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. 2017 Jan;40(1):81-90.
doi: 10.1007/s40264-016-0456-3.

Current Safety Concerns With Human Papillomavirus Vaccine: A Cluster Analysis of Reports in VigiBase ®

Free PMC article

Current Safety Concerns With Human Papillomavirus Vaccine: A Cluster Analysis of Reports in VigiBase ®

Rebecca E Chandler et al. Drug Saf. .
Free PMC article


Introduction: 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.

Objective: The aim of this study was to explore global reporting patterns for HPV vaccine for subgroups of reports with similar adverse event (AE) profiles.

Methods: 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.

Results: 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.

Conclusions: 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.

Conflict of interest statement

Compliance with Ethical Standards Funding This work was entirely funded by the UMC, WHO Collaborating Centre for International Drug Monitoring. Conflict of interest Rebecca Chandler, Kristina Juhlin, Jonas Fransson, Ola Caster, I. Ralph Edwards and G. Niklas Noren have no conflicts of interest that are directly relevant to the content of this study.


Fig. 1
Fig. 1
Diagram of the four largest clusters and the four smaller clusters of interest. The four largest clusters described well charaterised clinical scenarios which are included in the product labels for HPV vaccines. Representative case narratives have been chosen to exemplify the types of cases included in these clusters. T max Maximal recorded body temperature, POTS postural orthostatic tachycardia syndrome
Fig. 2
Fig. 2
Timeline displaying the number of case reports (per year and by country of origin) that were included in the four clusters. As can be seen from the figure, case reports included in the clusters have been received throughout the whole of the HPV vaccine postmarketing period, with the earliest reports received from those countries who were the first to introduce the HPV vaccine into their vaccination programmes. Countries of origin are diverse, with the first reports from Denmark and Japan (signalling countries) received in 2013. In that same year, the largest number of reports were received from the USA (64) Denmark (55) the UK (13), and Germany (12). In 2010, a large backlog of vaccine reports from the USA, which were not specific to HPV vaccines, were entered into VigiBase. HPV human papillomavirus, AUS Australia, DEU Germany, IRL Ireland, USA United States of America, UK United Kingdom, ESP Spain, HUN Hungary, CAN Canada, DEN Denmark, JPN Japan, SWE Sweden, BEL Belgium, FRA France, NOR Norway, AUT Austria

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    1. HPV vaccines: EMA confirms evidence does not support that they cause CRPS or POTS. EMA/749763/2015. 2015. Available at:
    1. Tabrizi S, Brotherton J, Kaldor J, Skinner SR, Cummins E, Lui E, et al. Fall in human papillomavirus prevalence following a national vaccination program. J Infect Dis. 2012;206(11):1645–1651. doi: 10.1093/infdis/jis590. - DOI - PubMed
    1. European Centre for Disease Prevention and Control. ECDC guidance. Introduction of HPV vaccines in European Union countries: an update. 2012. Available at:
    1. ACA Preventative Services Benefits for Women and Pregnant Women. Immunization for women. Retrieved 10 Dec 2015.
    1. Human papillomavirus vaccines: WHO position paper, October 2014. Wkly Epidemiol Rec. 2014;89(43):465–491. - PubMed

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