Introduction

COVID-19, an acute respiratory infectious disease instigated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1], poses a formidable global challenge. As of 7 June 2023, the World Health Organization reported an excess of 700 million COVID-19 cases and over six million associated fatalities all over the world [2]. As the pandemic spreads, researchers have found that SARS-CoV-2 infection can affect not only the respiratory system but also multiple organs, including the endocrine glands [3,4,5,6]. At present, the emergence of conditions such as GD, subacute thyroiditis, and diabetes mellitus in association with COVID-19 has been reported [7,8,9,10,11,12,13,14]. In response to this global crisis, COVID-19 vaccination efforts are being intensified globally to control the COVID-19 pandemic. In a meta-analysis, Zheng et al. [15] found that the effectiveness of COVID-19 vaccines against SARS-CoV-2 infection, COVID-19-related hospitalization, intensive care unit hospitalization and death was 89.1%, 97.2%, 97.4%, and 99.0%, respectively, among fully vaccinated populations. Thus, COVID-19 vaccination emerges as a crucial strategy for curtailing SARS-CoV-2 infection and related adverse outcomes,which can provide substantial population protection.

Based on statistics from Our World in Data, as published by the University of Oxford, 70.1% of the global population have received at least a single dose of COVID-19 vaccine, with a total of 13.41 billion doses administered worldwide, and 102,962 doses administered daily [16]. With the rise in COVID-19 vaccination rates, several associated adverse effects have been observed, including fever, fatigue, muscle aches, and some autoimmune diseases [17,18,19,20,21,22]. Hyperthyroidism refers to thyrotoxicosis caused by the thyroid gland itself producing excessive thyroid hormones, and GD is the most common etiology of hyperthyroidism [23, 24]. GD falls under the umbrella of autoimmune thyroid diseases, characterized primarily by the presence of thyrotropin receptor antibody (TRAb) in the serum [24,25,26]. While the pathophysiology of GD remains unclear, recent studies suggest that genetic, epigenetic, and environmental factors may all be significant contributors to the disease [27,28,29,30]. Recently, there has been a succession of reported cases of GD following COVID-19 vaccination [32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64]. However, it is unclear whether COVID-19 vaccination has any effect on the occurrence and development of GD. This article reviewed 47 new-onset GD cases and 15 relapsed GD cases following COVID-19 vaccination in order to explore whether there is a correlation between COVID-19 vaccination and GD onset and the pathogenic mechanisms.

Methods

We performed a comprehensive literature review to identify all reports of GD cases following COVID-19 vaccination by searching for indexed articles up to 7 June 2023 in databases including PubMed, Web of Science, and Scopus. Only articles written and published in English were considered. The search strategy employed various keywords both individually and in combination, namely: SARS-CoV-2, COVID-19, thyroid, Graves’ disease, autoimmune thyroid disease, hyperthyroidism, thyrotoxicosis, vaccine, and vaccination. The main inclusion criteria were as follows: 1. case reports, case series, and original articles with adequate case data; 2. letters and comments to the editor published in international journals with adequate case data. The main exclusion criteria were as follows: 1. cases with inadequate data; 2. cases with overlapping patient data; 3. patients previously infected with SARS-CoV-2. From an initial selection of 71 articles, 33 articles met our inclusion criteria, and a total of 62 GD cases following COVID-19 vaccination were included in the analysis.

For each patient, we collected demographic data including sex and age, the type of administered COVID-19 vaccine (mRNA vaccine, viral vector vaccine, inactivated vaccine), the onset time of hyperthyroidism symptoms following COVID-19 vaccination, symptoms and signs at presentation, thyroid function tests (TFTs) such as free thyroxine (fT4), free triiodothyronine (fT3), and thyroid-stimulating hormone (TSH), thyroid antibody tests such as thyroid-stimulating immunoglobulin (TSI), thyroid peroxidase antibodies (TPOAb), and thyroglobulin antibodies (TgAb), as well as other diagnostic examinations such as thyroid ultrasonography and thyroid scintigraphy."

Specific medical therapies and clinical or hormonal follow-up data were also recorded. Based on the 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis [24], the diagnostic criteria for GD included: (a) TFTs consistent with hyperthyroidism; (b) positive TRAb or TSI; (c) the presence of a thyroid scan showing high radioactive iodine or 99mtechnetium uptake; or (d) a thyroid ultrasound showing diffuse hypervascularization of the glandular parenchyma.

