Virus-like particles derived from major capsid protein VP1 of different polyomaviruses differ in their ability to induce maturation in human dendritic cells

AbstractAs polyomavirus major capsid protein VP1-derived virus-like particles (VLPs) have been demonstrated to be highly immunogenic, we studied their interaction with human dendritic cells (hDCs). Exposure of hDCs to VLPs originating from murine (MPyV) or hamster polyomavirus (HaPyV) induced hDC maturation. In contrast, exposure of hDCs to VLPs derived from human polyomaviruses (BK and JC) and simian virus 40 (SV40) only marginally induced DC maturation. The hDCs stimulated by HaPyV- or MPyV-derived VLPs readily produced interleukin-12 and stimulated CD8-positive T-cell responses in vitro. The highest frequencies of activated T cells were again observed after pulsing with HaPyV- and MPyV-derived VLPs. Monocyte-derived hDCs both bound and internalized the various tested polyomavirus VP1-derived VLPs with different levels of efficiency, partially explaining their individual maturation potentials. In conclusion, our data suggest a high variability in uptake of polyomavirus-derived VLPs and potency to induce hDC maturation

Oropharyngeal Cancer Epidemic and Human Papillomavirus

Patients with HPV-positive cancer were young and lacked traditional risk factors

Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis

Background More than 10 years have elapsed since human papillomavirus (HPV) vaccination was implemented. We did a systematic review and meta-analysis of the population-level impact of vaccinating girls and women against human papillomavirus on HPV infections, anogenital wart diagnoses, and cervical intraepithelial neoplasia grade 2+ (CIN2+)to summarise the most recent evidence about the effectiveness of HPV vaccines in real-world settings and to quantify the impact of multiple age-cohort vaccination.Methods In this updated systematic review and meta-analysis, we used the same search strategy as in our previous paper. We searched MEDLINE and Embase for studies published between Feb 1, 2014, and Oct 11, 2018. Studies were eligible if they compared the frequency (prevalence or incidence) of at least one HPV-related endpoint (genital HPV infections, anogenital wart diagnoses, or histologically confirmed CIN2+) between pre-vaccination and post-vaccination periods among the general population and if they used the same population sources and recruitment methods before and after vaccination. Our primary assessment was the relative risk (RR) comparing the frequency (prevalence or incidence) of HPV-related endpoints between the pre-vaccination and post-vaccination periods. We stratified all analyses by sex, age, and years since introduction of HPV vaccination. We used random-effects models to estimate pooled relative risks.Findings We identified 1702 potentially eligible articles for this systematic review and meta-analysis, and included 65 articles in 14 high-income countries: 23 for HPV infection, 29 for anogenital warts, and 13 for CIN2+.After 5\u20138 years of vaccination, the prevalence of HPV 16 and 18 decreased significantly by 83% (RR 0\ub717, 95% CI 0\ub711\u20130\ub725) among girls aged 13\u201319 years, and decreased significantly by 66% (RR 0\ub734, 95% CI 0\ub723\u20130\ub749) among women aged 20\u201324 years. The prevalence of HPV 31, 33, and 45 decreased significantly by 54% (RR 0\ub746, 95% CI 0\ub733\u20130\ub766) among girls aged 13\u201319 years. Anogenital wart diagnoses decreased significantly by 67% (RR 0\ub733, 95% CI 0\ub724\u20130\ub746) among girls aged 15\u201319 years, decreased significantly by 54% (RR 0\ub746, 95% CI 0.36\u20130.60) among women aged 20\u201324 years, and decreased significantly by 31% (RR 0\ub769, 95% CI 0\ub753\u20130\ub789) among women aged 25\u201329 years. Among boys aged 15\u201319 years anogenital wart diagnoses decreased significantly by 48% (RR 0\ub752, 95% CI 0\ub737\u20130\ub775) and among men aged 20\u201324 years they decreased significantly by 32% (RR 0\ub768, 95% CI 0\ub747\u20130\ub798). After 5\u20139 years of vaccination, CIN2+ decreased significantly by 51% (RR 0\ub749, 95% CI 0\ub742\u20130\ub758) among screened girls aged 15\u201319 years and decreased significantly by 31% (RR 0\ub769, 95% CI 0\ub757\u20130\ub784) among women aged 20\u201324 years.Interpretation This updated systematic review and meta-analysis includes data from 60 million individuals and up to 8 years of post-vaccination follow-up. Our results show compelling evidence of the substantial impact of HPV vaccination programmes on HPV infections and CIN2+ among girls and women, and on anogenital warts diagnoses among girls, women, boys, and men. Additionally, programmes with multi-cohort vaccination and high vaccination coverage had a greater direct impact and herd effects

Prognostic implications of p16 and HPV discordance in oropharyngeal cancer (HNCIG-EPIC-OPC): a multicentre, multinational, individual patient data analysis

