Authors’ reply: Human papillomavirus vaccine and primary ovarian failure

We are grateful for the interest of Drs. Pellegrino et al. in our recent publication as well as their effort in exploring further the possible association between HPV vaccination and primary ovarian failure (POF). We completely agree with the authors that further analyses are required to determine the prevalence of POF among the populations exposed to the HPV vaccine and, to identify the presence of possible risk factors that may predispose to POF following HPV vaccination. At present, however, we cannot firmly conclude that the causal relationship with the HPV vaccine is unlikely simply because of the low number of POF reports in various vaccine surveillance databases. In particular, Pellegrino et al. retrieved four reports of POF associated with the HPV vaccine from the US Vaccine Adverse Event Reporting System (VAERS), one from the Australian database and two from the European database of suspected adverse drug reaction reports. It should be noted that these vaccine surveillance databases rely exclusively on passive reporting, and hence, these systems cannot be used to determine the presence or absence of causality. This fact was well recognized even by the Australian manufacturer of the HPV vaccine. In particular, as noted by Little and Ward who reported the very first case of POF in a 16-year-old girl following Gardasil vaccination, the Australian sponsor of the vaccine has stated after notification of the case that ‘the post-market reporting of adverse events is voluntary and from a population of uncertain size, and consequently, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure’. Moreover, POF is currently not listed as a possible adverse reaction in the HPV vaccine product leaflet. Thus, physicians as well as parents would most likely not regard POF-related complaints in HPV vaccinated girls as vaccine related. This would further lead to underreporting of potentially vaccine-associated events. Indeed, since the publication of our paper, we have received numerous e-mails from both parents and doctors concerning other cases of possible HPV vaccine-related POFs. Primary ovarian failure is an extremely rare and serious occurrence in the teenage population, and the emergence of POF cases following HPV vaccine (which is a relatively ‘young’ vaccine) should alert physicians to more rigorous follow-up and monitoring of vaccinated girls. Many times symptoms start after the first or second dose (two of three cases we described experienced adverse manifestations after the first dose). If such symptoms consistent with POF are noted, the vaccination may be contraindicated in such subjects. Indeed, it is not unusual that a full-blown manifestation of autoimmunity occurs in individuals who have previously reacted adversely to vaccination. For example, recently, we described six cases of systemic lupus following Gardasil vaccination. In all six cases, several common features were observed, namely a personal or familial susceptibility to autoimmunity and an adverse response to a prior dose of the vaccine, both of which were associated with a higher risk of post-vaccination full-blown autoimmunity. Little and Ward have also cautioned that there may be a group of women for whom the HPV vaccine is contraindicated. They further suggested that long-term follow-up of ovarian function in a cohort of vaccinated girls and women be undertaken as the occurrence of POF may represent broader public health implications. The HPV vaccines do not replace currently available methods to screen or treat cervical cancer, and their effectiveness in preventing any cancer death will not be known for several decades. In preventive vaccination, where a relatively new vaccine is administered to healthy individuals, an increased emphasis on safety should not be viewed as unreasonable. Indeed, at present, we cannot exclude the possibility that the reason why there are very few POF reports in various vaccine surveillance databases is simply because the public is not aware of the possibility that POF may be triggered by the HPV vaccine. Increased awareness and vigilance among physicians is thus warranted.