SARS-CoV-2 infection has been demonstrated to cause a wide range of autoimmune/inflammatory thyroid disorders via direct entry of the virus in the follicular cells, molecular mimicry, or dysregulated immune responses [8]. Similarly, an association between SARS-CoV-2 vaccination and inflammatory and autoimmune disorders has been emerging in the last year. Typical subacute thyroiditis (SAT) represents to be the most common thyroid disease secondary to vaccine administration, with more than 60 cases reported in the literature, and affects mostly women [11,12,13]. Most patients (about 70%) were vaccinated with a mRNA vaccine, and developed SAT after a median of 10 days after the first or second dose. Vaccine-associated SAT does not differ from the classic form of virus-related SAT in terms of clinical and epidemiological features and outcomes. These were usually self-limiting cases of mild/moderate severity that could be easily treated with symptomatic therapy or a short course of anti-inflammatory drugs, with overall favourable outcomes [11,12,13].

More recently, an increasing number of cases of AITDs potentially triggered by SARS-CoV-2 vaccines administration have been reported [13, 14]. Among these, GD is the most common one, accounting for about one-third of the thyroid abnormalities observed after vaccination [13]. Reviewing the pertinent literature, up to date 51 cases of Graves’ disease following vaccination against COVID-19 have been reported in the literature [13,14,15,16,17,18,19]. As briefly summarized in Table 2, most of patients were females (39 F, 76.57% and 12 M, 23.5%), with no previous history of thyroid disease; the median age was 42 years (range 28–73 yr). The onset of hyperthyroidism occurred 1–63 days after the first (26 pts, median: 10 days) or the second dose (25 pts, median: 13 days) of vaccine. According to vaccine type, 39 subjects (76.5%) had received an mRNA-based vaccine and nine (17.6%) the vector-based one, while the remaining three subjects (5.9%) had received an inactivated vaccine (Table 2). Clinical presentation was dominated by the typical signs and symptoms of hyperthyroidism (palpitation, anxiety and insomnia, diarrhoea, weight loss), and both biochemical features (low TSH, elevated FT3 and FT4, TRAb positive) and thyroid ultrasonography or scintigraphy imaging were consistent with the diagnosis of GD. The patients were managed with anti-thyroid drugs and beta-blockers, as appropriate, with favourable responses in all cases. Among these GD patients, three developed a new onset TED, while one male patient experienced a relapse [12,13,14,15,16,17,18]. However, some other cases of TED new-onset or recrudescence after vaccination have been reported, not associated with the occurrence of hyperthyroidism (Table 2). Two middle-age females with a silent personal history developed signs and symptoms of TED after receiving their first or second dose of mRNA-based vaccine [20, 21]. Also, three middle-age female patients and a 43-year-old male with a history of inactive TED with stable thyroid function tests experienced a flare of TED few days after the administration of mRNA-based SARS-CoV-2 vaccine [21, 22].

A few cases of painless thyroiditis were also reported [13, 23], and only one case of overt hypothyroidism associated with acute thyroid swelling may be due to silent thyroiditis precipitating overt autoimmune hypothyroidism [24]. A clear increase in HT occurrence and hypothyroidism following vaccination has not been reported yet, but this is not surprising may be due to its chronic and slow course with hypothyroidism usually occurring years after the appearance of thyroid autoantibodies [25]. Moreover, it might be underestimated more frequently than hyperthyroidism or SAT, which are characterized by a rapid onset of clinical symptoms that facilitate diagnosis [25]. Long-term prospective studies could clarify the impact of SARS-CoV-2 infection and vaccines on TH epidemiology.

