Our analysis of global reports of suspected AEs following HPV vaccination has revealed a large number of reports with a pattern of AEs, including headache, dizziness, fatigue and syncope, distinguished from more common AEs by their serious nature (causing/prolonging hospitalisation and/or disabling/incapacitating), resulting in an impact on the quality of life of the patient. Included in this group are reports that have been labelled as POTS, CFS, and CRPS, but the majority of the reports lack explicit diagnoses. Furthermore, our analyses suggest that the combination of headache and dizziness with either fatigue or syncope is reported significantly more often in HPV vaccine reports compared with non-HPV vaccine reports for females aged 9–25 years; this disproportionality remains when results are stratified by age and when those countries reporting the signals of CRPS (Japan) and POTS (Denmark) are excluded.
Given concerns regarding the influence in reporting secondary to media, we restricted our analyses to reports that had been collected up to 1 January 2015 in order to reduce any influence in reporting secondary to both the widely publicised regulatory action of the EMA taken in July 2015 and the widely viewed television program ‘De vaccinerede piger’, which first aired in Denmark in March 2015 and was subsequently placed on YouTube with English subtitles. In addition, we have shown that cases within the clusters have been distributed over the entire postmarketing life of HPV vaccines, with cases first reported from those countries that were the first to recommend and/or implement HPV vaccination into routine use. Furthermore, in our PRR analyses, we have found an increased reporting of this combination of AE events in HPV vaccines compared with other vaccines, even when reports from Japan and Denmark are excluded. Finally, the proportion of serious cases among reports with the AE combination was at least as high (but not significantly higher) for HPV vaccines as for non-HPV vaccines, which might not have been so if attention in the media would have led to increased reporting, primarily of less severe events.
The greatest limitation of this study is the lack of information on many of the reports in VigiBase. Missing data means that it may be difficult to make a clinical judgment regarding case relevancy, and thus there is the potential for a lack of consistency between different assessors. Consequently, there may be a lower or greater number of relevant cases within the clusters that would contribute to the final signal. Given the high proportion of cases considered relevant from our review (77.5 %), some variation in clinical judgment between assessors is unlikely to change the overall conclusion of our analysis.
The cases within the clusters are notably similar to those described in a number of safety signals for the HPV vaccines. In The Netherlands, the Pharmacovigilance Centre Lareb has published the document “Long-lasting adverse events following immunization with Cervarix®” . Given a large number of reports of long lasting (>2 months) AEs following immunisation, a survey to enhance the clinical documentation level of these reports was performed. Overall 230 reports were considered relevant. Several combinations of frequently reported AEs were found, with the most common being fatigue, headache and musculoskeletal discomfort. Furthermore, the follow-up survey revealed that these long-lasting, unexplained symptoms have had a considerable impact on both the lives of the girls and their family members. In Japan, Kinoshita et al. reported a cohort of 40 subjects in whom they described headaches, general fatigue, coldness of the legs, limb pain and weakness. Eighteen girls met the criteria for a diagnosis of CRPS and, using the Schellong test, four were identified as having POTS. The authors in Japan hypothesised that the symptoms could be explained by abnormal peripheral sympathetic responses . In Denmark, Brinth et al. reported a cohort of 35 subjects in whom they described nausea, chronic headache, fatigue, palpitations, reduced cognitive function, skin changes, intermittent tremor/myoclonic twitches, neuropathic pain, sleep disturbances, and muscular weakness. All subjects were diagnosed with orthostatic intolerance . In the US, Blitshteyn reported a case series whose symptoms included dizziness, fatigue, nausea, weight loss and exercise intolerance , while in Mexico, Martinez-Lavín described two patients with fibromyalgia-type symptoms, including severe pain, insomnia, profound fatigue, and paraesthesia . A signal of gastrointestinal motility disorders from the UMC described a case series of 26 subjects, in whom 15 reported concomitant fatigue, 13 reported either headache or migraine, and 9 reported dizziness . The most recent publication is a report from Italy that describes a case series of 18 girls (aged 12–24 years) who were referred to a ‘Second Opinion Medical Network’ for the evaluation of ‘neuropathy with autonomic dysfunction’ after HPV vaccination; all girls complained of long-lasting and invalidating somatoform symptoms (including asthenia, headache, cognitive dysfunctions, myalgia, sinus tachycardia and skin rashes) . It is acknowledged that these publications represent case series and thus have the limitations that are traditionally associated with these types of reports. However, the collection of a number of case series displaying similar patterns of AEs from geographically distributed locations potentially adds to the overall strength of the signal.
The EMA referral procedure focused on the two specific syndromes of POTS and CRPS; the reviews of the safety database and observed versus expected analyses performed on spontaneous reports by the MAHs considered each of these two syndromes separately. Furthermore, although it was requested that the MAH use ‘common search strategies’ to identify potentially undiagnosed case reports with combinations of signs and symptoms common in CRPS or POTS, the details of these search strategies have not been provided in the publically available assessment report. However, the total number of additional cases identified by these queries, even prior to their assessment according to CRPS and POTS diagnostic criteria, were less than the cases identified by the explicit reporting of the terms POTS and CRPS . In contrast, our analysis identified a greater number of potentially undiagnosed cases than the total number of cases that had been labelled with one of these diagnoses.
There have been a number of epidemiological investigations regarding safety concerns of the HPV vaccine that have relied primarily on the reporting of a specific diagnosis or single-symptom concept, either as a diagnostic billing code or single or synonymous AE terms to define the relevant case series. An epidemiological study in The Netherlands was designed to investigate the potential for an increased risk of migraine headaches after HPV vaccination . As part of a proactive pharmacovigilance plan, the Medicines and Health Regulatory Authority (MHRA) performed an epidemiological study using self-controlled case-series methodology in which they identified cases reporting ‘fatigue-containing’ terms, such as chronic fatigue, chronic fatigue syndrome, post-viral fatigue and fibromyalgia . Although laudable that it considered a variety of fatigue-related terms, the study did not account for co-reported symptoms of a more varied nature. Similarly, while the results of the largest post-authorisation safety studies have been reassuring overall, it must be remembered that such studies have used predefined, well-defined medical pathologies as endpoints [23–26]. The use of epidemiological studies that require specific case definitions are useful to quantify the risks of safety concerns after a signal has been identified and well-characterised from AE reports.
Given the lack of consensus on the specific diagnosis these spontaneous reports describe, a focus on symptomatology and seriousness in combination with an investigation of the underlying pathology may be required to fully elucidate this safety signal. Evidence of a common pathophysiology in girls with this symptomatology is, in fact, currently emerging, with a focus on autoantibodies to G protein-coupled receptors in the nervous system, such as β2-adrenergic and muscarinic-2 receptors which have been isolated from one subject in the US  and in a large proportion of a sample of patients in Denmark (Mehlsen J, personal communication). These results could explain the variety of labels that have been used to explain this symptomatology, as autoantibodies to these receptors have been previously linked with CRPS, POTS, and CFS [28–31].
A causal association with the HPV vaccine remains uncertain; however, we believe that a more thorough investigation of this signal is required to ensure continued public trust in both vaccination programmes and regulatory authorities.