New-onset and relapsed GD following COVID-19 vaccination

Among the 62 GD cases following COVID-19 vaccination, the mean age was 42.98 ± 14.34 years, with 45/62 (72.6%) of the patients being female and 17/62 (27.4%) male (Table 2). All patients tested positive for TRAb or TSI. Although GD can affect all ages, it is notably more prevalent among women of reproductive age, and the female-to-male ratio is 5–10: 1 [30, 31]. This gender and age distribution of GD cases following COVID-19 vaccination aligned with that of classical GD cases. The distribution of new-onset and relapsed GD after administration of COVID-19 mRNA vaccines and viral vector vaccines was illustrated in Table 1. However, neither reports have presented new-onset GD cases after receiving inactivated vaccines, nor were there any new-onset and relapsed GD cases after protein subunit vaccine administration. Of the 62 GD patients after receiving COVID-19 vaccines, six female patients and two males were diagnosed with hyperthyroidism through TFTs rather than by presenting hyperthyroidism-related symptoms. Two female patients had received two doses of COVID-19 inactivated vaccines before the mRNA and viral vector vaccines. Excluding the aforementioned 10 patients, the remaining 52 patients developed common hyperthyroidism symptoms after receiving COVID-19 vaccines, such as weight loss, palpitations, and hyperhidrosis, with a median symptom onset time of 12 days. The median durations to symptoms onset for new-onset (12 days vs 7 days) and relapsed GD (21 days vs 14 days) were longer following COVID-19 mRNA vaccine administration than viral vector vaccination. In female patients, the incidences of both new-onset and relapsed GD following the first dose of COVID-19 vaccines were higher than those after the second dose (Table 2).

Table 1 Distribution of the new-onset and relapsed GD after COVID-19 vaccination according to the vaccine type
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Table 2 Age of subjects and the onset time of GD-related symptoms following COVID-19 vaccination according to the gender of patients
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The main characteristics of the 47 new-onset GD patients associated with COVID-19 vaccination were summarized in Table 3. In the reported new-onset GD cases, the main clinical manifestations, thyroid functions, and thyroid ultrasonography were consistent with those of the classical GD cases (Table 3). Notably, a female patient (Case 5), who was inoculated with two doses of the COVID-19 inactivated vaccine, followed by a dose of the mRNA vaccine, experienced hyperthyroidism symptoms, such as palpitations in two days after the mRNA vaccination (Table 3) [33]. Among all the new-onset GD patients following COVID-19 vaccination, 3 female patients (Cases 17, 26, and 47) and 2 males (Cases 15 and 31) did not exhibit hyperthyroidism symptoms after COVID-19 vaccination [37, 39, 47, 49, 52]. Their hyperthyroidism was incidentally identified due to routine TFTs (Table 3). According to literature, most of those patients found symptoms relieved following anti-thyroid drug (ATD) treatment [34, 35, 37,38,39]. It is worth noting that 3 female patients (Cases 8, 9, and 11) developed hyperthyroidism symptoms after the first COVID-19 mRNA vaccine dose and were diagnosed as new-onset GD [35], as another 2 female patients (Cases 42 and 44) after the first COVID-19 viral vector vaccine dose did [60]. These patients had also received their second doses of COVID-19 vaccines when their conditions stabilized post-ATD treatment. Their conditions did not worsen or require adjusting the doses of ATD and beta-blocker after receiving the second doses [35, 60]. Filippo et al. [65] conducted a case–control study and found that among 64 patients who developed new-onset GD after COVID-19 vaccination, and 20/64 (31.2%) patients experienced post-vaccine early-onset GD (PoVEO) within 4 weeks. The patients with PoVEO GD exhibited unique clinical characteristics as compared to the other 44 patients, including older age at onset, higher male prevalence, and a better initial biochemical and immunologic response to ATD treatments. However, in contrast to those clinical trials, our study is a review of the existing patients, which has aimed to observe the clinical characteristics of new-onset GD cases following COVID-19 vaccination. Based on their clinical characteristics, we analyzed the potential impacts of COVID-19 vaccines on the development of GD. The limited series suggest that for new-onset GD patients following the first COVID-19 mRNA and viral vector vaccine injections, a second dose may be administered once the hyperthyroid conditions are adequately controlled. Nonetheless, constant monitoring of thyroid functions should be kept after the second dose administration.

