Quadrivalent human papillomavirus vaccine and autoimmune adverse events: a case–control assessment of the vaccine adverse event reporting system (VAERS) database

The present epidemiological study of the VAERS database evaluated the potential relationship between HPV4 vaccine administration and the risk of various types of SAAEs. It was observed that the SAAEs of gastroenteritis, rheumatoid arthritis, thrombocytopenia, systemic lupus erythematosus, vasculitis, alopecia, CNS demyelinating conditions, ovarian damage, and irritable bowel syndrome were associated with HPV4 vaccine administration, whereas the SAAE of Guillain–Barre syndrome was not associated with HPV4 vaccine administration. In addition, it was observed that the general health outcomes of infection, conjunctivitis, diarrhea, and pneumonia were not associated with HPV4 vaccine administration. Finally, it was observed that the previously established HPV4-related outcome of syncope was significantly associated with HPV4 vaccine administration. The importance of these findings is that the present study provides additional epidemiological evidence to support a significant association between HPV4 vaccine administration and specific SAAEs.

The results obtained in the present study are consistent with a previous assessment of the VAERS database for the relationship between HPV4 vaccine administration and SAAEs [10]. The previous study of VAERS revealed a significant link between HPV4 vaccine administration and the outcomes of gastroenteritis, arthritis, systemic lupus erythematosus, vasculitis, alopecia, and CNS conditions [10]. The present assessment of the VAERS is differentiated from the previous assessment of the VAERS because the data examined in the present study included a more updated VAERS database (the previous study examined vaccines administered from January 2006 through December 2012 vs. the present study examined vaccines administered from January 2006 through December 2014) and wider age range of reports (the previous study examined vaccines administered to recipients from 18 to 39 years old vs. the present study examined vaccines administered recipients from 6 to 39 years old).

The results obtained in the present study are consistent with several previous clinical studies. For example, researchers investigated the association between HPV vaccination and autoimmune manifestations compatible with systemic lupus erythematosus or systemic lupus erythematosus-like disease in six women who presented with such symptoms following HPV vaccination [11]. These investigators reported that in their cases, several common features were observed, such as personal or familial susceptibility to autoimmunity or adverse response to a prior dose of the vaccine, both of which may be associated with a higher risk of postvaccination autoimmunity. Favorable response to immunosuppressant was observed in all patients, and there was a temporal association between HPV vaccine and the appearance of systemic lupus erythematosus-like conditions. Similarly, other investigators observed a case series of three women that had onset or exacerbation of lupus following HPV immunization [12]. Other researchers have suggested that an increasing number of cases of ovarian damage has been observed following HPV4 vaccine administration [13].

The results found in the present study are also supported by biological plausible mechanisms of the constitute components of HPV4 vaccine to induce SAAEs. The HPV4 vaccine contains purified VLPs of HPV Types 6, 11, 16, and 18, which are adsorbed on preformed aluminum-containing adjuvant (amorphous aluminum hydroxyphosphate sulfate). The HPV4 vaccine is then prepared by combining the adsorbed VLPs of each HPV type and additional amounts of the aluminum-containing adjuvant in a sterile liquid suspension [3].

A previous female animal model study revealed HPV4 vaccine administration via its aluminum-containing adjuvant, and HPV antigens have the ability to trigger neuroinflammation and autoimmune reactions, further leading to behavioral changes [14]. Other investigators described animal models that showed aluminum exposure to inhibit expression of female reproductive hormones and to induce histologic changes in the ovaries [13].