Background p16(INK4a) (p16) immunohistochemistry is the most widely used biomarker assay for inferring HPV causation in oropharyngeal cancer in clinical and trial settings. However, discordance exists between p16 and HPV DNA or RNA status in some patients with oropharyngeal cancer. We aimed to clearly quantify the extent of discordance, and its prognostic implications. Methods In this multicentre, multinational individual patient data analysis, we did a literature search in PubMed and Cochrane database for systematic reviews and original studies published in English between Jan 1, 1970, and Sept 30, 2022. We included retrospective series and prospective cohorts of consecutively recruited patients previously analysed in individual studies with minimum cohort size of 100 patients with primary squamous cell carcinoma of the oropharynx. Patient inclusion criteria were diagnosis with a primary squamous cell carcinoma of oropharyngeal cancer; data on p16 immunohistochemistry and on HPV testing; information on age, sex, tobacco, and alcohol use; staging by TNM 7th edition; information on treatments received; and data on clinical outcomes and follow-up (date of last follow-up if alive, date of recurrence or metastasis, and date and cause of death). There were no limits on age or performance status. The primary outcomes were the proportion of patients of the overall cohort who showed the different p16 and HPV result combinations, as well as 5-year overall survival and 5-year disease-free survival. Patients with recurrent or metastatic disease or who were treated palliatively were excluded from overall survival and disease-free survival analyses. Multivariable analysis models were used to calculate adjusted hazard ratios (aHR) for different p16 and HPV testing methods for overall survival, adjusted for prespecified confounding factors. Findings Our search returned 13 eligible studies that provided individual data for 13 cohorts of patients with oropharyngeal cancer from the UK, Canada, Denmark, Sweden, France, Germany, the Netherlands, Switzerland, and Spain. 7895 patients with oropharyngeal cancer were assessed for eligibility. 241 were excluded before analysis, and 7654 were eligible for p16 and HPV analysis. 5714 (74middot7%) of 7654 patients were male and 1940 (25middot3%) were female. Ethnicity data were not reported. 3805 patients were p16-positive, 415 (10middot9%) of whom were HPV-negative. This proportion differed significantly by geographical region and was highest in the areas with lowest HPV-attributable fractions (r=-0middot744, p=0middot0035). The proportion of patients with p16+/HPV- oropharyngeal cancer was highest in subsites outside the tonsil and base of tongue (29middot7% vs 9middot0%, p<0middot0001). 5-year overall survival was 81middot1% (95% CI 79middot5-82middot7) for p16+/HPV+, 40middot4% (38middot6-42middot4) for p16-/HPV-, 53middot2% (46middot6-60middot8) for p16-/HPV+, and 54middot7% (49middot2-60middot9) for p16+/HPV-. 5-year disease-free survival was 84middot3% (95% CI 82middot9-85middot7) for p16+/HPV+, 60middot8% (58middot8-62middot9) for p16-/HPV-; 71middot1% (64middot7-78middot2) for p16-/HPV+, and 67middot9% (62middot5-73middot7) for p16+/HPV-. Results were similar across all European sub-regions, but there were insufficient numbers of discordant patients from North America to draw conclusions in this cohort. Interpretation Patients with discordant oropharyngeal cancer (p16-/HPV+ or p16+/HPV-) had a significantly worse prognosis than patients with p16+/HPV+ oropharyngeal cancer, and a significantly better prognosis than patients with p16-/HPV- oropharyngeal cancer. Along with routine p16 immunohistochemistry, HPV testing should be mandated for clinical trials for all patients (or at least following a positive p16 test), and is recommended where HPV status might influence patient care, especially in areas with low HPV-attributable fractions. Copyright (c) 2023 The Author(s). Published by Elsevier Ltd

Prognostic implications of p16 and HPV discordance in oropharyngeal cancer (HNCIG-EPIC-OPC): a multicentre, multinational, individual patient data analysis

