BACKGROUND: Immunocompromised individuals were identified early in the pandemic as being at increased risk of severe COVID-19 and have demonstrated variable immune responses to SARS-CoV-2 vaccination. Although coordinated vaccination programmes are now well established, their long-term effects on sustained immunity in the present patient populations remain insufficiently understood. METHODS: The prospective SARS-CoV-2 mRNA vaccine trial COVAXID was conducted in a well-characterised, real-world cohort of 539 immunocompromised and healthy individuals across 21 subgroups, organised into six main categories. At the 36-month time point, 218 participants remained. Participants provided blood samples for assessment of binding antibody titres and pseudo-neutralisation activity against ancestral SARS-CoV-2 and 21 variants, including Omicron sub-lineages. T cell responses were evaluated in a defined subset of participants. Immunogenicity outcomes were analysed over a three-year period in relation to SARS-CoV-2 vaccination, SARS-CoV-2 infection, and immunoglobulin replacement therapy (IGRT). FINDINGS: Between years two and three, antibody titres and neutralisation capacity showed a consistent pattern of maintenance or increase across most study groups and subgroups. These increases were driven by cumulative exposure to vaccine booster doses, SARS-CoV-2 infection, and, in some cases, passive immunisation through IGRT. CD4 INTERPRETATION: The findings support continued, tailored vaccination strategies for elderly and immunocompromised individuals. Integrating immune monitoring with infection history and adjunctive therapies may help refine booster policies, optimise protection, and strengthen future vaccination programmes for high-risk populations. FUNDING: The present studies were supported by the European Research Council, Karolinska Institutet, Knut and Alice Wallenberg Foundation, Nordstjernan AB, Region Stockholm, and the Swedish Research Council.