Histopathological Tracing of HPV Genotypes 6 and 11 in Pediatric Patients in Medical City with Chronic Palatine and Pharyngeal Tonsillitis.

BACKGROUND: HPVs are considered to have high-oncogenic risk. These genotypes have been proven to have a causal link to cancers, in pediatric and youth patients, with high rates of HPV presence in the tonsillar tissues. OBJECTIVE: A prospective case-control research for determining HPV 6/11 genotypes in tonsillar specimens of children who underwent operations in the otolaryngology departments of the Medical City Complex, Baghdad, Iraq, for their non-oncologic palatine and pharyngeal tonsillar hypertrophies. METHODS: This study enrolled 102 tonsillar tissues, 82 from pediatric patients aged from 4 to 12 years and who underwent tonsillectomies for non-oncologic palatine and pharyngeal tonsillar hypertrophies; 38 specimens were from single operations while 22 were multiple specimens from the same pediatric patients, represented as a total of 44 tissues). In addition, trimmed nasal tissues from 20 patients, with unremarkable pathological changes, were included as the control group. For HPV 6/11 DNA detection, specific DNA probes were used for the chromogenic in situ hybridization (CISH) technique. RESULTS: In the palatine tonsillar hypertrophied tissue group, 26.2% of the tissues revealed positive CISH signals for HPV 6/11 DNA. Regarding the pharyngeal tonsillar hypertrophied tissues, 22.5% of the specimens expressed positive CISH reactions. Among the 22 pediatric patients who had combined pharyngeal and palatine tonsillectomies, in 22.7% both sites expressed positive signals. No positive-CISH reactions were documented in the control nasal tissues. Statistically a significant difference was seen when compared to the control group. CONCLUSIONS: Significant rates of HPV were observed which pointed to the spread of HPV, among other STIs, and in mothers of at least this studied pediatric group. Also, this represented a critical mark as reservoir tissue sites, allowing transmission to other mucosal tissue localizations, playing part in their pathogenesis.

[Anogenital warts-An update]. / Anogenitalwarzen ­ ein Update.

With a prevalence of around 1% in the sexually active population anogenital warts are the most frequent human papillomavirus (HPV)-related disease. In the vast majority of cases the underlying cause of the infection is due to HPV types 6 and 11. The diagnosis can usually be clinically established but in certain cases a histopathological work-up can be useful. Buschke-Lowenstein tumors represent such a scenario. The current therapeutic armamentarium for anogenital warts ranges from surgical ablative procedures up to local immunomodulatory treatment. All procedures have different advantages and disadvantages and are relatively time-consuming and sometimes also unpleasant for the patient. Anogenital warts are also a possible expression of an incomplete immunological control of HPV. Therefore, it should be emphasized that for certain affected individuals, especially immunosuppressed patients, special attention should be given to ensuring that screening investigations for HPV-associated dysplasia is carried out according to the respective valid guidelines. The primary prophylaxis by vaccination of girls and boys prior to first HPV exposure represents a very effective option to drastically reduce the prevalence of anogenital warts and other HPV-related diseases.

Rational design of a cross-type HPV vaccine through immunodominance shift guided by a cross-neutralizing antibody.

In vaccine development, broadly or cross-type neutralizing antibodies (bnAbs or cnAbs) are frequently targeted to enhance protection. Utilizing immunodominant antibodies could help fine-tune vaccine immunogenicity and augment the precision of immunization strategies. However, the methodologies to capitalize on the attributes of bnAbs in vaccine design have not been clearly elucidated. In this study, we discovered a cross-type neutralizing monoclonal antibody, 13H5, against human papillomavirus 6 (HPV6) and HPV11. This nAb exhibited a marked preference for HPV6, demonstrating superior binding activity to virus-like particles (VLPs) and significantly higher prevalence in anti-HPV6 human serum as compared to HPV11 antiserum (90% vs. 31%). Through co-crystal structural analysis of the HPV6 L1 pentamer:13H5 complex, we delineated the epitope as spanning four segments of amino acids (Phe42-Ala47, Gly172-Asp173, Glu255-Val275, and Val337-Tyr351) on the L1 surface loops. Further interaction analysis and site-directed mutagenesis revealed that the Ser341 residue in the HPV6 HI loop plays a critical role in the interaction between 13H5 and L1. Substituting Ser341 with alanine, which is the residue type present in HPV11 L1, almost completely abolished binding activity to 13H5. By swapping amino acids in the HPV11 HI loop with corresponding residues in HPV6 L1 (Ser341, Thr338, and Thr339), we engineered chimeric HPV11-6HI VLPs. Remarkably, the chimeric HPV11-6HI VLPs shifted the high immunodominance of 13H5 from HPV6 to the engineered VLPs and yielded comparable neutralization titers for both HPV6 and HPV11 in mice and non-human primates. This approach paves the way for the design of broadly protective vaccines from antibodies within the main immunization reservoir.

