High-dimensional profiling following third MMR vaccination or mumps virus infection reveals individuals with suboptimal immunity

Interindividual variation in vaccine responsiveness can help to identify tailored vaccine strategies for groups with suboptimal responses and potentially higher risk. 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. 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. 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. This study examined how young adults’ immune systems respond after receiving a third dose of the Mumps-Measles-Rubella (MMR) vaccine compared to a mumps virus infection. The aim was to understand why some have weaker immune responses and how an additional vaccine dose might boost their protection against disease. Researchers measured antibodies and different types of immune cells in blood samples. Both the third MMR dose and mumps infection increased immunity, although infection led to stronger effects. However, the study also identified groups with higher or lower immune responses to vaccination. Understanding these different immune profiles may help identify individuals who are less protected by vaccination and guide the development of more effective vaccination strategies. Raeven et al. investigate the immune response to third-round MMR vaccination in comparison to natural mumps virus infection. They find that third-round vaccination boosts mumps-specific responses, though not as strongly as mumps virus infection, and that distinct immune response profiles determine the efficacy of response.