Mechanisms of Action in the Association Between COVID-19 Vaccination and Autoimmunity

Background: Associations between autoimmune diseases and vaccination for infectious diseases have long been the subject of inquiry and concern for clinicians and researchers. The 2020-2023 COVID-19 pandemic saw an unprecedented global vaccination campaign to inoculate billions of people against the SARS-CoV-2 virus with priority for vulnerable populations including patients with compromised immune systems and autoimmune disorders. Public health mass vaccination campaigns proceeded with newly and rapidly developed vaccines, including novel mRNA vaccines, viral vector vaccines, inactivated viral vaccines, and protein subunit vaccines. As a result, significant evidence for various mechanisms of action underlying the associations between COVID-19 vaccination and autoimmunity have emerged along with concerns about how potential iatrogenic events should be properly reported in the literature. Objective and Methods: Proposed mechanisms of action were summarized from over 150 published reports on the most common autoimmune diseases (i.e., Graves' disease, Hashimoto's thyroiditis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes mellitus) (i.e., Chaufan et al., 2023, 2025) and more recent article on other disorders. Findings: Mechanisms of action included the following: immune priming, pathways related to antigen delivery systems, autoimmune/inflammatory syndrome induced by adjuvants (ASIA), interactions with immunosuppressive and disease modifying therapies (DMTs), bystander immune activation, molecular mimicry, polyclonal activation, epitope spreading, genetic vulnerability, shifting imbalance in endocrine systems, cross-reactive immunity, nonspecific immunity "boosting", and immune system dysregulation. Several issues with supporting evidence, inconsistencies, and contradictions between study findings and clinical recommendations were highlighted. Future research should aim to distinguish causal from coincidental associations for adverse events and vaccinations recommendations should be based on quality cost-benefit analyses.