Immunogenicity and safety of a new quadrivalent HPV vaccine in girls and boys aged 9-14 years versus an established quadrivalent HPV vaccine in women aged 15-26 years in India: a randomised, active-controlled, multicentre, phase 2/3 trial.

BACKGROUND: To meet global cervical cancer elimination efforts, a wider range of affordable and accessible vaccines against human papillomavirus (HPV) are needed. We aimed to evaluate the immunogenicity and safety of a quadrivalent HPV vaccine (targeting HPV types 6, 11, 16, and 18), developed and manufactured by the Serum Institute of India (SIIPL). Here we report outcomes in the 9-14 years cohort. METHODS: This randomised, active-controlled, phase 2/3 trial was conducted at 12 tertiary care hospitals across India. Healthy participants aged 9-14 years or 15-26 years with no history of HPV vaccination were eligible for enrolment. Female participants were randomly assigned (1:1) with an interactive web response system, by use of a central computer-generated schedule and block randomisation (block sizes of 2, 4, 6, and 8), to receive the SIIPL quadrivalent HPV vaccine (Cervavac; SIIPL, Pune, India) or the comparator quadrivalent HPV vaccine (Gardasil; Merck Sharp & Dohme, Harleem, the Netherlands). Participants, investigators, laboratory technicians, and sponsors were masked to treatment allocation of female participants. Male participants were given the SIIPL quadrivalent HPV vaccine in an open-label manner. Study vaccines were administered intramuscularly with a two-dose schedule (at day 0 and 6 months) in the cohort aged 9-14 years, and with a three-dose schedule (at day 0, month 2, and month 6) in the cohort aged 15-26-years. Immunogenicity was assessed 30 days after the last dose by use of multiplexed ELISA. The primary outcome was the non-inferiority of immune response in terms of the geometric mean titre (GMT) of antibodies against HPV types 6, 11, 16, and 18 generated by the SIIPL quadrivalent HPV vaccine in girls and boys (aged 9-14 years) compared with the GMT generated by the comparator quadrivalent HPV vaccine in women aged 15-26 years at month 7 in the modified per-protocol population (ie, all participants who received all doses of study vaccines per assigned treatment group and had both day 0 and 1-month immunogenicity measurements after the last dose following protocol-defined window periods with no major protocol deviations). Non-inferiority was established if the lower bound of the 98·75% CI of the GMT ratio was 0·67 or higher. The co-primary outcome of occurrence of solicited adverse events (within 7 days of each dose) and unsolicited adverse events (up to 30 days after the last dose) was assessed in all participants who were enrolled and received at least one dose of study vaccine. The trial is registered with the Clinical Trials Registry - India (CTRI/2018/06/014601), and long-term follow-up is ongoing. FINDINGS: Between Sept 20, 2018, and Feb 9, 2021, 2341 individuals were screened, of whom 2307 eligible individuals were enrolled and vaccinated: 1107 (738 girls and 369 boys) in the cohort aged 9-14 years and 1200 (819 women and 381 men) in the cohort aged 15-26 years. No race or ethnicity data were collected. 350 girls and 349 boys in the SIIPL quadrivalent HPV vaccine group and 338 women in the comparator vaccine group were included in the modified per-protocol population for the primary endpoint analysis. The median follow-up for the analyses was 221 days (IQR 215-231) for girls and 222 days (217-230) for boys in the SIIPL quadrivalent HPV vaccine group, 223 days (216-232) for girls in the comparator vaccine group, and 222 days (216-230) for women in the comparator vaccine group. GMT ratios were non-inferior in girls and boys receiving the SIIPL quadrivalent HPV vaccine compared with women receiving the comparator vaccine: GMT ratios for girls were 1·97 (98·75% CI 1·67-2·32) for HPV type 6, 1·63 (1·38-1·91) for HPV type 11, 1·90 (1·60-2·25) for HPV type 16, and 2·16 (1·79-2·61) for HPV type 18. For boys the GMT ratios were 1·86 (1·57-2·21) for HPV type 6, 1·46 (1·23-1·73) for HPV type 11, 1·62 (1·36-1·94) for HPV type 16, and 1·80 (1·48-2·18) for HPV type 18. The safety population comprised all 1107 participants (369 girls and 369 boys in the SIIPL quadrivalent HPV vaccine group, and 369 girls in the comparator group). Solicited adverse events occurred in 176 (48%) of 369 girls and 124 (34%) of 369 boys in the SIIPL vaccine group and 179 (49%) of 369 girls in the comparator vaccine group. No grade 3-4 solicited adverse events occurred within 7 days of each dose. Unsolicited adverse events occurred in 143 (39%) girls and 147 (40%) boys in the SIIPL vaccine group, and 143 (39%) girls in the comparator vaccine group. The most common grade 3 unsolicited adverse event was dengue fever, in one (<1%) girl in the SIIPL vaccine group and three (1%) girls in the comparator group. There were no grade 4 or 5 adverse events. Serious adverse events occurred in three (1%) girls and three (1%) boys in the SIIPL vaccine group, and five (1%) girls in the comparator vaccine group. No vaccine-related serious adverse events were reported. There were no treatment-related deaths. INTERPRETATION: We observed a non-inferior immune response with the SIIPL quadrivalent HPV vaccine in girls and boys aged 9-14 years and an acceptable safety profile compared with the comparator vaccine. These findings support extrapolation of efficacy from the comparator vaccine to the SIIPL quadrivalent HPV vaccine in the younger population. The availability of the SIIPL quadrivalent HPV vaccine could help meet the global demand for HPV vaccines, and boost coverage for both girls and boys globally. FUNDING: Biotechnology Industry Research Assistance Council, Department of Biotechnology (DBT), Government of India, and Serum Institute of India.