In contrast to the results observed in the present study and observed by other investigators, Arnheim-Dahlstrom et al. [15] evaluated autoimmune, neurological, and venous thromboembolic adverse events after immunization of adolescent girls with HPV4 in Denmark and Sweden. These investigators examined a cohort of 997,585 girls aged 10–17, among whom 296,826 received a total of 696,420 HPV4 vaccine doses. Unlike the present study that examined adverse event reports to the VAERS database, Arnheim-Dahlstrom et al. examined incident hospital diagnosed autoimmune, neurological, and venous thromboembolic events (53 different outcomes) up to 180 days after each HPV4 vaccine dose, and rate ratios of the outcomes were adjusted for age, country, calendar year, parental country of birth, education, and socioeconomic status, comparing vaccinated and unvaccinated person-time. These investigators observed that the rate ratios for 20 of 23 autoimmune events were not significantly increased. Exposure to HPV4 vaccine was significantly associated with Behcet’s syndrome, Raynaud’s disease, and Type 1 diabetes, but these investigators described that each of these three outcomes fulfilled only one of three predefined signal strengthening criteria. In addition, these investigators observed that the rate ratios for five neurological events were not significantly increased and there was no association between exposure to HPV4 vaccine and venous thromboembolism. It is interesting to note that despite the number of individuals examined by Arnheim-Dahlstrom et al., their study was significantly underpowered to even examine many types of outcomes, and of those outcomes examined, in many cases, relatively few outcomes were observed in the HPV4 vaccinated group. This may potentially be a consequence of the fact that the source for detecting outcomes in the Arnheim-Dahlstrom et al. study was from hospital records. It seems reasonable to hypothesize that many of the conditions examined by Arnheim-Dahlstrom et al. would not necessarily require hospitalization, and worse still, even if the condition eventually might require hospitalization, the Arnheim-Dahlstrom et al. study examined the diagnosis of the outcome in a hospital within the first 181 days after vaccination. As a result, for many of the outcomes examined by Arnheim-Dahlstrom et al. that overlap that with the outcomes examined in the present study, it was observed that there similar potential trends for outcomes in both studies (i.e., odds ratio for vasculitis in VAERS = 3.420 versus adjusted rate ratio in Arnheim-Dahlstrom study = 1.55 or odds for systemic lupus erythematosus in VAERS = 7.626 versus adjusted rate ratio in Arnheim-Dahlstrom study = 1.35), but none of the outcomes were significantly associated with HPV4 vaccination in the Arnheim-Dahlstrom et al. study.

Also in contrast to the present study findings, Chao et al. [16] undertook an observation safety study of HPV4 in 189,629 women who receive one or more doses of HPV4 vaccine between August 2006 and March 2008 for new diagnoses of autoimmune conditions within 180 days following each dose of HPV vaccine. These investigators identified new-onset autoimmune conditions among HPV recipients by electronic medical records, but then the medical records were reviewed by clinicians to confirm the diagnosis and determine the date of onset (only 31–40 % of the cases were confirmed as new onset). It was observed that there was no cluster of disease onset in relations to vaccination timing, dose sequence or age was found for any autoimmune condition. None of the incidence rate ratios was significantly elevated except for Hashimoto’s disease, but further investigation failed to reveal consistent evidence for a safety signal for autoimmune thyroid conditions. These investigators concluded that no autoimmune safety signal was found in women vaccine with HPV4. Once again, the Chao et al. [16] study, just like the previously discussed Arnheim-Dahlstrom et al. [15] study, was apparently significantly underpowered to find potential autoimmune conditions associated with HPV vaccination, since more than half of the new-onset autoimmune cases identified from electronic medical records were subsequently eliminated from the study following review by clinicians.

Another study by Grimaldi-Bensouda et al. [17] evaluated whether HPV4 vaccination was associated with newly diagnosis autoimmune conditions. In Grimaldi-Bensouda et al. study a total of 211 female cases aged 14–26 years old from across France and diagnosed with autoimmune diseases, and 875 controls were recruited from general practices and were examined. There were no significant increases in the risks of diagnosed thrombocytopenia, multiple sclerosis, connective disorders, Type 1 diabetes, Guillain–Barre syndrome or thyroiditis. The investigators concluded that none of the autoimmune disorders studied had an increased risk following HPV4 vaccination within the time periods studied, but the authors acknowledged that their study was limited by statistical power. Yet again, the Grimaldi-Bensouda et al. study, just like the previously discussed Chao et al. [16] and Amheim-Dahlstrom et al. [15] studies, was significantly underpowered to find potential autoimmune conditions associated with HPV vaccination, since there were fewer than 10 cases exposed for each of the autoimmune disorders examined (thrombocytopenia = 6, connective tissue disorders = 6, central demyelination = 4, Guillain–Barre syndrome = 0, and Type 1 diabetes = 9).