The efficacy and effectiveness of the quadrivalent human papillomavirus (HPV) vaccine in preventing high-grade cervical lesions have been shown. However, data to inform the relationship between quadrivalent HPV vaccination and the subsequent risk of invasive cervical cancer are lacking.

High-risk human papillomavirus (hrHPV) infection is established as the major cause of invasive cervical cancer (ICC). However, whether hrHPV status in the tumor is associated with subsequent prognosis of ICC is controversial. We aim to evaluate the association between tumor hrHPV status and ICC prognosis using national registers and comprehensive human papillomavirus (HPV) genotyping. In this nationwide population-based cohort study, we identified all ICC diagnosed in Sweden during the years 2002–2011 (4,254 confirmed cases), requested all archival formalin-fixed paraffin-embedded blocks, and performed HPV genotyping. Twenty out of 25 pathology biobanks agreed to the study, yielding a total of 2,845 confirmed cases with valid HPV results. Cases were prospectively followed up from date of cancer diagnosis to 31 December 2015, migration from Sweden, or death, whichever occurred first. The main exposure was tumor hrHPV status classified as hrHPV-positive and hrHPV-negative. The primary outcome was all-cause mortality by 31 December 2015. Five-year relative survival ratios (RSRs) were calculated, and excess hazard ratios (EHRs) with 95% confidence intervals (CIs) were estimated using Poisson regression, adjusting for education, time since cancer diagnosis, and clinical factors including age at cancer diagnosis and International Federation of Gynecology and Obstetrics (FIGO) stage. Of the 2,845 included cases, hrHPV was detected in 2,293 (80.6%), and we observed 1,131 (39.8%) deaths during an average of 6.2 years follow-up. The majority of ICC cases were diagnosed at age 30–59 years (57.5%) and classified as stage IB (40.7%). hrHPV positivity was significantly associated with screen-detected tumors, young age, high education level, and early stage at diagnosis (p < 0.001). The 5-year RSR compared to the general female population was 0.74 (95% CI 0.72–0.76) for hrHPV-positive cases and 0.54 (95% CI 0.50–0.59) for hrHPV-negative cases, yielding a crude EHR of 0.45 (95% CI 0.38–0.52) and an adjusted EHR of 0.61 (95% CI 0.52–0.71). Risk of all-cause mortality as measured by EHR was consistently and statistically significantly lower for cases with hrHPV-positive tumors for each age group above 29 years and each FIGO stage above IA. The difference in prognosis by hrHPV status was highly robust, regardless of the clinical, histological, and educational characteristics of the cases. The main limitation was that, except for education, we were not able to adjust for lifestyle factors or other unmeasured confounders. In this study, women with hrHPV-positive cervical tumors had a substantially better prognosis than women with hrHPV-negative tumors. hrHPV appears to be a biomarker for better prognosis in cervical cancer independent of age, FIGO stage, and histological type, extending information from already established prognostic factors. The underlying biological mechanisms relating lack of detectable tumor hrHPV to considerably worse prognosis are not known and should be further investigated.

The Swedish National Cervical Screening Registry collects and evaluates comprehensive, nationwide health data to optimise organised cervical cancer prevention. Since all cervical cancer specimens are saved in biobanks, population-based data from the specimens should be available for analysis and linkage with other health information. We identified all cervical cancers diagnosed in Sweden during 2002–2011 (4254 confirmed cases) and requested the tissue blocks to retrieve human papillomavirus (HPV) genotype data using general primer PCR with Luminex genotyping and real-time PCR targeting the E6/E7 regions of HPV16/18. We obtained blocks from 2932/4254 (69%) of cases. Valid HPV genotyping data was retrieved for 2850 cases (97%). The most common type was HPV16 (60%), followed by HPV18 (19%), HPV45 (7%), HPV31 (3%), HPV33 (2%), HPV52 (2%), HPV39 (1%), HPV70 (1%), HPV56 (1%), HPV35 (1%), HPV58 (1%) and HPV59 (1%). Ninety-six percent of all HPV-positive cases had a single infection. Eighty-nine cases were HPV-positive only when testing for the HPV16/18-E6/E7 region. We present one of the largest series of HPV-genotyped cervical cancers to date. The systematic collection of cervical cancer HPV genotyping data by the screening registry will facilitate prevention and monitoring of HPV type-specific disease burden.

