Background <p>Interindividual variation in vaccine responsiveness can help to identify tailored vaccine strategies for groups with suboptimal responses and potentially higher risk.</p> Methods <p>Here we assessed and compared such interindividual variation in humoral and cellular immune responses following a third Mumps-Measles-Rubella (MMR3) immunization and mumps virus infection in young adults with a multiparameter analysis.</p> Results <p>We demonstrate that MMR3 boosts (neutralizing) antibody, IgG⁺ B cell and CD4⁺ T cell responses against mumps virus whereas a mumps virus infection induces similar but stronger immune responses, including robust mumps-specific CD8⁺ T cell immunity. Interindividual variation in pre-existing and vaccine-induced immunity unravels subpopulations with low and high mumps-specific responses that are distinct in magnitude, kinetics, longevity and correlation profiles. High-dimensional immunophenotyping subsequently reveals that circulating Th1/Th17 central memory T cells (CD127⁺CD25⁻CD38⁻) correlate with MMR3-induced mumps-specific activated (CD137⁺CD154⁺OX40⁺) CD4⁺ T cell responses, particularly in high-responder groups, while a minor IgG⁺ memory B cell subset (CD38⁺CD21⁺CD95⁺CD24⁻CXCR5⁺CCR6⁺CXCR3⁺) modestly correlates with virus-neutralizing antibody titers. Notably, infected individuals are characterized by elevated frequencies of innate lymphocyte subsets.</p> Conclusions <p>Overall, our results indicate that a third MMR immunization boosts humoral and cellular responses in young adults albeit with clear distinct immune response profiles. This may enable the identification and more effective targeting of groups with suboptimal immunity.</p>