Five-Year Effectiveness and Adherence Outcomes of SARS-CoV-2 Vaccination in Immunocompromised Patients Since the Launch of the Vaccination Campaign

Background: Immunocompromised patients are at heightened risk for severe COVID-19 and its complications. While vaccination is critical for this population, long-term adherence and the durability of vaccine-induced immunity remain significant public health concerns. This study aimed to evaluate the longitudinal serological response associated with hybrid immunity and to assess temporal trends in SARS-CoV-2 vaccination adherence among immunocompromised patients. Methods: A prospective observational cohort study was conducted on 170 immunocompromised patients followed longitudinally for five years at an Italian Teaching Hospital. Humoral response was assessed by quantifying IgG antibodies against the spike receptor-binding domain (RBD) of SARS-CoV-2 (anti-RBD IgG titers) at multiple time points, from baseline through the first booster dose. Vaccination uptake and reasons for vaccine refusal were monitored throughout the study period. Results: Of the 170 enrolled patients, 159 (94.1%) completed the primary three-dose schedule. Following the initial two-dose regimen, 88% of patients were classified as non- or low-responders (mean anti-RBD IgG: 84.9 BAU/mL). Administration of an additional third dose and subsequent booster markedly enhanced immunogenicity, increasing the mean anti-RBD IgG titer to 3447.5 BAU/mL, with 87.7% of patients classified as high responders post-booster. Despite favorable clinical outcomes, with no COVID-19-related deaths recorded, vaccination uptake demonstrated a significant and continuous decline, dropping from 97% during the pandemic phase to 8.3% during the 2025–2026 campaign. Primary reasons for refusal included doubts regarding vaccine efficacy (55%) and weak indications or contraindications provided by healthcare professionals (22%). Conclusions: Repeated SARS-CoV-2 vaccine doses significantly improve humoral immunity and clinical outcomes in immunocompromised individuals. However, the progressive decline in long-term vaccine uptake, driven largely by efficacy concerns and insufficient provider recommendations, poses a major public health challenge.