Our case series gives a description of the full spectrum of autoimmune disorders that may occur after SARS-CoV-2 vaccines administration, ranging from new-onset Graves’ disease to autoimmune hypothyroidism in patients with pre-existing autoimmune disorders. All three patients had a personal and/or family history of autoimmune disorders, confirming that genetic predisposition is an important risk factor for the development of AITDs following vaccination. Even if two out of three of our patients were males, female gender is another well-recognized risk factor, as it emerges from the revision of the current literature. Two patients, namely case 1 and 2, presented with typical signs and symptoms of thyrotoxicosis, due to autoimmune hyperthyroidism (GD) in the male patient and to destructive painless thyroiditis in the female. Since the clinical presentation of GD and thyroiditis is similar, early differentiation of these two entities is important for timely initiation of treatment. Indeed, GD requires medical treatment with anti-thyroid drugs to block the excessive thyroid hormone synthesis, while painless thyroiditis does not and rather should be followed without any treatment. In case 2, the occurrence of painless thyroiditis precipitated persistent hypothyroidism as a consequence of inflammatory damage of the gland superimposed on a pre-existing autoimmune disease, whereas in patient 3, vaccine administration might have triggered reactivation of AITD with a shift from pre-existing GD to over-hypothyroidism with the typical features of HT. All patients responded well to medical treatment and became euthyroid within few weeks, with no need to discontinue their vaccination program when scheduled. All cases showed a clear temporal relationship between the administration of the vaccine and the onset of symptoms, suggesting that AITDS may represent an adverse event after SARS- CoV-2 vaccines in susceptible individuals. A history of AITDs and/or positivity of thyroid autoantibodies may represent risk factors for the development of vaccine-related AITDs, as already described for other treatments [26], but further prospective studies and larger cohorts are needed to verify this hypothesis.

Like infections, vaccines can trigger the development of autoimmunity by several mechanisms, including molecular mimicry, epitope spreading, polyclonal activation, bystander activation, and presentation of cryptic antigenic determinants [27]. In the case of SARS-CoV-2 vaccines, a cross-reactivity between the virus spike protein targeted by the vaccines and antigens expressed on the surface of the thyroid follicular cell has been postulated [6, 28]. Vojdani et al. reported cross-reactivity to human antigens, including thyroid peroxidase, of antibodies against spike protein S, nucleoprotein and membrane protein, and demonstrated that numerous thyroid peroxidase peptide sequences shared homology or similarity with sequences in various SARS-CoV-2 proteins [28]. Based on these findings, they suggested that the cross-reactivity between thyroid cell antigens and the spike protein of the coronavirus might represent a possible link between COVID-19 infection and an increase in autoimmune diseases. By the same mechanism, due to the molecular mimicry, SARS-CoV-2 vaccination might trigger autoimmune thyroid disorders in genetically predisposed individuals [6, 7]. These phenomena could be enhanced by adjuvants in the context of the post-vaccination so-called ASIA syndrome. First described in 2011, the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) refers to a number of autoimmune disorders induced by exposure to adjuvants added to vaccines to enhance their immunogenicity [29]. Indeed, vaccine adjuvants can trigger adverse autoimmune reactions in predisposed individuals, as a consequence of dysregulation of both innate and adaptive immune systems [29, 30]. Since the ASIA syndrome was described, a wide range of autoimmune conditions have been reported to occur after the administration of HBV, HPV and influenza vaccines [31] and more recently SARS-CoV-2 vaccine. Among endocrine manifestations, cases of HT, ovarian insufficiency, type1 diabetes mellitus, and autoimmune adrenal insufficiency have already been described with the use of various vaccines, while GD has been reported only after SARS-CoV-2 vaccine administration [13,14,15,16,17,18,19, and the present paper]. Peculiarly, ASIA syndrome is often associated with a personal or familial history of autoimmune diseases [31].

In conclusion, it might be hypothesized that SARS-CoV-2 vaccines (mainly mRNA-based) can trigger AITDs, either as a new-onset disease or a recurrence of previously diagnosed ones. To date, mostly cases of Graves’ disease have been reported in the literature but growing evidence and our real-life experience suggest that SARS-CoV-2 vaccines, as other vaccines, can cause autoimmune hypothyroidism in susceptible individuals. The purpose of the present case series is to make clinicians aware of full spectrum of AITDs that may occur following vaccination, so that onset of symptoms with a temporal relationship with the administration of the vaccine are not overlooked and treated timely. However, it should be pointed that up to date, about 70 cases of AITDs following SARS-CoV-2 vaccination have been recorded in the face of several billion vaccine doses that have been administered globally so far [32]. Thus, at a population level, the benefits of mass vaccination largely outweigh any issues concerning thyroid side effects, and the possible and rare occurrence of thyroid disorders should certainly not discourage vaccination.