Papiloma Conjuntival: revisión bibliográfica / Conjunctival Papilloma: a literature review

Objetivo: El objetivo de la realización del presente artículo de revisión bibliográfica es analizar las características del Papiloma conjuntival como: el pronóstico, prevalencia, relación con el VPH, diagnóstico, tratamiento e importancia que representa la presencia del mismo. Métodos: El siguiente artículo se realizó mediante la búsqueda de artículos científicos en español e inglés, mismos que fueron obtenidos a través de base de datos como Scopus, PubMed y Google Academic. Se hizo usó de la plataforma virtual de la biblioteca católica de Cuenca utilizando comandos de búsqueda avanzada (""), AND, OR. Finalmente se incluyeron 15 artículos dentro de la revisión bibliográfica. Para el trabajo conjunto de los colaboradores se hizo uso de la plataforma Google Drive. Resultados: Papiloma conjuntival es un tumor de células escamosas benigno de la conjuntiva con una tendencia mínima a la malignidad. Estos tumores están relacionados con el VPH específicamente los tipos VI y XI. Para obtener un diagnóstico es importante realizar una anamnesis y un examen oftalmológico exhaustivo, una biopsia posterior a la extirpación de la lesión, la tomografía de coherencia óptica de alta definición (HR-OCT), y la biomicroscopia ultrasónica (UBM). El MSP, ha elaborado una iniciativa denominada "Programa Ampliado de Inmunizaciones (PAI)", mismo que consiste en el proceso de vacunación de la población femenina de 9, 10 y 11 años pertenecientes a escuelas públicas y privadas. Conclusiones: Es importante que las instituciones educativas fomenten más la salud ocular porque al momento de que existe un contagio de VPH hay riesgo de tener papiloma conjuntival y las personas desconocen este medio de transmisión. Además, se debe promover la vacunación en niños porque cualquier género es propenso a adquirir el VPH