Table 3 Characteristics of cases presenting with new-onset GD following COVID-19 vaccination
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Table 4 summarized the main characteristics of the 15 relapsed GD cases associated with COVID-19 vaccination. Among those cases, a female patient (Case 14), who had received two doses of inactivated COVID-19 vaccines followed by a viral vector vaccine, developed hyperthyroidism symptoms like palpitations four days after viral vector vaccination (Table 4) [36]. However, among all the relapsed GD patients following COVID-19 vaccination, 3 female patients (Cases 4, 5, and 7) did not present any hyperthyroidism symptoms after COVID-19 vaccination (Table 4) [35]. Their hyperthyroidism was incidentally identified due to routine TFTs. Studies have suggested that approximately 50% of GD patients treated with ATD would experience relapse and it typically occurs between 6 and 18 months after the cessation of ATD treatment [66,67,68]. Among the 15 cases of relapsed GD after COVID-19 vaccination, a male patient and a female (Cases 1 and 2) relapsed approximately 12 months after ceasing ATD treatment [34]. This potentially represents the natural course of GD. However, in the 3 female patients (Cases 9, 10, and 15), their GD relapse occurred at the 17th, 7th, and 12th years, respectively, after ceasing ATD treatment [34, 37, 62]. This underlines the necessity for further investigations into the potential correlation between COVID-19 vaccination and GD relapse. Furthermore, a 30-year-old female (Case 14) was diagnosed with GD in October 2018 and has been treated with 2.5 mg of methimazole daily to maintain euthyroidism. She received two doses of COVID-19 inactivated vaccine on April 7 and 26, 2021, and her thyroid function remained normal after COVID-19 vaccination. However, following a dose of the viral vector vaccine on July 19, 2021, she developed symptoms such as palpitations and weight loss four days later. By self-increasing the methimazole dose to 5 mg, she managed to relieve some symptoms, but her fT3 level remained elevated and TRAb was positive one month after adjusting the dose of methimazole [56]. Due to the limited number of reported GD cases following COVID-19 vaccination, and the lack of GD cases after receiving the protein subunit vaccine, it is currently impossible to clarify the causal relationship between COVID-19 vaccination and the onset of GD. Fortunately, most patients who developed GD following COVID-19 vaccination experienced positive outcomes after ATD treatment. In the broader context of ending the COVID-19 pandemic and reducing mortality rates, the benefits of COVID-19 vaccination significantly outweigh mild risks such as treatable GD.

Table 4 Characteristics of cases presenting with relapsed GD following COVID-19 vaccination
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Possible pathogenesis of COVID-19 vaccination-related GD

Currently, the pathogenic mechanisms of COVID-19 vaccination-related GD has not yet been fully elucidated. Several studies suggest that new-onset and relapsed GD following COVID-19 vaccination may be linked to several potential mechanisms as follows [32,33,34,35,36,37,38,39,40, 56, 57, 62]. One possible mechanism could be molecular mimicry. The antigen structure of the COVID-19 vaccine closely resembles some autoantigens, eliciting an immune response that could erroneously target host cells with similar autoantigens [32,33,34,35,36, 38, 39, 57]. There are four genera of the coronavirus family: α, β, γ, and δ coronaviruses [69, 70]. SARS-CoV-2, the causative agent of COVID-19, is a member of the Coronaviridae family. This virus is enveloped and possesses a positive single-stranded RNA genome [71,72,73]. The genome's length varies between 26 and 32 kb, including 6 to 11 open reading frames [74]. It encodes four essential structural proteins—spike, envelope, membrane, and nucleocapsid, all of which play critical roles in the assembly and infectivity of SARS-CoV-2 [69, 75, 76]. Among these proteins, the spike protein is particularly important in facilitating the virus's pathogenicity [77, 78]. It operates as a trimeric fusion type I glycoprotein, binding to the angiotensin converting enzyme 2 (ACE2) on the host cell membrane through its receptor-binding domain (RBD) on the S1 subunit [79]. The binding of the RBD to the ACE2 receptor on the host cell membrane instigates the shedding of the S1 subunit. This event prompts the S2 subunit to adopt a stable post-fusion conformation. The consequent structural changes within the S2 subunit facilitate the integration of the viral lipid membrane into the host cell membrane. This action thereby allows the viral RNA to enter the host cell for replication [80,81,82]. Hence, due to its crucial role in the infection process, the spike protein is the primary immunogen in the development of the COVID-19 vaccine [83]. Vojdani et al. [84] found that SARS-CoV-2 antibodies could immunoreact with multiple tissue antigens, including those of the thyroid gland. They employed the Basic Local Alignment Search Tool provided by the National Institutes of Health/National Library of Medicine to conduct a sequence matching analysis. Their findings revealed that the amino acid sequences of the SARS-CoV-2 spike protein, nucleoprotein, and membrane protein share a similarity ranging from 50 to 70% with that of thyroid peroxidase [84]. Given that the spike protein plays a pivotal role as an immunogen in the development of the COVID-19 vaccine [83], there is a possibility that the COVID-19 vaccine could incite an autoimmune response against thyroid tissue through molecular mimicry, thereby contributing to the onset of GD. It is important to note that molecular similarity does not necessarily result in the development of GD. A systematic review, including 48 new-onset and 15 relapsed GD cases following COVID-19 vaccination, proposed that individual susceptibility appears to play a critical role in the development of GD following COVID-19 vaccination, regardless of the underlying pathogenic mechanisms [85]. Therefore, other factors such as genetic susceptibility may also contribute to the development of GD. However, it should be noted that unlike our study, this systematic review did not exclude patients with a history of SARS-CoV-2 infection. In our study, we specifically excluded patients who had previously been infected with SARS-CoV-2 to further eliminate the potential impact of SARS-CoV-2 infection on the pathogenesis of GD.

