Safety Concerns with HPV Vaccines Continue to Linger: Are Current Vaccine Pharmacovigilance Practices Sufficient?

The current paradigm of vaccine pharmacovigilance includes three stages: signal detection, development of a causality hypothesis, and testing of the causality hypothesis [1]. Signal detection in the postmarketing setting largely relies on spontaneous reports of adverse events (AEs) following immunization (AEFI) and literature case reports. The development of a causality hypothesis involves an assessment of the relevant case series using standardized case definitions [2], individual-level causality criteria [3], and ‘observed versus expected’ calculations [4]. Testing of the causality hypothesis follows, using large epidemiology studies that rely on diagnostic coding or insurance claims data for measuring outcomes of interest. Such studies allow regulatory and public health agencies to make an estimation of risk at the population level from which conclusions on causality are drawn. Over the last several years, there has been focus on a number of safety signals for the human papillomavirus (HPV) vaccines, including complex regional pain syndrome (CRPS), postural orthostatic tachycardia syndrome (POTS), and chronic fatigue syndrome (CFS). These signals have been a challenge for public health authorities because routine vaccine pharmacovigilance practice is not sufficient to understand suspected harms that are poorly defined and whose pathophysiology are not completely understood. Furthermore, estimations of risk at the population level fail to acknowledge that vaccines may cause harm in subgroups with individual-level risk factors for AEFI. Novel approaches to vaccine pharmacovigilance are required to more fully understand this safety concern for HPV vaccines. In this issue of Drug Safety, Ozawa et al. describe a case series of girls from Japan who experienced multiple symptoms suspected to be caused by the HPV vaccine. They report on diagnostic findings underlying these symptoms and they take a unique approach to the analysis of temporality in their causality assessment [5].