Objective: The aim of this literature review article is to analyze the characteristics of: conjunctival papilloma such as prognosis, prevalence, relationship with HPV, diagnosis, treatment and importance of its presence. Methods: The following article was carried out by searching scientific articles in Spanish and English, which were obtained through databases such as Scopus, PubMed and Google Academic. We used the virtual platform of the Catholic Library of Cuenca using advanced search commands (""), AND, OR. Finally, 15 articles were included in the biliographic review. For the joint work of the collaborators, use was made of the Google Drive platform. Results: Conjunctival papilloma is a benign squamous cell tumor of the conjunctiva with a minimal tendency to malignancy. These tumors are related to HPV specifically types VI and XI. To obtain a diagnosis it is important to perform a thorough anamnesis and ophthalmologic examination, a biopsy after removal of the lesion, high-definition optical coherence tomography (HR-OCT), and ultrasonic biomicroscopy (UBM). The MSP has developed an initiative called "Expanded Program of Immunizations (PAI)", same that consists of the vaccination process of the female population of 9, 10 and 11 years old belonging to public and private schools. Conclusions: It is important that educational institutions promote more eye health because when there is an HPV infection there is a risk of having conjunctival papilloma and people are unaware of this means of transmission. In addition, vaccination should be promoted in children because any gender is prone to acquire HPV.

Interim Results of a Phase 1/2 Open-Label Study of INO-3107 for HPV-6 and/or HPV-11-Associated Recurrent Respiratory Papillomatosis.

OBJECTIVE: To evaluate the safety, immunogenicity, and efficacy of INO-3107, a DNA immunotherapy designed to elicit targeted T-cell responses against human papillomavirus (HPV) types 6 and 11, in adult patients with recurrent respiratory papillomatosis (RRP; NCT04398433). METHODS: Eligible patients required ≥2 surgical interventions for RRP in the year preceding dosing. INO-3107 was administered by intramuscular (IM) injection followed by electroporation (EP) on weeks 0, 3, 6, and 9. Patients underwent surgical debulking within 14 days prior to first dose, with office laryngoscopy and staging at screening and weeks 6, 11, 26, and 52. Primary endpoint was safety and tolerability, as assessed by treatment-emergent adverse events (TEAEs). Secondary endpoints included frequency of surgical interventions post-INO-3107 and cellular immune responses. RESULTS: An initial cohort of 21 patients was enrolled between October 2020 and August 2021. Fifteen (71.4%) patients had ≥1 TEAE; 11 (52.4%) were Grade 1, and 3 (14.3%) were Grade 3 (none treatment related). The most frequently reported TEAE was injection site or procedural pain (n = 8; 38.1%). Sixteen (76.2%) patients had fewer surgical interventions in the year following INO-3107 administration, with a median decrease of 3 interventions versus the preceding year. The RRP severity score, modified by Pransky, showed improvement from baseline to week 52. INO-3107 induced durable cellular responses against HPV-6 and HPV-11, with an increase in activated CD4 and CD8 T cells and CD8 cells with lytic potential. CONCLUSION: The data suggest that INO-3107 administered by IM/EP is tolerable and immunogenic and provides clinical benefit to adults with RRP. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:3087-3093, 2023.

Association between human papillomavirus particle production and the severity of recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) has a wide range of severity. We investigate the relationship between human papillomavirus (HPV) particle production and severity of RRP. From September 2005 to June 2021, 68 RRP samples (from 29 patients) were included. HPV type was determined. HPV viral load, physical status, and demographic and clinical characteristics were assessed. Immunohistochemistry (IHC) was performed for p16, Ki-67, L1, and E4. We used NanoSuit-CLEM (correlative light and electron microscopy) and transmission electron microscopy (TEM) to examine the samples. The total number of surgeries in HPV-positive and HPV-negative cases were 3.78 (n = 55/68, range: 1-16) and 1.30 (n = 13/68, range: 1-3), respectively (p = 0.02). IHC showed that L1 and E4 were correlated and expressed on the tumour surface. NanoSuit-CLEM and TEM revealed HPV particles in L1-positive nuclei. L1 IHC-positive cases had a shorter surgical interval (p < 0.01) and more frequent surgeries (p = 0.04). P16 IHC, viral load, and physical status were not associated with disease severity. This study visualised HPV particle production in RRP for the first time. Persistent HPV particle infection was associated with severity. We suggest L1 IHC for evaluating RRP severity in addition to the Derkay score.

Human papillomavirus vaccination in Africa: An airway perspective.