Background: p16INK4a (p16) immunohistochemistry is the most widely used biomarker assay for inferring HPV causation in oropharyngeal cancer in clinical and trial settings. However, discordance exists between p16 and HPV DNA or RNA status in some patients with oropharyngeal cancer. We aimed to clearly quantify the extent of discordance, and its prognostic implications. Methods: In this multicentre, multinational individual patient data analysis, we did a literature search in PubMed and Cochrane database for systematic reviews and original studies published in English between Jan 1, 1970, and Sept 30, 2022. We included retrospective series and prospective cohorts of consecutively recruited patients previously analysed in individual studies with minimum cohort size of 100 patients with primary squamous cell carcinoma of the oropharynx. Patient inclusion criteria were diagnosis with a primary squamous cell carcinoma of oropharyngeal cancer; data on p16 immunohistochemistry and on HPV testing; information on age, sex, tobacco, and alcohol use; staging by TNM 7th edition; information on treatments received; and data on clinical outcomes and follow-up (date of last follow-up if alive, date of recurrence or metastasis, and date and cause of death). There were no limits on age or performance status. The primary outcomes were the proportion of patients of the overall cohort who showed the different p16 and HPV result combinations, as well as 5-year overall survival and 5-year disease-free survival. Patients with recurrent or metastatic disease or who were treated palliatively were excluded from overall survival and disease-free survival analyses. Multivariable analysis models were used to calculate adjusted hazard ratios (aHR) for different p16 and HPV testing methods for overall survival, adjusted for prespecified confounding factors. Findings: Our search returned 13 eligible studies that provided individual data for 13 cohorts of patients with oropharyngeal cancer from the UK, Canada, Denmark, Sweden, France, Germany, the Netherlands, Switzerland, and Spain. 7895 patients with oropharyngeal cancer were assessed for eligibility. 241 were excluded before analysis, and 7654 were eligible for p16 and HPV analysis. 5714 (74·7%) of 7654 patients were male and 1940 (25·3%) were female. Ethnicity data were not reported. 3805 patients were p16-positive, 415 (10·9%) of whom were HPV-negative. This proportion differed significantly by geographical region and was highest in the areas with lowest HPV-attributable fractions (r=–0·744, p=0·0035). The proportion of patients with p16+/HPV– oropharyngeal cancer was highest in subsites outside the tonsil and base of tongue (29·7% vs 9·0%, p<0·0001). 5-year overall survival was 81·1% (95% CI 79·5–82·7) for p16+/HPV+, 40·4% (38·6–42·4) for p16–/HPV–, 53·2% (46·6–60·8) for p16–/HPV+, and 54·7% (49·2–60·9) for p16+/HPV–. 5-year disease-free survival was 84·3% (95% CI 82·9–85·7) for p16+/HPV+, 60·8% (58·8–62·9) for p16–/HPV–; 71·1% (64·7–78·2) for p16–/HPV+, and 67·9% (62·5–73·7) for p16+/HPV–. Results were similar across all European sub-regions, but there were insufficient numbers of discordant patients from North America to draw conclusions in this cohort. Interpretation: Patients with discordant oropharyngeal cancer (p16–/HPV+ or p16+/HPV–) had a significantly worse prognosis than patients with p16+/HPV+ oropharyngeal cancer, and a significantly better prognosis than patients with p16–/HPV– oropharyngeal cancer. Along with routine p16 immunohistochemistry, HPV testing should be mandated for clinical trials for all patients (or at least following a positive p16 test), and is recommended where HPV status might influence patient care, especially in areas with low HPV-attributable fractions

Murine Polyomavirus Virus-Like Particles Carrying Full-Length Human PSA Protect BALB/c Mice from Outgrowth of a PSA Expressing Tumor

Virus-like particles (VLPs) consist of capsid proteins from viruses and have been shown to be usable as carriers of protein and peptide antigens for immune therapy. In this study, we have produced and assayed murine polyomavirus (MPyV) VLPs carrying the entire human Prostate Specific Antigen (PSA) (PSA-MPyVLPs) for their potential use for immune therapy in a mouse model system. BALB/c mice immunized with PSA-MPyVLPs were only marginally protected against outgrowth of a PSA-expressing tumor. To improve protection, PSA-MPyVLPs were co-injected with adjuvant CpG, either alone or loaded onto murine dendritic cells (DCs). Immunization with PSA-MPyVLPs loaded onto DCs in the presence of CpG was shown to efficiently protect mice from tumor outgrowth. In addition, cellular and humoral immune responses after immunization were examined. PSA-specific CD4+ and CD8+ cells were demonstrated, but no PSA-specific IgG antibodies. Vaccination with DCs loaded with PSA-MPyVLPs induced an eight-fold lower titre of anti-VLP antibodies than vaccination with PSA-MPyVLPs alone. In conclusion, immunization of BALB/c mice with PSA-MPyVLPs, loaded onto DCs and co-injected with CpG, induces an efficient PSA-specific tumor protective immune response, including both CD4+ and CD8+ cells with a low induction of anti-VLP antibodies

Human Papillomavirus (HPV) 16 E6 Variants in Tonsillar Cancer in Comparison to Those in Cervical Cancer in Stockholm, Sweden

Background: Human papillomavirus (HPV), especially HPV16, is associated with the development of both cervical and tonsillar cancer and intratype variants in the amino acid sequence of the HPV16 E6 oncoprotein have been demonstrated to be associated with viral persistence and cancer lesions. For this reason the presence of HPV16 E6 variants in tonsillar squamous cell carcinoma (TSCC) in cervical cancer (CC), as well as in cervical samples (CS), were explored. Methods: HPV16 E6 was sequenced in 108 TSCC and 52 CC samples from patients diagnosed 2000–2008 in the County of Stockholm, and in 51 CS from young women attending a youth health center in Stockholm. Results: The rare E6 variant R10G was relatively frequent (19%) in TSCC, absent in CC and infrequent (4%) in CS, while the well-known L83V variant was common in TSCC (40%), CC (31%), and CS (29%). The difference for R10G was significant between TSCC and CC (p = 0.0003), as well as between TSCC and CS (p = 0.009). The HPV16 European phylogenetic lineage and its derivatives dominated in all samples (.90%). Conclusion: The relatively high frequency of the R10G variant in TSCC, as compared to what has been found in CC both in the present study as well as in several other studies in different countries, may indicate a difference between TSCC and CC with regard to tumor induction and development. Alternatively, there could be differences with regard to the oral an