Background. From smallpox variolation practiced in imperial China in the 10th century to the messenger RNA vaccines deployed in 2020, vaccination ranks among the most effective public health interventions in the history of medicine. Nevertheless, the rare but clinically significant occurrence of serious adverse events following immunization (AEFI) remains a major challenge for contemporary pharmacovigilance. Identifying the individual determinants of susceptibility represents a leading scientific and ethical priority. Objective. To critically analyze the available scientific literature in order to determine the extent to which three families of host factors the HLA immunogenetic profile, undiagnosed mild immunodeficiencies, and chronic inflammatory comorbidities contribute to the occurrence of serious AEFI, and to identify biomarkers and prevention strategies likely to improve vaccine safety. Methods. Narrative and critical literature review. The PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar databases were searched for the period 1990–2025. Original articles, systematic reviews, meta-analyses, and case series describing a link between vaccination and HLA profiles, mild immunodeficiencies, or inflammatory comorbidities were included. Editorials without data and exclusively animal studies were excluded. Results. The data converge toward an integrative model in which serious AEFI result from the interaction between a platform-specific vaccine stimulus and a permissive host background. Certain HLA alleles (HLA-A*03:01, HLA-DRB1*11:04, HLA-DQB1*06) modulate antigen presentation and predispose to inadequate or autoreactive immune responses. Mild immunodeficiencies, particularly type I interferon deficits and dysregulation of regulatory T lymphocytes, compromise immune-braking mechanisms. Chronic inflammatory comorbidities, diabetes, hypertension, pre-existing autoimmune diseases raise the baseline level of inflammation and lower the threshold for triggering a pathological response. Four etiological categories of serious AEFI are identified: (A) with a dominant cause linked to the vaccine platform; (B) multifactorial metabolic; (C) mixed, resulting from the interaction between a vaccine mechanism and a latent host susceptibility; (D) with a mechanism not yet elucidated. Conclusion. The systematic integration of HLA typing, type I interferon assays, and cytokine profiling into pharmacovigilance algorithms would refine individual causal assessment and pave the way for personalized vaccination. Multicenter prospective studies, including African populations underrepresented in the literature, are needed to validate these biomarkers in clinical practice.