INTRODUCTION: Recurrent respiratory papillomatosis (RRP) is a chronic condition caused by Human papillomavirus six (HPV-6) and HPV-11 that involves the respiratory tract. Disease severity ranges from mild (hoarseness), through to severe (stridor, respiratory distress and airway emergencies). Africa has the fastest growing and youngest population of all the continents. It also has the greatest burden of cervical cancer. There is an association with infection of the oncogenic HPV strains and the strains responsible for RRP. It is reasonable to conclude that although RRP may be underestimated in low-to-middle-income countries, it poses a considerable health risk to Africa. The primary aim of this project was to assess the suitability of HPV vaccination coverage on the African continent. METHODS: A prospective study was designed to consist of an online survey. It was distributed to 135 African otolaryngologists. Questions focussed on HPV vaccination programmes; whether they were government directed; and their rollout. Information from countries that had multiple otolaryngologists respond to the survey were compared. Additionally, data review and corroboration were performed. RESULTS: There were 58 (43%) participants from 19 countries. Nine countries reported a national vaccination programme (NVP), five used Cervarix; four used quadrivalent Gardasil. Collateral data revealed 18 of 54 countries had NVP in Africa and 26 countries had completed HPV vaccine pilot or demonstration projects. CONCLUSIONS: HPV vaccination in Africa should be urgently re-evaluated to include the HPV-6 and HPV-11 strains that cause JORRP, which have not been recognised during national vaccination programme planning.

Human papillomavirus in men.

OBJECTIVE: To describe the clinical behavior of human papillomavirus in men. MATERIALS AND METHODS: Current international literature was reviewed to describe the clinical behavior of human papillomavirus in men. RESULTS: Internationally, the overall prevalence of HPV DNA is 50.8%, HPV considered high risk are 14 types. Prevalence of HPV DNA in invasive penile cancer ranges from 33.1% to 47%. HPV-16 has been the most frequent (68.3%), followed by HPV-6 (8.1%) and HPV-18 (6.9%). Positive HPV is described as an independent prognostic factor for cancer-specific survival. CONCLUSION: It is not clear why HPV infection has a predilection in specific areas of the genital tract. However, it is important to note that there are factors that increase the risk of HPV infection.

Communicating with caregivers about the Human Papillomavirus vaccination: facilitator’s guide

This guide is designed to accompany the training module, Communicating with caregivers about the Human Papillomavirus vaccination: a tool to build confidence in communication skills among health workers. It provides detailed explanations, resources, guidance and training activities to accompany the slides in the training module and support those implementing the training. It is intended for facilitators who will be conducting the training either in-person or online. Facilitators can use this guide to help them adapt the training content to their local context and facilitate discussion with training participants. Facilitators are encouraged to have this guide available to them as a tool during the training session.

Communicating with caregivers about the Human Papillomavirus vaccination: a tool to build confidence in communication skills among health workers

This training module is designed to equip health workers (HWs) with knowledge, skills, confidence and resources to help them in their role to recommend the Human Papillomavirus (HPV) vaccine. It provides a structured approach to assist HWs when communicating with caregivers about HPV vaccination.

Systematic review of the use of human papillomavirus vaccine as adjuvant therapy for juvenile-onset recurrent respiratory papillomatosis.

INTRODUCTION: Juvenile-onset RRP (JoRRP) is considered a rare disease with high morbidity and healthcare costs. The management of RRP has received much scientific attention in recent years and several treatment methodologies have been explored, including therapeutic use of HPV vaccine. There has been increasing interest in the off-label use of the vaccine in virus-induced disease processes such as RRP, due to its immunomodulatory effect and activating role on the innate and adaptive immune system. This review explores the efficacy of the HPV vaccination as a therapeutic tool in the pediatric population. METHODS: The review of the English literature included three electronic databases, PubMed, SCOPUS, and Cochrane, without publication date restrictions. Studies and reports identified by the database search were reviewed and assessed by two independent reviewers. RESULTS: The literature searches identified 768 unique citations, from which 204 duplicates were removed (n = 564). A total of 547 articles were excluded as they did not meet our inclusion criteria. A total of 12 studies (3 experimental studies, 3 case series, 6 case reports) that met the inclusion criteria and reported one or more of the outcomes of interest were included for our review. The assessment of the outcome measures evaluated (number of surgeries during the follow-up period, ISI, SPM, Derkay or severity scores, and remission status) revealed that eight out of 12 studies included in the review showed varying degrees of potential benefits from the administration of the vaccine as a treatment modality compared to surgical interventions and/or concurrent adjuvant therapies alone. CONCLUSION: We conclude that while the therapeutic use of HPV vaccination has shown promise for some JoRRP patients, it overall remains uncertain with the currently available data. There is a need for a prospective multi-centric trial with a larger sample size to fully characterize the potential use of the vaccine in the management of JoRRP.

