidence reduced by 58% and 73%, respectively, and these reductions lead to 48-56% fewer cervical cancer cases. Increasing coverage can lead to over 96% reduction in HPV incidence. Vaccinating boys reduced incidence by 79-89% for HPV-16 and 83-98% for HPV-18 in women. CONCLUSIONS: Effectiveness estimates of HPV vaccination differ slightly between different acquired immunity mechanisms, yet these differences are unlikely to affect policy decisions. Offering vaccination to boys as well may be considered to further reduce cancer incidence.

A Century of Shope Papillomavirus in Museum Rabbit Specimens.

Sylvilagus floridanus Papillomavirus (SfPV) causes growth of large horn-like tumors on rabbits. SfPV was described in cottontail rabbits (probably Sylvilagus floridanus) from Kansas and Iowa by Richard Shope in 1933, and detected in S. audubonii in 2011. It is known almost exclusively from the US Midwest. We explored the University of Kansas Natural History Museum for historical museum specimens infected with SfPV, using molecular techniques, to assess if additional wild species host SfPV, and whether SfPV occurs throughout the host range, or just in the Midwest. Secondary aims were to detect distinct strains, and evidence for strain spatio-temporal specificity. We found 20 of 1395 rabbits in the KU collection SfPV symptomatic. Three of 17 lagomorph species (S. nuttallii, and the two known hosts) were symptomatic, while Brachylagus, Lepus and eight additional Sylvilagus species were not. 13 symptomatic individuals were positive by molecular testing, including the first S. nuttallii detection. Prevalence of symptomatic individuals was significantly higher in Sylvilagus (1.8%) than Lepus. Half of these specimens came from Kansas, though new molecular detections were obtained from Jalisco-Mexico's first-and Nebraska, Nevada, New Mexico, and Texas, USA. We document the oldest lab-confirmed case (Kansas, 1915), pre-dating Shope's first case. SfPV amplification was possible from 63.2% of symptomatic museum specimens. Using multiple methodologies, rolling circle amplification and, multiple isothermal displacement amplification in addition to PCR, greatly improved detection rates. Short sequences were obtained from six individuals for two genes. L1 gene sequences were identical to all previously detected sequences; E7 gene sequences, were more variable, yielding five distinct SfPV1 strains that differing by less than 2% from strains circulating in the Midwest and Mexico, between 1915 and 2005. Our results do not clarify whether strains are host species specific, though they are consistent with SfPV specificity to genus Sylvilagus.

Four historic legends in human papillomaviruses research.

Human papillomaviruses (HPVs) infection and HPVs-associated lesions, including skin warts in children and adults and cervical neoplasia in women, have been excessively studied since ancient years. In our article, we present briefly four major researchers from the HPVs pre-vaccination historic period: Hippokrates the Asclepiad, Domenico Antonio Rigoni-Stern, George N. Papanicolaou and Harald zur Hausen.

Fighting against human papillomavirus: the 25-year old contribution of the University of Crete School of Medicine.

Twenty five years have passed since the first research efforts in Greece on human papillomavirus (HPV) performed by the Department of Clinical Virology at the University of Crete School of Medicine. HPV infection in the human cervix was initially evaluated in relation to the host mutational and transcriptional activation of the ras/raf genes pathway, p53 gene polymorphisms, neo-angiogenesis- related gene expression and G1/S phase transition. A series of epidemiological studies ensued, evaluating HPV infection in the ophthalmic pterygium, benign laryngeal tumors, parotid lesions, nasal polyposis, actinic keratosis, aborted material and non-genital cancers. The observed geographical variations of different HPV types within the Hellenic population indicated a higher prevalence of HPV 18 on the island of Crete compared to mainland Greece. Moreover, our research led to the investigation of the mother-to-infant HPV transmission via human breast milk and the detection of novel HPV types in juvenile recurrent respiratory papillomatosis. We also evaluated the presence of HPV in the respiratory tract of asymptomatic children and the relationship between maternal HPV infection and neonatal prematurity. Despite the introduction of the current prophylactic vaccines against HPV into clinical practice, HPV remains a challenging target for the next generation of researchers, as the war against HPV continues.

[The visionary concept of "lymphoepithelioma" by A. Schmincke in 1921. Subsequent confusion over terminology and current approach to a solution]. / Das visionäre Konzept des "Lymphoepithelioms" 1921 und A. Schmincke. Nachfolgende terminologische Verwirrung und aktuelle Lösungsansätze.

