Determinants of Measles Vaccine Failure and Breakthrough Infections: A Systematic Review of IgG Avidity Based Immunological Markers and Host Genetic Polymorphisms

Background Measles remains a leading cause of vaccine‐preventable mortality, despite high reported coverage. Determinants of measles vaccine failure remain incompletely characterized. Methods Five databases (PubMed/MEDLINE, Embase, Web of Science, Scopus, Cochrane Library) were searched from inception. Studies in vaccinated individuals evaluating IgG avidity markers or host genetic polymorphisms were included. Risk of bias was assessed using the Newcastle–Ottawa Scale, JBI checklist and modified HuGENet framework. Findings were synthesized narratively (PROSPERO: CRD420261415732). Results Sixteen studies (8169 participants; 1998–2025) met inclusion criteria. Across seven studies with event‐level data, primary vaccine failure ranged from 24.2% to 90.8%. Reproducible host genetic associations were observed for HLA Class I/II alleles, measles receptor genes (SLAM/CD150, CD46, CD209), TLR pathway genes, antiviral effector genes and cytokine/cytokine receptor genes. No study reported extractable breakthrough infection or dichotomous IgG avidity data. Conclusion Reproducible host genetic determinants of measles antibody response cluster at HLA loci, the measles receptor axis and the TLR pathway. Inconsistent definitions and absent standardized reporting preclude firm conclusions. Prospective harmonized studies are required.