Moreover, another pathogenesis connected to Autoimmune/Inflammatory Syndrome Induced by Adjuvants (ASIA) has been proposed in the literature [32,33,34,35,36,37,38,39,40, 56, 57, 62]. The term 'ASIA', first proposed by Shoenfeld et al., describes the aberrant autoimmune response post-exposure to a vaccine adjuvant [86]. Common types include post-vaccination syndrome, Gulf War syndrome, and macrophagic myofasciitis syndrome [87]. According to the diagnostic criteria outlined in Table 5, all 62 patients with new-onset or relapsed GD after COVID-19 vaccination satisfied the diagnosis of ASIA [32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64]. In 2013, Perricone et al. [88] first revealed that adjuvant stimuli, such as aluminum and tetramethylpentadecane, could provoke autoimmunity. For instance, aluminum hydroxide was associated with postinoculation phenomena, and silicone was associated with silicosis. In the cohort of patients with relapsed GD after COVID-19 vaccination, a 44-year-old female (Case 15) stood out. With a medical history of GD spanning 13 years, she was administered the first dose of COVID-19 inactivated vaccine on June 10, 2021. A mere week later, symptoms such as hyperhidrosis, palpitations, and fatigue manifested. Subsequently, she was diagnosed with relapsed GD based on laboratory and imaging tests [34]. Given that the inactivated vaccine employs aluminum hydroxide as the adjuvant [89], her GD relapse might be attributed to ASIA triggered by adjuvant-induced enhancement of immune response. However, Perricone et al. [88] suggested that adjuvant-induced autoimmunity could involve multiple mechanisms, including genetic predisposition. Emerging as one of the most promising vaccine types, the mRNA vaccine has been proven with a robust capacity to induce both cellular and humoral immunity [90,91,92]. The functionality of the mRNA vaccine necessitates its entry into the cell cytoplasm. In this context, Lipid Nanoparticles (LNPs) play an indispensable role as carriers, encapsulating mRNA molecules and facilitating their targeted delivery to specific cells for subsequent action [93]. Animal experiments by Alameh et al. [92] indicated that LNPs could enhance the responses of follicular helper T cells and germinal center B cells, suggesting the potential contribution of LNPs as adjuvants to ASIA syndrome. Furthermore, polyethylene glycol (PEG), a lipid adjuvant in COVID-19 mRNA vaccines, can stabilize LNPs, and PEG exposure may also provoke an amplified immune response leading to thyroid autoimmunity [40]. PEG reactions have been reported, but this condition is exceedingly rare [94]. Despite these insights, the related mechanisms remain unclear, and await large-scale clinical epidemiological studies and systematic experiments to clarify the relationship between the development of GD and COVID-19 vaccination.

Table 5 Suggested criteria for the diagnosis of ASIA
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Limitations

We must acknowledge the limitations of our study. Firstly, due to the limited number of existing papers and clinical cases, our results may not fully represent all instances of GD that could potentially appear after COVID-19 vaccination. Secondly, there are variations in the number of individuals receiving different types of COVID-19 vaccines across different regions, which may lead to an overestimation of GD risks associated with certain types of COVID-19 vaccines. Lastly, the proposed pathogenic mechanisms presented in this review are merely attempts to describe the progression of this immune event. Due to a lack of systematic experimental studies, we cannot establish a clear causal relationship between COVID-19 vaccination and the onset of GD. Despite these limitations, our study still provides preliminary information on GD following COVID-19 vaccination, laying a foundation for further research.

Conclusion

In summary, the COVID-19 vaccination may promote the onset of GD through pathogenic mechanisms such as cross-immune responses triggered by molecular mimicry and ASIA caused by LNPs with adjuvant activity. However, due to the limited number of observed GD cases following COVID-19 vaccination and the lack of systematic experimental studies, a causal relationship between COVID-19 vaccination and the onset of GD could not be definitively confirmed yet. When compared to the total vaccinated population, the occurrence rates of new-onset and relapsed GD after COVID-19 vaccination were extremely low, and most of those GD patients following COVID-19 vaccination experienced positive outcomes after treatment. Therefore, the extensive benefits of COVID-19 vaccination significantly outweigh mild risks such as treatable GD. For patients who have developed GD following the first dose, and those with a history of GD, the COVID-19 vaccine should be actively administered once their conditions are stabilized after treatment. It should be reminded to immediately seek medical attention and have thyroid functions monitored if symptoms of hyperthyroidism develop after COVID-19 vaccination. Treatment regimen may be adjusted as necessary. Currently, clinical epidemiological studies with large sample sizes and systematic experimental studies are needed to elucidate the correlation between COVID-19 vaccination and GD occurrence, and the underlying pathogenic mechanisms.