HPV Vaccination and the Risk of Invasive Cervical Cancer Lei, Jiayao; Ploner, Alexander; Elfström, K Miriam ...
New England journal of medicine/The New England journal of medicine,
10/2020, Volume:
383, Issue:
14
Journal Article
Peer reviewed
Open access
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.
We used nationwide Swedish demographic and health registers to follow an open population of 1,672,983 girls and women who were 10 to 30 years of age from 2006 through 2017. We assessed the association between HPV vaccination and the risk of invasive cervical cancer, controlling for age at follow-up, calendar year, county of residence, and parental characteristics, including education, household income, mother's country of birth, and maternal disease history.
During the study period, we evaluated girls and women for cervical cancer until their 31st birthday. Cervical cancer was diagnosed in 19 women who had received the quadrivalent HPV vaccine and in 538 women who had not received the vaccine. The cumulative incidence of cervical cancer was 47 cases per 100,000 persons among women who had been vaccinated and 94 cases per 100,000 persons among those who had not been vaccinated. After adjustment for age at follow-up, the incidence rate ratio for the comparison of the vaccinated population with the unvaccinated population was 0.51 (95% confidence interval CI, 0.32 to 0.82). After additional adjustment for other covariates, the incidence rate ratio was 0.37 (95% CI, 0.21 to 0.57). After adjustment for all covariates, the incidence rate ratio was 0.12 (95% CI, 0.00 to 0.34) among women who had been vaccinated before the age of 17 years and 0.47 (95% CI, 0.27 to 0.75) among women who had been vaccinated at the age of 17 to 30 years.
Among Swedish girls and women 10 to 30 years old, quadrivalent HPV vaccination was associated with a substantially reduced risk of invasive cervical cancer at the population level. (Funded by the Swedish Foundation for Strategic Research and others.).
Abstract Established Human Papillomavirus (HPV) types, up to HPV202, belong to 49 species in five genera. International standardization in classification and quality standards for HPV type ...designation and detection is ensured by the International HPV Reference Center. The center i) receives clones of potentially novel HPV types, re-clones and re-sequences them. If confirmed, an HPV type number is assigned and posted on www.hpvcenter.se . ii) distributes reference clone samples, for academic research, under Material Transfer Agreements agreed with the originator. iii) provides preliminary checking of whether new sequences represent novel types iv) issues international proficiency panels for HPV genotyping. The rate of HPV type discovery is increasing, probably because of metagenomic sequencing. γ -genus today contains 79 HPV types and 27 species, surpassing ∝ and β genera with 65 and 51 HPV types, respectively. Regular issuing of proficiency panels based on HPV reference clones has resulted in global improvement of HPV genotyping services.
Human papillomavirus (HPV) is the most common sexually transmitted infectious agent; its 14 oncogenic types are causally associated with 5-10% of all cancers. The major structural HPV protein ...self-assembles into immunogenic virus-like particles. Two licensed HPV vaccines--the bivalent vaccine comprising HPV types 16 and 18, and the quadrivalent vaccine comprising HPV types 6, 11, 16 and 18--have proven to be safe and efficacious against 6-month-persistent cervical infections of HPV16 and HPV18 and associated precancerous lesions, and both have efficacies of 90-100%. Among baseline HPV-negative adolescent females, vaccine efficacies against the immediate precursor of cervical cancer (intraepithelial neoplasia grade 3) irrespective of HPV type are 93.2% and 43.0% for the bivalent and quadrivalent vaccines, respectively. The quadrivalent vaccine is efficacious (>75% vaccine efficacy) against any of the more-severe precursors of vulval, vaginal and anal cancers. A strong increase in vaccine efficacy with increasing severity of the precancerous lesion is explained by accumulation of the most-oncogenic HPV types 16 and 18 in these lesions. Therefore, prophylactic HPV vaccination will exceed the best results from screening for cancer. With the extremely efficacious prophylactic HPV vaccines, the focus of organized intervention (vaccination and screening) programmes should, however, shift from reducing the HPV disease burden to controlling the prevalence of oncogenic HPV (and nononcogenic HPV) types. Eradication of the major oncogenic HPV types should be pursued.
