Neisseria meningitidis infections can cause life-threatening meningitis and septicemia. In Europe, serogroup B (MenB) is the leading cause of invasive meningococcal disease (IMD), particularly in young children. Genomic surveillance of circulating MenB strains through whole genome sequencing (WGS) provides a powerful tool to assess the potential impact of vaccination strategies, including the 4CMenB vaccine, which is available for infants from 2 months of age. Here, we present a retrospective WGS based analysis of clinical MenB IMD cases (n = 311) recovered in Belgium from 2016 to 2022 by the Belgian National Reference Center. High-quality WGS data were obtained for 281 of these strains, demonstrating high genetic diversity of the antigen targets included in the 4-component meningococcal serogroup B vaccine 4CMenB (fHbp, PorA, NHBA and NadA) and at the 4CMenB Antigen Sequence Types (BAST) level. Novel antigen combinations, not yet assigned a BAST ID, were detected in 23.5% of isolates. Vaccine coverage was predicted using the Genetic Meningococcal Antigen Typing System (gMATS) and the Meningococcal Deduced Vaccine Antigen Reactivity (MenDeVAR) index. Of the 281 strains, 79.5% (lower limit–upper limit: 68.0–91.5%) were predicted to be covered by the vaccine by gMATS, and 80.7% (lower limit–upper limit: 66.5–95.4%) by MenDeVAR. No evidence of variation in vaccine coverage was found throughout the study period nor between different age groups, demonstrating the broad applicability of 4CMenB. This study highlights the benefits of a pathogen surveillance program and the need for experimental characterization of continuously evolving antigenic subvariants of Neisseria meningitidis.