Introduction: mRNA vaccines have been pivotal in combating COVID-19, yet their deployment is associated with reports of adverse events (AEs). A better understanding and study of adverse reactions can promote the advancement of vaccine technology. Therefore, this study comprehensively characterizes these AEs, elucidates underlying mechanisms, and proposes management strategies to advance vaccine safety.
Methods: A systematic literature search was conducted across ScienceDirect, PubMed, SpringerLink, and Web of Science from January 2019 to April 2025, using the search terms "mRNA vaccine adverse" in the title, abstract, and keywords. Global pharmacovigilance databases, including EudraVigilance, VAERS, and CANVA, were also included. After deduplication and relevance analysis of the literature, the required documents were obtained, based on whom AEs were classified according to anatomical systems and mechanisms. Finally, visual analysis was conducted to complete the study.
Results: According to the method above, 87 articles, comprising clinical trials and case reports, met the inclusion criteria, following the PRISMA workflow referring to academic standard. AEs were categorized by anatomical systems and mechanistic axes. Anatomically, AEs are classified into four categories: cardiovascular AEs, neurological AEs, inflammatory AEs and mucocutaneous disorders. Cardiovascular AEs included myocarditis, thrombosis, and systemic capillary leak syndrome. Neurological AEs encompassed headaches, acute transverse myelitis, Bell’s palsy, and delirium. Mucocutaneous disorders featured urticaria, vitiligo, and oral ulcers. Inflammatory AEs involved IgA nephropathy, subacute thyroiditis, rhabdomyolysis, and autoimmune flares like SLE, RA. Mechanistically, AEs were categorized into three axes: host susceptibility, delivery system interactions, mRNA component immunogenicity.
Conclusions: mRNA vaccine AEs arise from complex interactions between host biology, delivery systems, and mRNA immunogenicity. Key strategies for mitigation include: nucleotide chemistry refinement like pseudouridine modification, codon optimization, tissue-targeted LNPs, tunable adjuvants, and biomarker-guided risk stratification. Future research must prioritize mechanistic insights into molecular mimicry and host-specific vulnerabilities to enable safer, precision-engineered mRNA platforms.