Despite its clinical importance, detection of highly divergent or yet unknown viruses is a major challenge. When human samples are sequenced, conventional alignments classify many assembled contigs ...as "unknown" since many of the sequences are not similar to known genomes. In this work, we developed ViraMiner, a deep learning-based method to identify viruses in various human biospecimens. ViraMiner contains two branches of Convolutional Neural Networks designed to detect both patterns and pattern-frequencies on raw metagenomics contigs. The training dataset included sequences obtained from 19 metagenomic experiments which were analyzed and labeled by BLAST. The model achieves significantly improved accuracy compared to other machine learning methods for viral genome classification. Using 300 bp contigs ViraMiner achieves 0.923 area under the ROC curve. To our knowledge, this is the first machine learning methodology that can detect the presence of viral sequences among raw metagenomic contigs from diverse human samples. We suggest that the proposed model captures different types of information of genome composition, and can be used as a recommendation system to further investigate sequences labeled as "unknown" by conventional alignment methods. Exploring these highly-divergent viruses, in turn, can enhance our knowledge of infectious causes of diseases.
At the onset of the COVID-19 pandemic cervical screening in the capital region of Sweden was canceled for several months. A series of measures to preserve and improve the cervical screening under the ...circumstances were instituted, including a switch to screening with HPV self-sampling to enable screening in compliance with social distancing recommendations.
We describe the major changes implemented, which were (1) nationwide implementation of HPV screening, (2) switch to primary self-sampling instead of clinician sampling, (3) implementation of HPV screening in all screening ages, and (4) combined HPV vaccination and HPV screening in the cervical screening program.
A temporary government regulation allowed primary self-sampling with HPV screening in all ages. In the Stockholm region, 330,000 self-sampling kits were sent to the home address of screening-eligible women, instead of an invitation to clinician sampling. An increase in organized population test coverage was seen (from 54% to 60% in just 1 year). In addition, a national campaign for faster elimination of cervical cancer with concomitant screening and vaccination for women in ages 23-28 was launched.
The COVID-19 pandemic necessitated major changes in the cervical cancer preventive strategies, where it can already be concluded that the strategy with organized primary self-sampling for HPV has resulted in a major improvement of population test coverage.
Funded by the Swedish Association of Local Authorities and Regions, the Swedish Cancer Society, the European Union's Horizon 2020 Research and Innovation Program, the Swedish government, and the Stockholm county.
The rapidly increasing incidence and mortality of cancer calls for a focused effort to increase the effect of cancer‐prevention efforts. In the area of early detection, there are major differences in ...the preventive impact of implemented screening policies, even when solid, evidence‐based international recommendations are issued. Studies are needed to determine why evidence‐based interventions are not used and to investigate why effects are less than predicted by solid research on the subject. Currently, population‐based screening is recommended only for three forms of cancer (cervical, breast and colorectal cancer) but, given the increasing cancer burden, efforts are required to facilitate the discovery of new biomarkers for screening, as well as the identification of barriers to implementation of new cancer screening discoveries. The creation of a network of excellence in research on Cancer Prevention (Cancer Prevention Europe) is likely to significantly contribute to progress in these areas. In the present review, some possible strategies to ensure progress are discussed, with specific examples from the cervical cancer screening area.
The rapidly increasing incidence and mortality of cancer calls for a focused effort to increase the effect of cancer prevention strategies. In the area of early detection, there are major differences in the preventive impact of implemented screening policies, even when solid, evidence‐based international recommendations are issued. In the present review, some possible strategies to ensure progress are discussed, with specific examples from the cervical cancer screening area.
Abstract Systematic reviews of the prevalence of different types of Human Papillomavirus (HPV) across a broad range of disease grades from normal to cancer are essential to gain basic knowledge of ...how widespread infections with the different HPV types are, and to provide information on the possible carcinogenicity of different HPV types. For HPV types that infect human mucosa, of which 12 are established causes of cervical cancer, we present the results of a systematic review and meta-analysis of 47 HPV types in cervical samples across the entire range of cervical diagnoses from normal to cervical cancer, restricted to studies using a number of well characterized PCR assays. For the cutaneous HPV types, which have been linked to the development of squamous cell carcinoma of the skin, their presence has been measured in a variety of different sample types and by assays with variable performance. Therefore, we restricted a systematic review of their prevalence to studies that assayed for cutaneous HPV infection in a case-control format.
Abstract
Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). This study aimed to determine if SARS-CoV-2 RNA in serum at admission ...correlated with clinical outcome in COVID-19.
Methods
COVID-19 patients admitted to the infectious diseases department of a tertiary level Swedish hospital and sampled for SARS-CoV-2 RNA in serum at admission during 10 April to 30 June 2020 were included. Primary outcomes were day 28 all-cause mortality and progress to critical disease.