Tumor de Buschke ­ Löwenstein: Presentación de un Caso y Revisión Bibliográfica / Buschke ­ Löwenstein Tumor: A Case Report and Review of the Literature

Introducción: El tumor de Buschke ­ Lowenstein (TBL) es enfermedad de transmisión sexual causada por el virus del papiloma humano (VPH), descrita como una forma intermedia entre un condiloma acuminado y un carcinoma de células escamosas. Afecta principalmente al área genital y anorrectal, posee capacidad de transformación maligna y una alta tasa de recurrencia. La cirugía es el tratamiento de primera línea. Caso clínico: Presentamos el caso de un paciente masculino de 27 años con lesiones verrucosas de crecimiento progresivo en el área inguinal y genital. Mediante la correlación clínico-patológica se llegó al diagnóstico de TBL. Tras discusión en comité multidisciplinario se declaró irresecable y se resolvió tratamiento con radioterapia, además vacunación terapéutica contra el VPH, tanto sistémica como intralesional. Conclusión: El TBL es localmente agresivo y de difícil tratamiento, por lo que la prevención contra el VPH es fundamental. La vacunación terapéutica en conjunto con la radioterapia ofreció mejoría clínica.

Introduction: Buschke-Lowenstein tumor (BLT) is a sexually transmitted disease caused by the human papillomavirus (HPV), described as an intermediate form between condyloma acuminata and squamous cell carcinoma. It mainly affects the genital and anorectal areas and has the capacity for malignant transformation and a high recurrence rate. Surgery is the first-line treatment. Clinical case: We present the case of a 27-year-old male patient with warty lesions of progressive growth in the inguinal and genital areas. Through the clinical-pathological correlation, the diagnosis of BLT was reached. After discussion in a multidisciplinary committee, it was declared unresectable, and treatment with radiotherapy was resolved, in addition to therapeutic vaccination against HPV, both systemic and intralesional. Conclusion: BLT is locally aggressive and challenging to treat, so prevention against HPV is essential. Therapeutic vaccination in conjunction with radiotherapy offered clinical improvement.

Virus del papiloma humano en varones menores de cuatro años / Human papillomavirus in boys under 4-year old

No disponible

Internal heating method of loop-mediated isothermal amplification for detection of HPV-6 DNA.

Loop-mediated isothermal amplification (LAMP) is a promising diagnostic tool for genetic amplification, which is known for its rapid process, simple operation, high amplification efficiency, and excellent sensitivity. However, most of the existing heating methods are external for completion of molecular amplification with possibility of contamination of specimens. The present research provided an internal heating method for LAMP using magnetic nanoparticles (MNPs), which is called nano-LAMP. Near-infrared light with an excitation wavelength of 808 nm was employed as the heating source; hydroxy naphthol blue (HNB) was used as an indicator to conduct methodological research. We demonstrate that the best temperature was controlled at a working power of 2 W and 4.8 µg/µL concentration of nanoparticles. The lowest limit for the detection of HPV by the nano-LAMP method is 102 copies/mL, which was confirmed by a gel electrophoresis assay. In the feasibility investigation of validated clinical samples, all 10 positive HPV-6 specimens amplified by nano-LAMP were consistent with conventional LAMP methods. Therefore, the nano-LAMP detection method using internal heating of MNPs may bring a new vision to the exploration of thermostatic detection in the future.

Seroprevalence of mucosal and cutaneous human papillomavirus (HPV) types among children and adolescents in the general population in Germany.

