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

Abstract

IntroductionA 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.ObjectiveThe aim of this study was to explore global reporting patterns for HPV vaccine for subgroups of reports with similar adverse event (AE) profiles.MethodsAll 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.ResultsOverall, 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.ConclusionsCluster 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s40264-016-0456-3) contains supplementary material, which is available to authorized users.

Adverse events following quadrivalent meningococcal CRM-conjugate vaccine (Menveo®) reported to the Vaccine Adverse Event Reporting system (VAERS), 2010–2015

“…In recent years, concerns have arisen regarding dysautonomic syndromes such as postural orthostatic tachycardia syndrome (POTS) following HPV vaccine [22]. In our study, one case of POTS was reported following vaccination with Menveo, TDaP and HPV vaccines and one case of orthostatic hypotension dysautonomic syndrome was reported following vaccination with Menveo and TDaP.…”

Safety profile of human papilloma virus vaccines: an analysis of the US Vaccine Adverse Event Reporting System from 2007 to 2017

“…From our analysis, noteworthy was the association between HPV vaccines and syncope (ROR = 6.28), and with related events with a high ROR as loss of consciousness, fall and presyncope. These vaccine-reaction pairs have been already highlighted in other articles [31,32] and investigated by the CDC [33]. The CDC pointed out that more than half of the syncope reports concerned adolescents and were mainly related to the three vaccines administered in teenagers: HPV, Tdap and MCV4.…”

“…This was possible due to the combined action of the early screening through the Papanicolaou test and prophylactic vaccination with HPV vaccines. Three HPV vaccines are now available: Cervarix (HPV 16 and 18), Gardasil (HPV 6,11,16,18) and Gardasil 9 (HPV 6,11,16,18,31,33,45,52,58). Several studies have emphasized the efficacy and safety of these vaccines [10][11][12][13][14][15].…”

Challenges of independent assessment of potential harms of HPV vaccines

“…In the late 2000s, reports of potential harms associated with HPV vaccines, including postural orthostatic tachycardia syndrome (POTS) and complex regional pain syndrome (CRPS), began appearing in the media (see supplementary data on bmj.com),23 followed by reports in scientific journals 456. Both syndromes are conglomerates of signs and symptoms and their diagnoses are complex.…”