Abstract
Background:
The autoimmune/inflammatory syndrome induced by adjuvants (ASIA) comprises four entities, including the postvaccination phenomenon, which appears after being exposed to adjuvants in vaccines that increase the immune response. There is limited information about autoimmune endocrine diseases and ASIA after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination.
Patient's Findings:
Two female health care workers received a SARS-CoV-2 vaccine, and three days later developed clinical manifestations of thyroid hyperactivity, with increased thyroid hormone levels on thyroid function tests, suppressed thyroid-stimulating hormone, and elevated antithyroid antibodies.
Summary:
Vaccines have been shown to trigger an immune response that leads to a broad spectrum of autoimmune diseases, including autoimmune thyroid disease. Our patients met the diagnostic criteria for ASIA; they were exposed to an adjuvant (vaccine), and they developed clinical manifestations of thyroid hyperfunction within a few days, with the appearance of antithyroid antibodies, despite being healthy before vaccination.
Conclusion:
Graves' disease can occur after SARS-CoV-2 vaccination.
Introduction
A
The autoimmune/inflammatory syndrome induced by adjuvants (ASIA), described for the first time a decade ago, is triggered by several adjuvants (a substance that enhances the antigen-specific immune response) and includes the following conditions: Gulf War syndrome, siliconosis, macrophagic myofasciitis syndrome, and postvaccination phenomena (4).
Adjuvants are an essential part of vaccines; they create an extended and lasting immune response. However, postvaccination phenomena have been described with autoimmune endocrine diseases (AIEDs), mostly after receiving human papillomavirus (HPV), influenza, and hepatitis B vaccines. AIED has been associated with different adjuvants (mineral oils, silicone implants, vaccines, etc.); the clinical spectrum includes Hashimoto's thyroiditis, Graves' disease (GD), thyroiditis, ovarian failure, and type 1 diabetes (5,6).
In addition, the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine shares a genetic similarity with a large heptapeptide human protein, so this is an additional factor that can trigger autoimmune disease (AID) after vaccination due to molecular mimicry (7 -9).
We present two cases of AIED after SARS-COV-2 vaccination.
Case Presentation
Patient 1
A 40-year-old health care worker with arterial hypertension and a history of COVID-19 8 months previously received a SARS-CoV-2 vaccine (Pfizer-BioNTech), and 2 days later she developed nausea, vomiting, fatigue, insomnia, and palpitations. Physical examination revealed fine distal tremors, increased stretch reflexes, and arhythmic heart sounds. Her blood biochemistry was unremarkable except for leukopenia and elevated liver enzymes. Thyroid function tests revealed that her thyrotropin (TSH) level was decreased and her thyroxine (T4) and triiodothyronine (T3) levels were elevated; antithyroid peroxidase (anti-TPO), antithyroglobulin, and anti-TSH antibody levels were significantly elevated; a test for thyroid-stimulating immunoglobulin (TSI) was positive (Table 1). She had previously been evaluated for infertility, ruling out pre-existing AID. Thyroid ultrasonography revealed enlargement and hypervascularity (Fig. 1A). Holter monitoring revealed sinus tachycardia and episodes of paroxysmal atrial fibrillation. She was treated with propranolol 60 mg, diltiazem 120 mg, ivabradine 5 mg, and thiamazole 10 mg daily with a good response.
Imaging of the thyroid gland in the two patients. (
Biochemical Data of Patients Who Developed Graves' Disease After SARS-CoV-2 Vaccine
Patient 1 had leukopenia 3 × 109/L, lymphopenia 0.5 × 109/L, and neutropenia 0.1 × 109/L, and elevated liver functions test, alanine aminotransferase 219 (4–40 IU/L), amino aspartate transferase 100 (0–40 IU/L), and alkaline phosphatase 220 (73–207 IU/L).
T3, triiodothyronine; T4, thyroxine; TSH, thyrotropin.
Patient 2
A previously healthy 28-year-old medical resident with no history of AIED received a SARS-CoV-2 vaccine (Pfizer-BioNTech), and 3 days later, she developed anxiety, insomnia, palpitations, and a distal tremor. Her blood biochemistry was normal, except for the thyroid function test results. Thyroid function tests revealed a decreased TSH level with elevated T4 and T3 and elevated antithyroid antibodies (Table 1). She underwent thyroid scintigraphy that revealed diffuse toxic goiter (Fig. 1B). Her Holter monitor test results were normal. She was treated with propranolol 40 mg daily and thiamazole 10 mg daily with an adequate response.
There were no signs of dermopathy, orbitopathy, or other undifferentiated connective tissue disease in either patient.
Discussion
To our knowledge, this is the first report of GD after SARS-CoV-2 vaccination, which meets the diagnostic criteria for ASIA (6).
Adjuvants, especially vaccine adjuvants, have been shown to trigger a pathogenic immune response that can lead to a range of AIDs, including thyroid disorders (10).
AID is an extrapulmonary manifestation of SARS-CoV-2 infection. The response to infection varies from person to person; it is hypothesized that some DNA encodes the immune system protein HLA-DRB1, which has been linked to autoimmunity (11).