BACKGROUND: In Germany, HPV vaccination of adolescent girls was introduced in 2007. Nationally representative data on the distribution of vaccine-relevant HPV types in the pre-vaccination era are, however, only available for the adult population. To obtain data in children and adolescents, we assessed the prevalence and determinants of serological response to 16 different HPV types in a representative sample of 12,257 boys and girls aged 1-17 years living in Germany in 2003-2005. METHODS: Serum samples were tested for antibodies to nine mucosal and seven cutaneous HPV types. The samples had been collected during the nationally representative German Health Interview and Examination Survey for Children and Adolescents in 2003-2006. We calculated age- and gender-specific HPV seroprevalence. We used multivariable regression models to identify associations between demographic and behavioral characteristics and HPV seropositivity. RESULTS: We found low but non-zero seroprevalence for the majority of tested HPV types among children and adolescents in Germany. The overall seroprevalence of HPV-16 was 2.6%, with slightly higher values in adolescents. Seroprevalence of all mucosal types but HPV-6 ranged from 0.6% for HPV-33, to 6.4% for HPV-31 and did not differ by gender. We found high overall seroprevalence for HPV-6 with 24.8%. Cutaneous HPV type seroprevalence ranged from 4.0% for HPV-38 to 31.7% for HPV-1. In the majority of cutaneous types, seroprevalence did not differ between boys and girls, but increased sharply with age, (e.g., HPV-1 from 1.5% in 1-3-years-old to 45.1% in 10-11-years-old). Associations between behavioral factors and type-specific HPV prevalence were determined to be heterogeneous. CONCLUSIONS: We report the first nationally representative data of naturally acquired HPV antibody reactivity in the pre-HPV-vaccination era among children and adolescents living in Germany. These data can be used as baseline estimates for evaluating the impact of the current HPV vaccination strategy targeting 9-14-years-old boys and girls.

Transcriptomic Landscape of Gene Expression Profiles and Pathways in Juvenile-Onset Recurrent Respiratory Papillomatosis Tumor Tissues and Human Papillomavirus 6 and 11 E6- and E7-Overexpressing Head and Neck Squamous Cell Carcinoma Cell Lines.

Juvenile-onset recurrent respiratory papillomatosis (JORRP) is the most common benign laryngeal neoplasm in children and is considered to be primarily caused by human papillomavirus (HPV) types 6 and 11. In the present study, we performed RNA sequencing (RNA-seq) of 8 tumors and 4 adjacent nontumor tissues to explore the transcriptional profiles of JORRP tumors. A total of 1,151 upregulated genes involved in the interleukin-17 (IL-17) signaling pathway and 1,620 downregulated genes involved in dysregulated inflammatory responses were reported. Immunohistochemistry (IHC) assays confirmed the upregulation of IL-17C in JORRP tumors compared with paired adjacent nontumor tissues. Real-time PCR (RT-PCR) assays showed positive correlations between CXCL1 (CXC chemokine ligands 1) and CXCL8 and the Derkay Clinic Score of JORRP patients. We further overexpressed the HPV6 or HPV11 E6 and E7 oncogenes in SNU-1076 head and neck squamous cell carcinoma (HNSCC) cell lines and carried out RNA-seq. We found that HPV6-E6-E7 gene overexpression resulted in only 16 upregulated genes and 1 downregulated gene; however, HPV11-E6-E7 gene overexpression resulted in 1,776 upregulated genes and 461 downregulated genes compared with the control cell lines. The differentially expressed genes (DEGs) of HPV11-E6-E7 gene overexpression were positively enriched in the DNA replication-related terms by Gene Ontology (GO) analysis and the IL-17 signaling pathway by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Taken together, our present findings revealed IL-17 signaling pathway-related gene profiles that might contribute to disease pathogenesis and that the HPV11 E6 and E7 oncogenes promote disease progression by enhancing tumor growth and activating the IL-17 signaling pathway in JORRP patients. IMPORTANCE Juvenile-onset recurrent respiratory papillomatosis (JORRP) is primarily caused by human papillomavirus 6 (HPV6) and HPV11 infection; however, the gene signatures of tumors are currently less understood. In the present study, we performed RNA sequencing and found upregulated genes associated with the IL-17 signaling pathway and downregulated genes associated with inflammatory-related pathways. Further RNA sequencing was performed in HPV6-E6-E7- or HPV11-E6-E7-overexpressing SNU-1076 HNSCC cells lines to explore the potential pathogenic molecular mechanisms of HPV virus. We found that HPV11-E6-E7 overexpression resulted in gene expression related to DNA replication and the IL-17 signaling pathway. Our results suggested enriched that the IL-17 signaling pathway resulting from HPV11 infection might contribute to JORRP pathogenesis.

