Global and Regional Burden of Vaccine-Associated Erythema Multiforme and Their Related Vaccines, 1967-2023: An In-Depth Analysis of the World Health Organization Pharmacovigilance Database

Objective: Vaccine-associated erythema multiforme (EM) remains under-researched, impacting global vaccine safety evaluations. This study examines the global and regional burden of EM and its association with specific vaccines to optimize vaccination strategies.

Subject and methods: We analyzed data from the WHO pharmacovigilance database on vaccine-associated EM from 1967 to 2023 (n = 131,255,418 reports). Reporting frequencies, reported odds ratios (RORs), and information components (IC) were calculated for 16 vaccines across 170 countries.

Results: We identified 6,355 cases (males, n = 3,182 [50.07%]) of vaccine-associated EM from a total of 46,378 reports of all-cause EM. While vaccine-associated EM has been consistently reported, there has been a notable increase in reported incidence particularly in 2010 and 2020. Measles, mumps, and rubella vaccines had the highest association with vaccine-associated EM reports (ROR: 8.75 [95% confidence interval, 8.11-9.44]; IC, 3.10 [IC0.25, 2.97]), followed by hepatitis B (8.54 [7.66-9.51]; 3.06 [2.88]), hepatitis A (8.11 [7.01-9.39]; 2.98 [2.74]), typhoid (6.50 [4.75-8.90]; 2.60 [2.07]), encephalitis (5.86 [4.35-7.91]; 2.47 [1.96]), diphtheria, tetanus toxoids, pertussis, polio, and Hemophilus influenza type b (5.70 [5.42-5.99]; 2.46 [2.38]), pneumococcal (5.56 [5.11-6.06]; 2.45 [2.31]), rotavirus (4.96 [4.21-5.84]; 2.29 [2.01]), varicella-zoster (4.44 [3.99-4.95]; 2.13 [1.95]). Vaccine-associated EM reports were more strongly correlated with younger age groups and males. The overall fatality rate of vaccine-associated EM was 0.04%.

Conclusions: The rise in vaccine-associated EM across multiple vaccines, especially in younger populations, highlights the need for closer monitoring and more informed vaccination practices to mitigate adverse reactions.