AID has been described after SARS-CoV-2 infection. The manifestations include immune thrombocytopenia, Guillain–Barré syndrome, Miller Fisher syndrome, antiphospholipid syndrome, and Kawasaki-like syndrome (12). Furthermore, it has been reported to affect the hypothalamus–pituitary–thyroid axis and causes direct damage to the thyroid with changes in thyroid function tests, which causes a negative impact on morbidity and mortality (13).
The BNT162B2 SARS-CoV 2 (Pfizer-BioNTech) is a two-dose vaccine composed of a lipid nanoparticle formulated with a nucleoside RNA encoding a modified SARS-CoV-2 spike protein. The vaccine has been shown to be safe and to have an efficacy of 94.6% (14). The vaccine contains four lipids, of which two have not been widely used in authorized medicinal products: 4-hydroxybutyl(azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate (ALC-0315) and ALC-0159 [2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide (ALC-0159) are polyethylene glycol (PEG) lipid conjugates that stabilize lipid nanoparticles and reduce the activity of nonspecific binding proteins (15). PEGs are relatively safe, but may act as an adjuvant and induce an immune response in predisposed individuals. Reactions to PEGs have been reported but are relatively rare (16).
Other SARS-CoV-2 vaccines and vaccine candidates currently undergoing clinical trials use a variety of platforms and adjuvants including aluminum salts, emulsions, oils, toll-like receptors, and AS01B. These adjuvants are combined with subunits or specific antigens to induce a more substantial and sustained humoral and cellular immune response (17). Squalene, polysorbate 80, and sodium citrate (MF59) are commonly used in influenza vaccines, and has been used in SARS and Middle East respiratory syndrome (MERS) vaccines. MF59 has also been used in inactivated vaccines including vaccines containing the receptor-binding domain of the MERS-CoV spike protein, leading to elevated CD4+ and CD8+ counts, and high titers of neutralizing antibodies. The experience of developing SARS vaccines has helped to accelerate the development of SARS-CoV-2 vaccines, but the possibility of vaccine-induced AIEDs should be considered as a possible adverse effect in trials currently in progress (8,17).
Bragazzi et al. (6) reported that ASIA is often associated with other endocrine diseases. In their study, thyroiditis was found in 54 cases, of which 50 cases were related to vaccines (42 after an HPV vaccine and 8 after an influenza vaccine), with the appearance of clinical manifestations 2–60 days after vaccination, but only 1 case was positive for thyroid autoantibodies. All individuals with vaccine-induced thyroiditis were reported to have a full recovery.
In the two cases presented in this article, the clinical manifestations of hyperthyroidism, antithyroid antibodies, TSI, and imaging made it possible to diagnose GD; however, in other case series, only a minority of AIED-associated thyroiditis were confirmed to be due to GD (5,6). Remarkably, the time to appearance of the manifestations of thyroid hyperfunction after vaccination was short in our patients (2–3 days). This timeframe is similar to that reported in other studies of vaccine-induced thyroiditis of different vaccines, in which up to 76% of cases started within the first 3 days postvaccination (18). A possible mechanism for the rapid symptom onset is that viral protein concentration reaches a peak in 24–48 hours, triggering an autoimmune response (3).
Pellegrino et al. (9) reported an association of ASIA with HPV vaccines in a cohort of 26,508 individuals, in whom 3932 (15%) met the diagnostic criteria for ASIA. In this study, the investigators detected 148 autoimmune disorders, of which rheumatoid arthritis and thyroiditis were the most common manifestation, with 42 and 41 cases, respectively. Although most HPV vaccines contain alum, the mechanism by which the adjuvant triggers immunological diseases seems to be similar with immunological disease developed in response to other adjuvant-associated vaccines, and include molecular mimicry, cytokine production, and activation of the immune system, which is accelerated by defective regulatory cells in individuals with a genetic predisposition (3,5).
In conclusion, our patients met the diagnostic criteria for ASIA, they were previously healthy, were exposed to an external stimulus (vaccine), developed manifestations of AIEDs, and tested positive for autoantibodies. These cases represent an example of the diversity of clinical manifestations of vaccine-induced autoimmune conditions.
We strongly recommend surveillance and safety monitoring of approved and candidate SARS-CoV-2 vaccines currently undergoing Phase 2 and 3 trials.
Footnotes
Acknowledgments
We thank the patients for granting permission to publish this information.
Authors' Contributions
Concept and design were carried out by O.V.-L. and A.O.N. Supervision was carried out by M.P.C.D., G.M., and L.J.J. Data collection was done by T.I.S.V. Literature review was by all authors. Critical review was carried out by M.P.C.D., G.M., and L.J.J. Drafting the manuscript was done by O.V.-L., A.O.N., M.P.C.D., G.M., and L.J.J. All coauthors have reviewed and approved the article before submission.
Informed Consent Statement
Informed consent was obtained from the patients.
Author Disclosure Statement
No competing financial interests exist.
Funding Information
No funding was received for this article.