In 1921 Alexander Schmincke established the visionary concept of a clinically and histomorphologically defined carcinoma entity of different lymphoepithelial organs that he named "lymphoepithelioma". This nowadays mainly comprises non-keratinizing oropharyngeal carcinomas frequently associated with human papillomavirus (HPV) and non-keratinizing nasopharyngeal carcinomas mostly associated with Epstein-Barr virus (EBV). The term lymphoepithelioma was originally defined by A. Schmincke and J. Ewing as a combined clinical and histological tumor entity of lymphoepithelial organs. The main reason for the longstanding terminological confusion regarding the term lymphoepithelioma is based on the fact that lateron a pure histological interpretation (lymphoepithelial differentiation) caused an artificial and nonreproducible exclusion of tumors with transitional and basaloid differentiation. For the forthcoming new WHO classification it has been suggested that squamous cell carcinoma of the head and neck should no longer be classified according to the heterogeneous histological differentiation but according to etiopathogenetic criteria (e.g. HPV-related, EBV-related, nicotine and alcohol-related). This proposed classification corresponds much better to the prognosis and therapy and would represent a late acknowledgement of Schmincke's visionary concept of a clinically and histomorphologically defined tumor entity. In addition, the ongoing terminological confusion over the heterogeneous and prognostically weak spectrum of histological differentiation would subside.

Changes in antibody seroprevalence of seven high-risk HPV types between nationwide surveillance studies from 1995-96 and 2006-07 in The Netherlands.

OBJECTIVE: This study evaluates trends in antibody seroprevalences of seven high-risk human papillomavirus (hr-HPV) serotypes (HPV16, 18, 31, 33, 45, 52, and 58) between the 1995-96 and 2006-07 sero-surveys among the Dutch general population in the pre-vaccination era. METHODS: Serum samples of men and women (0-79 years of age) from two cross-sectional population-based serosurveillance studies performed in 1995-96 (n = 3303) and 2006-07 (n = 6384) were tested for HPV-specific antibodies in a VLP-based multiplex immunoassay. RESULTS: HPV16-specific antibody seroprevalence increased during adolescence and shifted to younger ages in the 2006-07 survey compared to the 1995-96 survey. This step-up in HPV16 seroprevalence was most pronounced in women, while a more gradual increase was observed in men. Also in cohorts older than 49 years, HPV16 seroprevalence was higher in 2006-07 as compared to 1995-96 survey. A higher overall seroprevalence in individuals older than 15 years of age was found for HPV16, 18, 31 and 45 in 2006-07 as compared to 1995-96. For HPV33, 52 and 58 seroprevalences were comparable over this 11-year time period. Seropositivity for one or more HPV types was significantly higher in 2006-07 (23.1%) than in 1995-96 (20.0%) (p = 0.013). Multi-seropositivity increased from 7.1% in 1995-96 up to 10.2% in 2006-07 (p<0.0001). Differences in HPV seropositivity for at least one of the seven HPV types between both surveys could be explained in addition to demographic characteristics (age, sex, urbanization degree and ethnicity), also by changes in sexual behaviour (marital status, age of sexual debut and ever reported an STI). CONCLUSION: The observed increase in particular HPV16 seroprevalence could be due to changes in sexual behaviour over the years, and especially in age of sexual debut. Seroprevalence studies provide insight into the distribution of HPV types and infection dynamics in the general population over time, which is important to assess the impact of HPV-vaccination.

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

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

[Human papilloma virus and cervical cancer. An historical review on the development of research on cancer of the cervix uteri in Venezuela]. / El virus del papiloma humano y el cáncer cervical. Una revisión de la historia actualizada sobre la investigación del cáncer del cuello uterino en Venezuela.

The history on the relationship of VPH infection and cervical cancer was examined. Findings were initially reported in Maracaibo(1971), later in Mexico(1973) and thereafter several studies on the ultrastructure and immunohistochemistry of VPH infection and its role on cervical cancer were described. The ultrastructural findings of viral particles of HPV and their proteins, as well as their role in the incorporation of the viral genome to the human cervical cells were also described. Glycoproteins on the surface of cervical cells were reviewed and their importance on HPV infection was related to p16, blood group antigens and early genetic changes in the cell cycle with loss of heterozigocity, all of which, stimulated by the high risk HPV infection lead to cervical cancer.

The challenge of eliminating cervical cancer in the United States: a story of politics, prudishness, and prevention.

Exciting strides in reducing the incidence of and mortality from cervical cancer have been made over the last century in the United States. The issues surrounding the implementation of the human papillomavirus vaccine are remarkably similar to the issues involved in the gradual adoption of the Pap test and initiation of cervical cancer screening beginning nearly a century ago. The following review of the reduction of cervical cancer morbidity and mortality demonstrates the importance of the interplay between basic science, clinical medicine, social mores, and public policy.