In this pharmacovigilance study, we investigated the safety signals of AIDs following COVID-19 vaccination using the WHO global database, which included spontaneous reports of all potential AIDs after vaccination. Validated methods were utilized, and the safety signals of the four AIDs following COVID-19 vaccination were observed. The analysis showed that the risk of AID after vaccination was significantly higher in females than in males, suggesting that sex differences may further influence this risk. Sensitivity analyses involving AIDs after influenza vaccination and reports excluding immunosuppressants support these findings.
Although COVID-19 vaccines have demonstrated a well-documented safety profile in randomized clinical trials for approval, several retrospective studies and case series have described AIDs following vaccination since the launch of mass vaccination against COVID-19. Currently, in the literature, although few published studies have evaluated the risk of IBD after COVID-19 vaccination, an observational cohort study that used electronic medical records in Hong Kong found that COVID-19 vaccination did not increase the risk of IBD flare-ups (aIRR 0.69; 95% CI 0.35–1.36).[22] In contrast, our study showed a significant relationship between IBD and COVID-19 vaccines, suggesting that this inconsistency in results is due to the distinct influences of ethnicity on autoimmune responses.[23] AID differs between ethnic groups, and the incidence of IBD in Asian populations is much lower than that in Western populations.[24] Because the VigiBase is representative of ethnically diverse populations, especially Westerners, our findings may not correspond to cohort studies that are mainly composed of Asians. Other pharmacovigilance studies reported an increased risk of polymyalgia rheumatica and thyroid disorders after COVID-19 vaccination (ROR 2.3; 95% CI 2.0–2.6, ROR 1.9; 95% CI 1.1–2.5, respectively).[25, 26] These findings were consistent with our study, which showed higher odds of reporting these AIDs.
Despite the lack of evidence in the literature, vaccine-induced autoimmunity continues to attract the attention of many researchers. COVID-19 vaccines can trigger AID because of their ability to modify the immune system and induce robust systemic immunity. Although vaccines activate humoral and cellular immune responses, rare cases of nonspecific activation of autoreactive lymphocytes have been reported, causing an aberrant immune response.[27] Since the safety profiles of next-generation vaccine platforms, such as mRNA, are not yet well characterized, close vaccine safety surveillance is necessary. Two theoretical bases explain the potential relationship between the COVID-19 vaccination and AIDs. The molecular resemblance theory suggests that COVID-19 vaccines may exacerbate or initiate AIDs owing to the similarity between the vaccine spike protein and some human tissue proteins.[28] Furthermore, the vaccine-stimulated pro-inflammatory response can cause immune system dysregulation, with the mRNA vaccine pathway particularly activating pro-inflammatory cytokines, such as type I interferon, which can lead to the loss of immune tolerance.[29] However, further studies are necessary to determine the correlation between AIDs and COVID-19 vaccinations and the underlying mechanisms.
Previous studies have indicated that the median TTO of AIDs, such as multiple sclerosis and myasthenia gravis, is 1 d (IQR 0–3),[30] whereas cutaneous reactions, including purpura, are more likely to occur within 5 d.[31] Our TTO analysis also revealed that the period with the highest risk of AID was within 0–7 d of vaccination, with the greatest risks generally observed around day 4 following vaccination. Given the temporal association between symptom onset and COVID-19 vaccination, we hypothesized that vaccination could contribute to AIDs. Therefore, close monitoring for the early detection and appropriate care of AIDs is recommended during the first few days after vaccination.
Co-reported AEs with COVID-19 vaccines include musculoskeletal and connective tissue disorders such as arthralgia, myalgia, and nervous system disorders.[32–34] In fact, it is not surprising considering many AIDs include musculoskeletal manifestations. Moreover, facial paralysis occurred more frequently in vaccine groups than in placebo groups during clinical trials of mRNA vaccines, and previous studies reported a high incidence rate of Guillain–Barré syndrome following COVID-19 vaccination of 32.4 per 100,000 person-years (95% CI 14.8–61.5).[35] These two commonly co-reported AEs were simultaneously described in 747 AID reports, making it the fourth most frequently reported overlap. A better understanding of these co-reported AEs is necessary, and additional vaccine safety surveillance is required to manage their wide-ranging effects.
When evaluating the safety of COVID-19 vaccines, caution should be exercised regarding drug–drug interactions, such as immunosuppressants and antineoplastic agents. TNF-α inhibitor and rituximab, among other co-reported drugs, can impair the humoral immune response after vaccination, and their effects on vaccinated individuals need to be investigated.[36] Although concerns about vaccination in patients receiving immunosuppressants have been raised, the current literature has only assessed serological responses to COVID-19 vaccination. Further studies are necessary to clarify the potential interactions between immunosuppressants and COVID-19 vaccines. More intensive vaccination strategies are required for patients receiving multiple immunosuppressants.[37]
Our study raised awareness about the potential safety signals of AID following COVID-19 vaccination by comprehensively assessing diverse forms of AID using the largest pharmacovigilance database of its kind. The large-scale database provided opportunities to assess rare AIDs that could not be identified through trials, and disproportionality analysis on VigiBase was the most suitable for detecting the risk of undesirable AEs.[38]
However, this study has some limitations. First, a spontaneous reporting database is likely to be subject to underreporting of confirmed cases and no information for denominators, all of which are inherent limitations of this type of data source. However, the results of this study provide evidence for developing hypotheses for further research. Second, the characteristics of the recipients of COVID-19 vaccines may have differed from those of recipients of all other vaccines in unknown ways, which can affect AID risk. Concerns about unmeasured differences among vaccine recipients remain, and the results should be interpreted with caution. Third, we identified co-reported drug use from the data; however, it was difficult to determine the sequence of drug use. However, our study provides descriptive information on potential drug–drug interactions between COVID-19 vaccines and other drugs among patients with AIDs.