Age- and Sex-Dependent Heterogeneity in Mumps Virus Immunity Among US Blood Donors Born Between 1928-1993

BACKGROUND: Despite widespread vaccination, mumps outbreaks continue to occur, raising concerns about waning immunity and strain-specific differences in neutralizing antibody responses. METHODS: We evaluated seroprevalence, total antibody levels, and neutralization capacity against the vaccine (JL5) and outbreak (genotype G) mumps virus (MuV) strains from 187 US blood donors born between 1928 and 1993. Associations with age, sex, and donation site, were analyzed. RESULTS: MuV IgG seropositivity was 84.5% and did not differ by age, sex or blood donation site. However, ELISA index values increased with age, with individuals ≥60 years exhibiting higher total MuV antibody levels than donors ≤30 years, primarily driven by males. For most donors, neutralization was consistently higher against JL5 than genotype G, and ELISA index values positively correlated with neutralization titers for both strains. Age positively associated with genotype G neutralization but not JL5, with a significant increase in the genotype G:JL5 neutralization ratio with age (p<0.0001). Males exhibited significantly higher neutralization titers than females against both strains, with older males exhibiting greater neutralization against Genotype G than both age-matched females and younger males. CONCLUSIONS: Our study suggests that antibody quantity alone does not fully predict mumps protection, and factors such as sex may contribute to functional differences in immunity. Our findings highlight potential gaps in protection against circulating strains, possibly contributing to ongoing outbreaks despite high vaccination coverage. The age-dependent increase in total MuV antibodies, which correlates with genotype G neutralization, supports that cumulative antigenic exposure may shape the breadth of MuV-specific immunity over time.