No evidence of a link between multiple sclerosis and the vaccine against the human papillomavirus
- First Online:
- Cite this article as:
- Pellegrino, P., Carnovale, C., Perrone, V. et al. Eur J Epidemiol (2013) 28: 705. doi:10.1007/s10654-013-9830-y
Cervical lesions due to human papilloma virus (HPV) types 16 and 18 infection are associated with the development of almost 70 % of cervical cancer cases worldwide . The recent introduction of preventive vaccination against papilloma virus will significantly reduce the incidence of cervical cancer. Two virus-like particle (VLP)-based vaccines targeting HPV16 and HPV18 are now offered to adolescent girls and young women among various countries within different vaccine programs [1, 2]. The efficacy of these vaccines in reducing cervical lesions and the safety of this large-scale immunisation in the young adult population has been widely assessed in several clinical trials [1, 2] Furthermore both vaccines were monitored via post licensure safety surveillance study that showed a safety profile broadly consistent with pre marketing studies [1, 2].
More recently, however, cases regarding the onset or exacerbation of multiple sclerosis (MS) following HPV vaccination have been reported, indicating a possible relationship between anti HPV vaccination and MS [3, 4].
A relationship between MS and vaccination was previously reported for vaccination against hepatitis B (HB) in France, a large-scale, immunisation implemented in the early 1990s leading to the immunisation of almost 20 million of individuals. Reports on the temporal association between HB vaccination (HBV) and MS onset led to severe concerns in public opinion about the safety of this vaccine . Despite further epidemiological studies failed to demonstrate this relationship and no increase in MS prevalence was observed following any vaccine introduction, public confidence was lost and HBV coverage in France remains below 25 % .
HBV vaccination is not dissimilar to that with HPV in terms of target populations and large-scale implementation. An early evaluation of the possible relationship between MS and HPV immunisation appears therefore fundamental, also to avoid undue confidence loss in HPV vaccination.
To assess the relationship between HPV vaccination and MS, we analysed the information present in the Vaccine Adverse Event Reporting System (VAERS), one of the biggest national and international databases, which collects approximately 28,000 adverse drug reactions (ADRs) following immunisation per year.
Doses before onset
Time to symptom onset
Over 120 days
In a search within the European Medical Agency (EMA) adverse event database, we retrieved a further 130 cases of MS (124 cases of onset, 6 cases of exacerbation) of which 123 were associated with the qHPV vaccine and 7 with the bivalent HPV vaccine. Ten additional cases were retrieved from the Australian TGA Database of Adverse Event Notifications between April 2007 and February 2013, of which nine were new MS diagnosis and one was a disease relapse.
The incidence of MS reports following HPV vaccination was not formally evaluated within any previous studies. Considering the number of qHPV vaccine doses distributed in United States between June 1, 2006 through July 30, 2012 (46 million) and the VAERS domestic reports in this time-frame (31 reports) we estimated a reporting rates (RRs) of 0.08/100,000 doses.
A similar evaluation of qHPV vaccine doses (7 million of doses) and reports from the Australian TGA database yielded a RRs of 0.14/100,000 doses. Similar results were estimated from the EMA database.
The temporal relationship between HPV immunisation and symptom onset does not provide evidence about causality relationship. In addition the population in study (young women) have a higher risk of developing MS , thus HPV vaccination may casually occur closely to symptom onset in a patient who was developing MS independently from vaccine. The incidence of MS in the absence of HPV vaccination in young women within 6 weeks periods of observation has been estimated to be 1/100,000 . While these data are not directly comparable to those of the pharmacovigilance vaccination databases because limited to a specific region in the US, still they may provide insight about the aetiology of cases retrieved from our database research.
Even taking into account the known limitations of passive surveillance systems, i.e. under-reporting and report quality , the results of our analysis raise doubts about a possible relationship between HPV vaccination and MS onset or exacerbation. Concerns about the possible adverse reactions to vaccination occur on a regular basis in the public opinion. Considering the public health importance of preventing HPV infection, measures should be taken in order to dissipate concerns about possible increases in the risk of MS following HPV vaccination.
This work was supported by Grants from Agenzia Italiana del Farmaco (AIFA), the Regional Centre of Pharmacovigilance of Regione Lombardia.
Conflict of interest
The authors declare that they have no conflict of interest.