Background: Human papillomavirus (HPV) vaccination is predicted to lower the positive predictive value (PPV) of cytology. Methods: We included 153,250 girls born between 1989 and 1993, resident in Sweden since the introduction of HPV vaccines (October 2006) and attending cervical screening at age 23 years. We assessed their first cytology and following histopathological diagnosis using Swedish National Cervical Screening Registry (NKCx). By linkage with the national Swedish HPV vaccination registry, we determined PPV of abnormal cytology for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and the differences with 95% confidence intervals (CIs) according to vaccination status. Results: The PPV of high-grade cytology for CIN2+ was 69.9% (95% CI, 67.9–71.9), 64.9% (95% CI, 59.8–69.8) and 57.4% (95% CI, 50.9–63.7) among women unvaccinated, initiating vaccination at age 17–22 years and initiating vaccination before age 17 years, corresponding to reduction in PPV by 8% (95% CI, 0–15%) and 17% (95% CI, 7–26%) in vaccinated groups after adjustment for birth cohort, respectively. Conclusion: The PPV of cytology for CIN2+ decreased among vaccinated women, and the decrease was stronger for girls vaccinated at younger ages. A switch from cytology to HPV testing might potentially improve the screening performance.

Reporting of adverse events following immunization (AEFI) is a key component for functional vaccine safety monitoring system. The aim of our study is to document trends in the AEFI reporting ratio globally and across the six World Health Organization (WHO) regions. We describe the number of AEFI reports communicated each year through the World Health Organization/United Nations Children's Fund Joint Reporting Form on Immunization from 2000 to 2015. The AEFI reporting ratios (annual AEFI reports per 100,000 surviving infants) were calculated to identify WHO countries (n = 191 in 2000 and n = 194 by 2015) that met a minimal reporting ratio of 10, a target set by the Global Vaccine Action Plan for vaccine safety monitoring as a proxy measure for a functional AEFI reporting system. The number of countries reporting any AEFI fluctuated over time but with progress from 32 (17%) in 2000 to 124 (64%) in 2015. In 2015, the global average AEFI reporting ratio was 549 AEFI reports per 100,000 surviving infants. The number of countries with AEFI reporting ratios greater than 10 increased from 8 (4%) in 2000 to 81 (42%) in 2015. In 2015, 60% of countries in the WHO Region of the Americas reported at least 10 AEFI per 100,000 surviving infants, followed by 55% in European Region, 43% in Eastern Mediterranean Region, 33% in Western Pacific Region, 27% in South-East Asia Region and 21% in African Region. Overall, AEFI reporting has increased over the past sixteen years worldwide, but requires strengthening in a majority of low- and middle- income countries. The AEFI reporting ratio is useful for benchmarking and following trends over time; but does not provide information on the quality of the reporting system and does not guarantee capacity to detect and manage a vaccine safety problem at a national level. Additional efforts are required to ensure and improve data quality, AEFI reporting and surveillance of immunization safety in every country.

Background: Human papillomavirus (HPV) is a necessary cause of cervical cancer, although some invasive cervical cancers may test negative by HPV PCR. We previously requested all invasive cervical cancers in Sweden during 10 years and subjected them to PCR. We also optimised methods for deep sequencing of formalin-fixed paraffin-embedded samples. Methods: Using Novaseq 6000, we simultaneously sequenced total DNA and cDNA from 392 HPV PCR-negative cervical cancers. Non-human reads were queried against all known HPVs. The complete database now contains PCR and/or deep sequencing data on 2850 invasive cervical cancers. Results: HPV sequences were detected in 169/392 of HPV PCR-negative cervical cancers. Overall, 30 different HPV types were detected, but only 5 types were present in proportions above 3% of cancers. More than 92% of tumours were HPV-positive in PCR and/or sequencing (95% confidence interval: 91.1–93.1%). Exploring possible reasons for failure to previously detect HPV suggest that more sensitive type-specific PCRs for HPV 31, 33, 45 and 73 targeting retained regions of HPV would have detected most of these (117/392). Conclusions: Unbiased deep sequencing provides comprehensive data on HPV types in cervical cancers and appears to be an important tool for quality assurance of HPV screening.