Results
The cohort (N = 167) consisted of 106 SARS-CoV-2 RNA serum-negative and 61 serum-positive patients. Median sampling time for initial SARS-CoV-2 in serum was 1 day (interquartile range IQR, 1–2 days) after admission, corresponding to day 10 (IQR, 8–12) after symptom onset. Median age was 53 years (IQR, 44–67 years) and 63 years (IQR, 52–74 years) for the serum–negative and -positive patients, respectively. In the serum-negative and -positive groups, 3 of 106 and 15 of 61 patients died, respectively.
The hazard ratios for critical disease and all-cause mortality were 7.2 (95% confidence interval CI, 3.0–17) and 8.6 (95% CI, 2.4–30), respectively, for patients with serum–positive compared to serum–negative results.
Conclusions
SARS-CoV-2 RNA in serum at hospital admission indicates a high risk of progression to critical disease and death.
Severe acute respiratory syndrome coronavirus 2 RNA in serum at admission was associated with a 7-fold increased risk of critical disease and an 8-fold increased risk of death in a cohort of 167 patients hospitalized for coronavirus disease 2019.
This paper summarises the position of ESGO and EFC on cervical screening based on existing guidelines and opinions of a team of lead experts. HPV test is replacing cytology as this offers greater ...protection against cervical cancer and allows longer screening intervals. Only a dozen of HPV tests are considered as clinically validated for screening. The lower specificity of HPV test dictates the use of triage tests that can select women for colposcopy. Reflex cytology is currently the only well validated triage test; HPV genotyping and p16 immunostaining may be used in the future, although methylation assays and viral load also look promising. A summary of quality assurance benchmarks is provided, and the importance to audit the screening histories of women who developed cancer is noted as a key objective. HPV-based screening is more cost-effective than cytology or cotesting. HPV-based screening should continue in the post-vaccination era. Only a fraction of the female population is vaccinated, and this varies across countries. A major challenge will be to personalise screening frequency according to vaccination status. Still the most important factor for successful prevention by screening is high population coverage and organised screening. Screening with self-sampling to reach under-screened women is promising.
Only clinically validated HPV assays can be accepted in cervical cancer screening.
To update the list of high-risk HPV assays that fulfil the 2009 international validation criteria (Meijer-2009).
...PubMed/Medline, Embase, Scopus, references from selected studies; published in January 2014 to August 2020.
HPV test validation studies and primary screening studies, involving testing with an index HPV test and a comparator HPV test with reporting of disease outcome (occurrence of histologically confirmed cervical precancer; CIN2+).
Women participating in cervical cancer screening.
Testing with an index and a comparator HPV test of clinician-collected cervical specimens and assessment of disease outcome (<CIN2, CIN2+). Comparator HPV assays were HC2, GP5+/6+ PCR-EIA, recommended in validation guidelines, or tests with consistent previous validations.
Assessment of relative clinical accuracy (including non-inferiority statistics index vs comparator assay) and test reproducibility in individual studies; random effects meta-analyses of the relative clinical sensitivity and specificity of index vs comparator tests.
Seven hrHPV DNA tests consistently fulfilled all validation criteria in multiple studies using predefined test positivity cut-offs (Abbott RealTime High Risk HPV, Anyplex II HPV HR Detection, BD Onclarity HPV Assay, Cobas 4800 HPV Test, HPV-Risk Assay, PapilloCheck HPV-Screening Test and Xpert HPV). Another assay (Alinity m HR HPV Assay) was fully validated in one validation study. The newer Cobas 6800 HPV Test, was validated in two studies against Cobas 4800. Other tests partially fulfilled the international validation criteria (Cervista HPV HR Test, EUROArray HPV, Hybribio's 14 High-Risk HPV, LMNX Genotyping Kit GP HPV, MALDI-TOF, RIATOL qPCR and a number of other in-house developed assays) since the non-inferior accuracy was reached after a posteriori cut-off optimization, inconsistent accuracy findings in different studies, and/or insufficient reproducibility assessment. The APTIMA HPV Assay targeting E6/E7 mRNA of hrHPV was fully validated in one formal validation study and showed slightly lower pooled sensitivity but higher specificity than the standard comparator tests in seven screening studies. However, the current international validation criteria relate to DNA assays. The additional requirement for longitudinal performance data required for non-DNA based HPV assays was not assessed in this review.
Eleven hrHPV DNA assays fulfil all requirements for use in cervical cancer screening using clinician-collected specimens.
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