title: Current Safety Concerns with Human Papillomavirus Vaccine: A Cluster Analysis of Reports in VigiBase®.
abstract: A number of safety signals-complex regional pain syndrome (CRPS), postural orthostatic tachycardia syndrome (POTS), and chronic fatigue syndrome (CFS)-have emerged with human papillomavirus (HPV) vaccines, which share a similar pattern of symptomatology. Previous signal evaluations and epidemiological studies have largely relied on traditional methodologies and signals have been considered individually.
  
  
  
  The aim of this study was to explore global reporting patterns for HPV vaccine for subgroups of reports with similar adverse event (AE) profiles.
  
  
  
  All individual case safety reports (reports) for HPV vaccines in VigiBase®until 1 January 2015 were identified. A statistical cluster analysis algorithm was used to identify natural groupings based on AE profiles in a data-driven exploratory analysis. Clinical assessment of the clusters was performed to identify clusters relevant to current safety concerns.
  
  
  
  Overall, 54 clusters containing at least five reports were identified. The four largest clusters included 71 % of the analysed HPV reports and described AEs included in the product label. Four smaller clusters were identified to include case reports relevant to ongoing safety concerns (total of 694 cases). In all four of these clusters, the most commonly reported AE terms were headache and dizziness and fatigue or syncope; three of these four AE terms were reported in >50 % of the reports included in the clusters. These clusters had a higher proportion of serious cases compared with HPV reports overall (44-89 % in the clusters compared with 24 %). Furthermore, only a minority of reports included in these clusters included AE terms of diagnoses to explain these symptoms. Using proportional reporting ratios, the combination of headache and dizziness with either fatigue or syncope was found to be more commonly reported in HPV vaccine reports compared with non-HPV vaccine reports for females aged 9-25 years. This disproportionality remained when results were stratified by age and when those countries reporting the signals of CRPS (Japan) and POTS (Denmark) were excluded.
  
  
  
  Cluster analysis reveals additional reports of AEs following HPV vaccination that are serious in nature and describe symptoms that overlap those reported in cases from the recent safety signals (POTS, CRPS, and CFS), but which do not report explicit diagnoses. While the causal association between HPV vaccination and these AEs remains uncertain, more extensive analyses of spontaneous reports can better identify the relevant case series for thorough signal evaluation.
authors.affiliation: Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden. rebecca.chandler@who-umc.org.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Chandler
authors.affiliation: Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Juhlin
authors.affiliation: Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Fransson
authors.affiliation: Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden.|Department of Computer and Systems Sciences, Stockholm University, Kista, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Caster
authors.affiliation: Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden.
authors.forename: I Ralph
authors.initials: IR
authors.lastname: Edwards
authors.affiliation: Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden.
authors.forename: G Niklas
authors.initials: GN
authors.lastname: Norén
mesh_terms: D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D000465:Algorithms; D002648:Child; D016000:Cluster Analysis; D016208:Databases, Factual; D005260:Female; D006801:Humans; D053918:Papillomavirus Vaccines / Q000008:administration & dosage / Q000009:adverse effects*; D060735:Pharmacovigilance; D014611:Vaccination / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D053918:Papillomavirus Vaccines