Comprehensive multiomic characterization of human papillomavirus-driven recurrent respiratory papillomatosis reveals distinct molecular subtypes.

Recurrent respiratory papillomatosis (RRP) is a debilitating neoplastic disorder of the upper aerodigestive tract caused by chronic infection with low-risk human papillomavirus types 6 or 11. Patients with severe RRP can require hundreds of lifetime surgeries to control their disease and pulmonary papillomatosis can be fatal. Here we report the comprehensive genomic and transcriptomic characterization of respiratory papillomas. We discovered and characterized distinct subtypes with transcriptional resemblance to either a basal or differentiated cell state that associate with disease aggressiveness and differ in key molecular, immune and APOBEC mutagenesis profiles. Through integrated comparison with high-risk HPV-associated head and neck squamous cell carcinoma, our analysis revealed divergent molecular and immune papilloma subtypes that form independent of underlying genomic alterations. Cumulatively our results support the development of dysregulated cellular proliferation and suppressed anti-viral immunity through distinct programs of squamous cell differentiation and associated expression of low-risk HPV genes. These analyses provide insight into the pathogenesis of respiratory papillomas and provide a foundation for the development of therapeutic strategies.

Genomic diversity of human papillomavirus type 6 from patients with condyloma acuminatum in Eastern China.

OBJECTIVE: Human papillomavirus type 6 (HPV6) is the major etiological agent of anogenital warts both men and women. However, there is limited data on its genomic characterization in mainland China. The aim of this study was to understand the complete genomic diversity of HPV6 from patients with condyloma acuminatum (CA) and to explore the prevalence of different variant lineages/sublineages in eastern China. METHODS: CA samples were collected in 3 hospitals in Shandong Province, China from January 2020 to March 2021. DNA extraction, PCR amplification, Sanger sequencing and sequence assembly were performed on HPV6-positive samples. The complete genomes obtained in this study were analyzed phylogenetically with global HPV6 sequences in GenBank database using MEGA 11. RESULTS: A total of 55 complete genomic sequences of HPV6 were obtained in this study. They were classified as HPV6 variant lineage A (n = 20), sublineage B1 (n = 34) and sublineage B3 (n = 1) by phylogenetic analysis. Sequence alignment showed E1, E5A, E5B, L1, L2, LCR were relatively highly variable regions for sublineage B1 whereas E1, E5A, L2 for lineage A. Both phylogenetic trees of lineage A and sublineage B1 composed of two main branches. Chinese sequences of lineage A segregated into the major branch while those in sublineage B1 belonged to both branches. Genomic divergence between sequences from China and other countries was 0.00% - 0.33% in lineage A and 0.00% - 0.40% in sublineage B1. CONCLUSIONS: This is the first study on HPV variant lineages circulating in mainland China. The results revealed that lineage A and sublineage B1 were prevalent and they had different highly variable regions. Further surveillance is needed to understand the dynamic change of different variants in the population.

Development of Antibodies against HPV-6 and HPV-11 for the Study of Laryngeal Papilloma.

Laryngeal papilloma (LP), which is associated with infection by human papillomavirus (HPV)-6 or -11, displays aggressive growth. The precise molecular mechanism underlying the tumorigenesis of LP has yet to be uncovered. Building on our earlier research into HPV-6, in this study, the viral gene expression of HPV-11 was investigated by quantitative PCR and DNA/RNA in situ hybridization. Additionally, newly developed antibodies against the E4 protein of HPV-6 and HPV-11 were evaluated by immunohistochemistry. The average viral load of HPV-11 in LP was 1.95 ± 0.66 × 105 copies/ng DNA, and 88% of HPV mRNA expression was found to be E4, E5a, and E5b mRNAs. According to RNA in situ hybridization, E4 and E5b mRNAs were expressed from the middle to upper part of the epithelium. E4 immunohistochemistry revealed a wide positive reaction in the upper cell layer in line with E4 mRNA expression. Other head and neck lesions with HPV-11 infection also showed a positive reaction in E4 immunohistochemistry. The distribution pattern of HPV DNA, viral mRNA, and E4 protein in LP with HPV-11 infection was quite similar to that of HPV-6. Therefore, it might be possible to apply these E4-specific antibodies in other functional studies as well as clinical applications, including targeted molecular therapies in patients with HPV-6 and HPV-11 infection.